I agree with Dr. Sperling's assessment that we now have the tools for a more definitive assessment of the amyloid hypothesis than has been possible previously, and I agree that a "secondary prevention" trial should be a high priority for our field. At the same time, though, we should not give up on the possibility of finding disease-modifying treatments for our patients with established dementia. Patients with early dementia are capable of a very good quality of life if we can prevent progression to more dependent and ultimately vegetative phases of the disease.
The currently active Phase 3 bapineuzumab trial is expected to demonstrate clear-cut effects on cerebral amyloid, so the clinical outcomes will tell us whether an anti-amyloid approach is a viable treatment strategy at the stage of symptomatic dementia. If not, then we may conclude that anti-amyloid approaches are futile after the diagnosis of dementia, but that should not be interpreted to mean that meaningful treatment is impossible at that point. Instead, we should investigate other candidate mechanisms that may be independent of amyloid at later stages, such as "calcium dyshomeostasis, tau-mediated neurodegeneration, and mitochondrial dysfunction" cited by Dr. Sperling, and plan appropriate treatment trials targeting those mechanisms.
Dr. Sperling's analogy with heart failure may be revisited here: Certainly prevention is preferable to treatment, but heart failure is now a remarkably treatable condition due to efforts targeting the right mechanisms at the right time.
This commentary is very germane. A few major issues deserve further elaboration.
Testing the Aβ theory of AD (rather than the “amyloid hypothesis”) still has not been accomplished. The challenges are formidable. While the “right” target may not have been identified, we would suggest that it is the toxic oligomeric species of Aβ, which, in the human brain, are still poorly defined. The “right” drug will then turn on its ability to target these toxic species. Very few drugs or biologics in current clinical development can claim to act on these species. The “right” stage for intervention is clearly the presymptomatic one, but rather than talk of secondary prevention, it might be more realistic to initially aim for delay of onset, say by five years. How to demonstrate to the regulators that such an approach is feasible will also be a formidable challenge.
Finally, the authors have “rightly” identified the ethical issues of disclosing to presymptomatic individuals their biomarker status. We need to debate and resolve this issue urgently, as any intervention aimed at the presymptomatic stage will require this disclosure.
Is Prevention Better Than Cure?
The paper by Sperling and colleagues is a thought-provoking review of where we are presently with respect to Alzheimer's disease therapy, with the emphasis on treating patients earlier in the course of the disease. By the time someone presents with dementia, or even with MCI, the AD process is in full flow: with Aβ aggregation in the form of plaques, cerebral amyloid angiopathy (CAA) and oligomers; intraneuronal tau in the form of tangles, neuropil threads, and dystrophic neurites; activation of microglia and astrocytes; and neuronal and synaptic dysfunction and loss. It is, perhaps, expecting rather a lot to think that removing the trigger from the disease at this stage might halt or even reverse the multiple facets of the pathology. Many of the therapeutic avenues discussed in the paper are focused on the Aβ hypothesis, including the immunotherapy approach. As the authors point out, it has been shown that Aβ immunotherapy can result in plaque removal from the Alzheimer's brain, but that even when complete, this does not seem to halt the cognitive decline (Holmes et al., 2008). Possible reasons for this apparent self-perpetuation of the neurodegeneration in the absence of Aβ plaques include: persistent or increased soluble Aβ as plaques are disrupted; persistent inflammation; prion-like properties of tau; increased CAA; and finally, of course, the possibility that Aβ is the wrong target.
The seminal work of Dale Schenk and colleagues, which kicked off the whole Aβ immunotherapy field, was essentially two different experiments (Schenk et al., 1999). First, they immunized aged APP transgenic mice, which had brains full of plaques, and demonstrated that there was some removal of plaques in established disease—this is essentially what the studies in humans now show. In the second experiment, they immunized mice at a very early age, before any plaques had formed, and found a complete prevention of plaque formation during aging. To us, the really intriguing question at the moment in the immunotherapy field is, What would happen if you immunized humans at an early stage in life? Could it be done safely, without side effects? On the one hand, we happily routinely immunize our children against microorganisms to which they may never be exposed, but on the other hand, there is a niggling suspicion that Aβ, and perhaps even Aβ oligomers, have a physiological function. Secondly, would early immunization prevent the formation of Aβ plaques and oligomers during aging? Judging by the close parallels between the immunotherapy studies in aged animals and humans, it seems likely. If so, immunization before the disease begins (i.e., before the formation of any plaques) will avoid the side effects which appear to be associated with removing amyloid from the brain (Boche et al., 2010). Thirdly, if early immunotherapy were to prevent Aβ aggregation, would this then prevent the whole AD process: tau accumulation, glial pathology, neuronal and synaptic damage—and prevent the dementia? This would be the real test of the amyloid cascade hypothesis.
References:
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA.
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Reisa Sperling and colleagues have written a thoughtful commentary on the future of trials in AD. They describe the pros and cons of primary, secondary, and tertiary prevention trials and conclude that secondary prevention trials (i.e., prevention of cognitive impairment in subjects with amyloid pathology) are likely the best option for the moment. But, as they note, secondary prevention trials have their problems, and, in particular, clinically relevant endpoints will be difficult to reach within a reasonable trial duration and with a manageable sample size. Moreover, we do not exactly know what drives AD pathology in the preclinical stage of the disease. Any secondary prevention trial is therefore not only a proof of efficacy of a treatment but also an experiment, which tests assumptions on the underlying AD pathophysiology.
How to proceed from here? One strategy may be to test treatments considered for secondary prevention trials in a two-step approach. First, treatments may be tested in intermediately sized two-year studies with a range of biomarkers as an outcome, including biomarkers that reflect the target of the drug and biomarkers for neurodegeneration such as brain atrophy, synapse loss, disconnectivity, or tau in CSF. If these results look promising, large-scale trials with a longer duration may be performed with clinical endpoints. A minor comment on the paper is that the authors consider trials with carriers of autosomal-dominant AD mutations or ApoE4 homozygotes as candidates for secondary prevention trials. However, some of these subjects may not have yet developed AD pathology, and trials in such subjects could be considered as primary prevention trials.
To answer the rhetorical question presented by Sperling et al., "Why do we keep testing drugs aimed at the initial stages of the disease process in patients at the endstage of the illness?", it is because prevention trials are almost too daunting to consider, especially in these days of diminishing resources. However, the figure of 20 years of presymptomatic cerebral amyloidosis shown by the DIAN study earlier this year fulfilled our worst nightmares about when we should begin to intervene. Along the way, it is likely that amyloid imaging will be used off-label to create a new class of anxious pre-patients (or pre-escapees). Things are bad enough for our patients and their families with currently approved drugs that are almost universally disappointing and frustration-inducing without quadrupling, or more, the number of worried as well. But maybe that is the price of progress.
The first challenge is raising the $100 million-plus required to pay for the first prevention trial. I would argue that we should get on with raising the funds and get the trials going. It is likely that the first trial will not be definitive, and it is also likely that we will think most seriously about whom to include and exclude, and what parameters to follow once we are actually committed and involved. In other words, "There is nothing like a hanging to focus the mind."
The trial should be as adaptive as possible, because new data will come in over the many years that the trial will require, and we should be able to adjust to incorporate new information. The prevention cohort should include some subjects who have positive amyloid scans and perfect cognition, as well as some who may have positive scans and who are also already one standard deviation off. There is no obvious way to choose between these two groups, so I would say just commit to both from the get-go. The outcome with the latter group will be obvious sooner, but that could mean more disappointment.
Just last week, I attended an Alzheimer's event chaired by one of the world's pre-eminent cardiologists. According to this expert, cardiologists the world over are ready to embrace Alzheimer's as a cardiovascular disease and get on with taking the Framingham/cholesterol/statin approach to the problem. Seems to me that we should get off the dime and take serious steps toward prevention trials. Otherwise, the heart docs might just plow ahead and solve Alzheimer's while we are wringing our hands...!
Sperling et al. have put forward a now familiar argument (also proposed by others; 1-4) that amyloid-based therapies of the past decade have failed not because they were targeted at the wrong pathophysiological mechanism, but rather because the intervention came too late. Here they present cogent arguments that we should begin secondary prevention trials in asymptomatic individuals who are at a high risk for developing Alzheimer’s disease (AD).
No one can argue with the sensibility of the argument that a therapy has a greater chance of success if started early in the disease process. So there is some merit in advocating continuation of this approach. Also, as a practical matter, and having invested so heavily in amyloid-based therapeutic strategies, the field finds it difficult to walk away from this approach, especially since no alternative seems to be on the immediate horizon. Yet the complacent thinking that we must be on the right track and will have a successful treatment if we begin treatment earlier is dangerous. It also happens to be flawed for the following reasons.
First, neither Sperling et al. nor the other purveyors of this argument (1-4) define what "early" is. Suppose, having started the secondary prevention trial at an "early" enough time point and continuing it for a sufficient period, there are still no clinical benefits (biomarkers moving in the right direction is of little solace to an AD patient or a caretaker if cognition continues to deteriorate). Would this situation lead to further arguments that we should have started even earlier, or would it be enough to finally invalidate the amyloid-based approach?
Second, it is indeed advisable to identify at-risk populations and, as the authors have done, group them into those carrying familial AD (FAD) mutations, being homozygous for the ApoE4 allele, or being older amyloid-positive individuals as subjects for secondary prevention trials. However, to assume that all three risk groups develop AD through the same pathophysiological mechanism, that the therapeutic intervention being tested targets this mechanism, and that the same mechanism is responsible for the majority of cases of sporadic AD, is extremely risky and runs contrary to emerging evidence (5-8).
Finally, the amyloid hypothesis is still a "hypothesis," and despite a decade of failed clinical trials based on this hypothesis, there is reluctance to ask hard questions regarding the validity of many of its suppositions. Is the dominantly inherited FAD, where the amyloid hypothesis has a better chance of being correct, the same as sporadic AD, which afflicts 98 percent of AD patients? Autopsy studies (9-11), which are the gold standard for neuropathological observations, have provided impeccable evidence that in brain parenchyma, tau pathologies precede amyloid abnormalities, which is contrary to the currently favored view (12) that amyloid abnormalities occur prior to tau abnormalities. Historically, the presence of amyloid plaques has been considered a prerequisite for an AD diagnosis. With the knowledge that a third of the elderly population is PIB-positive and cognitively healthy, and that there is a growing number of cases of PIB-negative dementia patients (13), is the traditional definition of AD still consistent in terms of underlying mechanisms?
We all agree with the authors that "...the cost of caring for an ever-expanding number of AD dementia patients..." will be astronomical "...if we do not find a successful disease-modifying therapy." However, not fundamentally altering the course of our thinking about AD pathogenesis may prove to be even more expensive in the long run.
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The assumptions are that amyloid deposition is the instigating event and thus the right target, that drugs that reduce amyloid accumulation in the brain may be the right drugs, and that performing drug trials in normal people can be safe and reasonable. I have a long record of disagreeing with the first two assumptions, but I believe that pursuing the right target with appropriate drugs for which there are established safety records may delay the onset of mild cognitive impairment (MCI) symptoms and also delay the onset of dementia.
For decades, we have used the neuropathology of amyloid deposition as the Holy Grail of academic Alzheimer’s disease (AD) research, frankly at the expense of support for any new directions by the peer review system. Hypothesis testing has taken a back seat to the belief of many (who want grant support over a career in AD research) that amyloid deposition is the root cause for the development of AD. The rationale that amyloid is the “right” target is based on the pathological presence of amyloid in brains of AD patients, and by the fact that less than 1 percent of patients carrying rare mutations in amyloid-related genes develop the early onset form of AD. Linguistically, this is a false syllogism. Everyone thought the Earth was flat once upon a time as well. Majority belief systems do not replace hypothesis testing.
The authors introduce three hypotheses for the failure of the recent AD clinical trials—I favor the first two—that “we are targeting the wrong pathophysiological mechanisms” and “the drugs do not engage the right targets in patients.” The third hypothesis is partially correct: that “the drugs are hitting the right targets but are doing so at the wrong stage of the disease.” The authors implicitly accept that targeting amyloid-β is the right way to proceed. However, the fact that “the majority of clinical trials target brain amyloid-β” does not validate the target. A drug target is validated after its modulation produces a clinical effect. The authors postulate that the failure of recent trials, which were originally so highly touted, was because the treatment came too late, not because the target was wrong. I believe part of that argument is true. Treatment should begin early.
There is a solution. Let’s redefine the prevailing definition of the disease, focusing on a stage before symptoms appear rather than the time after death when brain autopsies can be performed. The argument that amyloid deposition in the brain precedes AD symptoms is supported, but no prospective studies that begin with cognitively normal adults have provided positive and negative predictive values for AD risk as a result of amyloid deposition. This lack of hypothesis testing continues despite available technologies for imaging amyloid plaques. Instead, most amyloid proponents have proceeded based on belief in a hypothetical “scheme of the proposed stages of AD” like that shown in Figure 1 of the Commentary. These constructions may be used in the future to make predictions for real subjects who would be entered into clinical trials. And note—these are subjects, not patients, as the people in the proposed prevention studies are asymptomatic. Defining subjects by amyloid testing as suitable candidates for a secondary prevention study is fine, but at this point in time, defining them as presymptomatic patients is questionable.
At this stage, it will be more useful to shift resources and inquire: Are there adequate prognostics of AD in asymptomatic subjects that could be useful in designing primary prevention studies? Prognosis-based enrichment designs can usher the possibility of testing truly preventive measures. Twenty years ago (this week, coincidentally), we determined that ApoE was an important constituent of the disease, and that it binds to amyloid and is found in plaques (1-3). For several years after the papers were published, the field said, “Aha, then it is amyloid.” Now the rest of the field suddenly (from my viewpoint) is proposing clinical trials stratified by ApoE genotypes. But over the years, we have investigated alternative mechanisms and researched whether the genetic predisposition data are due to ApoE or other polymorphic markers within the region of linkage disequilibrium (4,5). We now hypothesize that we have markers that can predict the relative risk for onset of symptoms in the next five years in normal individuals within the older age range, when AD becomes common (6). For Caucasians at least, a polymorphic poly-T tract (“523”) in TOMM40 defines variability in age of disease onset for ApoE3 and ApoE2 carriers.
Early experiments are, in general, supportive of our findings, with some exceptions (7,8). While we have questions about some technical aspects of these publications (the ascertainment heterogeneity for age of onset in the ADNI series in one, and methods for determining the poly-T length in the other), it is right to test the hypothesis. Similar to the history of testing ApoE, there will be some important naysayers. That is science. We will test the hypothesis using rational and adequately powered experimental designs, with clinically relevant endpoints. One way to test the suitability of the genetic data, or any biomarker for that matter, for predicting which individuals are at greatest risk of developing clinical symptoms of MCI will be to prospectively qualify the biomarker, or a multi-component biomarker algorithm composed of age, ApoE allele status, and TOMM40-523 genotype. This same experiment might also be used to measure the relative positive and negative predictive values of amyloid deposition over a practical time frame for a clinical trial. That is, there may well be a way to test the scheme that is republished as Figure 1 in the Commentary.
At the end of our planned five-year study, which will include periodic clinical neuropsychological testing, there will be data with which we calculate the positive and negative predictive values for the genetic algorithm. Simultaneously, the efficacy of a drug to delay the onset of cognitive impairment of the Alzheimer’s type will be tested within the high-risk group in a Phase 3 study. The drug, pioglitazone, targets a number of pathogenic pathways that have been implicated in the development of AD, most notably the mitochondrial pathogenic pathway that is supported by an extensive body of literature. This might be the right drug used in the right subjects at the right time. Pioglitazone has been used for more than 22 million human-years and has an extensively studied risk profile. A sister drug, rosiglitazone, had a positive clinical effect at three different doses in a Phase 2B monotherapy trial after stratification for ApoE genotype (9). But ApoE-stratified, Phase 3 trials in mild to moderate AD “failed”(10).
There is no doubt that ApoE has an isoform-specific role in disease pathogenesis, but perhaps this is mediated by differential interaction with mitochondrial Tomm40. Based on our current data for the distribution of TOMM40 alleles in different populations, we suggest that the large proportion of Far Eastern patients in those trials have a different risk algorithm than do Caucasians. That is, in contrast to the Phase 2B Caucasian-only study, the patient population was heterogeneous with respect to risk. If this is true, the Phase 3 trials performed in a mixed ethnic group had no chance to succeed because we did not account for the contribution of TOMM40-523 to the genetic risk.
Putting all these pieces together, the biomarkers of Figure 1 of the Science Translational Medicine Commentary, including amyloid deposition, must be evaluated so that positive and negative predictive values can be calculated. The context for the biomarker validation could be a delay-of-onset, clinical study similar to that which is proposed for pioglitazone. Amyloid deposition may be an effect, not a cause, of the disease process, and it may also be a later accelerant of clinical pathogenesis. Removing amyloid may be valuable. However, testing amyloid-directed drugs, which have an uncertain risk profile, in normal people seems premature and perhaps dangerous, especially in the absence of hard, quantitative, prospective data for amyloid deposition as a biomarker.
The best way to uncover the causative events culminating in AD is to perform clinical trials that measure neuropsychiatric endpoints adequate for detecting changes in normal, aging subjects. We have embarked on one such study and hope the field will shift its efforts accordingly.
Note: This comment was invited by the Alzheimer Research Forum.
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John Morris Washington University School of Medicine
Posted:
I am unaccustomed to posting comments in an online scientific debate, in this case regarding the challenge posed by Reisa Sperling, Clifford Jack, and Paul Aisen to conduct clinical trials of potential Alzheimer's therapies in the preclinical (presymptomatic) stages of the illness. Hence, I am sure to find myself in way over my head. Nevertheless, I here offer mild rebuttals to some previous comments about the paper by Sperling et al.
Sanjay Pimplikar rightly notes that the amyloid hypothesis remains unproven, and that its basis rests largely on genetic forms of Alzheimer's disease (AD) caused by dominantly inherited mutations or Down's syndrome. The exact causative mechanisms of Alzheimer's disease remain unknown, and whether changes in amyloid-β, tau, or other molecules are primary, secondary, or unrelated still must be determined. There also is little argument that molecular pathologies other than amyloid-β dysregulation contribute to the clinical syndrome of AD and clearly deserve investigation and treatment efforts. However, Dr. Pimplikar supports his comment by observing that tau pathologies precede amyloid pathologies in AD. This is only partially correct. Based on neuropathological evidence, it is known that tau abnormalities, manifested by neurofibrillary tangles, form in limbic structures in virtually everyone as they age. This process is independent of amyloid deposition in the form of cerebral cortical plaques. Plaques, however, do not occur in everyone as they age. When plaques do develop, the age-related tauopathy is accelerated and tangles begin to appear in the cerebral cortex. Thus, the initial and ubiquitous formation of tangles with age is both spatially and temporally independent from that of amyloid deposits (1) and does not represent the earliest stage of AD, as it is unassociated with detectable neuronal loss (2,3), at least during current life spans. In the presence of amyloid deposition, the age-related limbic tauopathy is converted into widespread tauopathy, which is associated with neuronal loss, with tangles, and neuritic pathology now present in cerebral cortex. Thus, Dr. Pimplikar is accurate in stating that tau pathologies occur first, but only the age-related limbic tauopathy that does not result in AD. The AD-related tauopathy occurs after amyloid is deposited in cerebral cortex. These neuropathological observations do not refute the amyloid hypothesis.
Allen Roses also makes cogent arguments against the amyloid hypothesis. One argument, that there is no evidence that cognitively normal persons with evidence of amyloid deposition progress to symptomatic Alzheimer's disease, again is only partially correct. It is true that there are no definitive studies, with positive and negative predictive values, demonstrating that such individuals are at greatly increased risk for converting from preclinical AD to symptomatic AD, because there still is insufficient longitudinal follow-up of such individuals. However, the available preliminary data in cognitively normal older adults do indicate that preclinical AD, defined either by abnormal cerebrospinal fluid levels of amyloid-β and tau or by amyloid imaging, indeed is associated with increased risk of progression to symptomatic AD within five years (4,5).
Alzheimer's disease caused by mutations in PSEN1, PSEN2, and APP genes is characterized by overproduction of amyloid-β, and late-onset “sporadic” AD is characterized by under-clearance of amyloid-β (6). Almost certainly it is too simplistic to attribute an illness as complex as AD solely to amyloid dysregulation, but nonetheless, it would be a serious mistake to dismiss testing anti-amyloid therapeutic strategies when toxic amyloid-β species appear and amyloid deposition begins—that is, in preclinical AD, prior to the onset of neurodegeneration and the cascade of associated pathologies that characterize symptomatic AD. Initiating “secondary prevention” studies in asymptomatic individuals who are destined to develop AD dementia by virtue of their inheritance of a deterministic mutation for AD is the current focus of the Dominantly Inherited Alzheimer Network (DIAN) as well as for other programs. The DIAN Therapeutic Trials Unit, led by my colleague Randall J. Bateman, M.D., is developing the infrastructure to launch these trials, hopefully within months, in the DIAN cohort. The results of such trials, even if clinical benefit is unrealized, will provide extremely valuable information about the mechanisms underlying AD and further inform the debate about the role of amyloid dysregulation. Ideally, of course, these trials will demonstrate efficacy and provide long-awaited optimism that truly effective therapies for AD one day will be available.
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PubMed.
I think that there is consensus about moving preclinical, but we should globally agree on the design of the clinical trials at presymptomatic stages: number of participants, criteria for enrollment, duration, treatments, and endpoints. Considering the large number of treatments that need to be tested, and the phenomenal expense and effort that go into clinical trials, we should aim at designing a universal model of inexpensive, minimalistic trials that give the maximum information in the shortest time. This should be, I believe, a priority for the Alzheimer's field.
The commentary by Sperling and colleagues is thought provoking and a welcome addition to a longstanding and important scientific debate. Regardless of the disappointing results of the clinical trials of anti-amyloid drugs, however, there are strong rational arguments against the amyloid cascade hypothesis of AD elaborated well before any clinical trials of anti-amyloid drugs were initiated (1). Thus, the negative results of these trials are not surprising. I agree, however, with the careful arguments of John Morris that it would be a mistake to dismiss all anti-amyloid drug testing. Although amyloid may not be the primary etiological agent of AD, there is a good chance that amyloid depositions cause secondary damage to neurons.
I'd like to clarify an important point in John’s arguments. His assertion that “Alzheimer's disease caused by mutations in PSEN1, PSEN2, and APP genes is characterized by overproduction of amyloid-β…” has been challenged by experimental data showing that many PS FAD mutations do not increase production of Aβ (for recent review, see reference 2 below and references therein). The Swedish APP mutation that affects the β-secretase cleavage rather than PS activity is among the few FAD mutations that cause a clear and robust increase in Aβ. Interestingly, this was the first increase in Aβ caused by an FAD mutation to be identified (3). Others followed. It is curious, though, that this mutation that increases in-vitro Aβ42 (often more than 10 times) precipitates AD at a later age than the London mutations that hardly cause any increase in Aβ. Thus, I consider it highly probable that PS and APP FAD mutations cause neurodegeneration by mechanisms independent of Aβ.
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Sperling and colleagues suggest that brain amyloid deposition drives the clinical sequelae associated with AD, and that anti-amyloid-based therapies continue to be the most promising treatment for the disease. They argue that a reason for the failure of numerous clinical trials employing anti-amyloid intervention is not due to targeting the wrong pathologic substrate, but rather that the time of the intervention was too late. The authors go on to present a series of cogent arguments that the field should begin secondary prevention trials in asymptomatic individuals who are at a high risk for developing Alzheimer’s disease (AD) using amyloid interventions.
Such trials would most likely be cases with familial AD (FAD) or even those with Down’s syndrome. However, there is evidence of different types of amyloid plaques found in FAD (“wooly”) compared to sporadic AD (1). Despite these differences and possibly other yet unknown variances across disorders, the amyloid cascade hypothesis of AD remains the dominant paradigm that is assumed will lead to an eventual therapeutic strategy.
However, the question still remains as to whether the amyloid hypothesis has run its course, and that the AD field should initiate a paradigm shift. An argument for such a shift could be based on the lackluster track record for anti-amyloid-based clinical trials, and that amyloid pathology may not define the substrate underlying the onset of AD. The observations that many aged people without cognitive impairment, and even those with mild cognitive impairment (MCI), a prodromal stage of AD, exhibit a similar degree of Aβ deposition based upon postmortem brain tissue (2) as well as in-vivo amyloid imaging studies (3) limits the use of these lesions as a true pathologic marker for the distinction between normal aging and preclinical AD. In this regard, cortical insoluble Aβ40 and Aβ42 levels were found to correlate with neuropathologic AD status (CERAD and Braak staging), but were not predictive of a clinical diagnosis of MCI (4).
The observation that extensive reduction of amyloid plaques following Aβ vaccination therapy failed to prevent further cognitive decline in people with a clinical diagnosis of early AD (5) suggests a lack of efficacy for this type of treatment. Although it is argued that treatment was not started early enough to alter the course of cognitive decline, these findings do suggest that solely targeting this protein for the treatment of dementia may be incorrect once the disease is initiated, which may occur some 20 years prior to clinical symptoms.
I would argue that we still do not know what component of amyloid, if any, to target. On the other hand, Aβ may normally function as an antimicrobial peptide in the innate immune system in response to clinically relevant pathogenic microorganisms (6) or activate neuroprotective properties (7). Therefore, its removal may result in increased vulnerability to infection and continued brain dysfunction during all disease phases. This would suggest that the field requires a paradigm shift that goes beyond the problems of Aβ protein cleavage, processing, and aggregation.
A more parsimonious treatment approach for AD, at any stage of the disease, must take into account the fact that the neuropathologic substrate(s) of AD are diverse. It may include amyloid pathology, but there is also molecular, cellular, and synaptic dysfunction, as well as the initiation of neuroplastic (positive or negative) events (8), which may be triggered by an increase in amyloid production. Data are emerging to suggest that the disease process may be initiated via a trans-synaptic neuron-to-neuron disconnection syndrome affecting multiple levels throughout the central nervous system (9), which may be independent of amyloidosis but related to hominoid evolutionary pressures placed upon the human brain during the expansion of the limbic cortex and neocortex in response to higher cortical cognitive function.
At this time in the history of the etiology of AD, an argument can be made that there is no “silver bullet” to target, which best fits the diverse pathologic, molecular, and cellular constellation of events that occurs years prior to clinical AD. The field should look forward and seriously consider alternative therapeutic strategies, or we may be in the same place as we are now but 10 years down the road without any drugs to treat this devastating neurologic disease. In the end, a poly- and not just a mono-pharmaceutical treatment approach is most likely to be the most effective treatment strategy, which would include anti-amyloid drugs as one component of a treatment cocktail.
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Alzheimer’s dementia is a human problem that is still woefully under-supported and underinvestigated. But investing so heavily in multibillion-dollar clinical trials based on current knowledge should not be the only solution. The costs, societal and economic, are too great for us to wait for the results of decades-long clinical trials to test our current notions as to what causes the disease. The confusing disagreements as to how amyloid contributes to disease masks our ignorance of the basic pathological mechanisms that begin the disease process.
The amyloid hypothesis is a valuable contribution to understanding dementia, but it has not been properly explored, since we know little about what might trigger the earliest events. Basically, we have no idea when AD starts, how it starts, and where it starts. These are difficult questions that have not been addressed by current animal models, nor will they be answered by focusing so many research dollars and investigator efforts on the study of advanced stages of the disease. These are questions that deserve at least as high a priority as the plans that have been proposed in this essay.
Sperling and colleagues cite three possible reasons why amyloid-targeted therapies may not yet have shown efficacy: 1) wrong mechanism, 2) right mechanism, but drug not hitting target, and 3) right mechanism, right target, but too late. That pretty much covers it.
Surprisingly, given their expense, most of the trials which have been run have been severely flawed and do not allow us to distinguish these (Golde et al., 2011). These heated discussions reflect that, while everyone has opinions, there are very few facts. I think all that it is safe to say at this point (based on the immunization trial) is that this is not a miracle cure.
The evidence for the amyloid hypothesis is, of course, genetic (see Glenner’s abstract in Glenner and Wong, 1984 for its first explicit statement). Given this, clearly the evidence that it contains some truth is strongest in mutation carriers, and yet these individuals (and Down's syndrome individuals) have been excluded from clinical trials. In my view, both for moral and scientific reasons, this omission needs to be corrected, and the DIAN study (led by Dr. Morris) and similar studies such as the Alzheimer's Prevention Initiative for the Colombian E280K families have to be priorities.
It is worth noting that the amyloid hypothesis was conceived on the basis of APP triplication in Down’s and APP mutations (Hardy and Higgins, 1992; Selkoe, 1991). Higgins and I, and separately Selkoe, predicted that other risk factors would impinge on the same pathway. This prediction was spectacularly borne out by St. George-Hyslop’s work identifying presenilins, and then by the work of De Strooper and Wolfe showing that this was the enzyme involved in Aβ formation, as well as by Roses’ groundbreaking identification of ApoE as the major brain-expressed and genetically variable Aβ-binding protein (Strittmatter et al., 1993). Given this history, I am constantly surprised by Dr. Roses' implicit rejection of his biggest contribution to the Alzheimer's field.
The amyloid hypothesis remains the only hypothesis which explains the genetic data: The only other which comes close is the presenilins inhibition hypothesis of Sambamurti et al., 2011 and Shen (Shen and Kelleher, 2007; see also ARF Live Discussion). This, of course, does not mean it is right, but clearly it deserves proper testing. My two concerns are, first, not so much that the amyloid hypothesis is wrong, but rather that because we do not know the function of APP or Aβ, we are missing why the protein is deposited in those individuals who do not have dominant mutations (Hardy, 2009), and second that drug trials will be abandoned before a clear answer is reached. So I offer three explicit (not original) suggestions: Do prevention trials in mutation carriers. Work out the function of APP and whether Aβ has a function.
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Golde TE, Schneider LS, Koo EH.
Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift.
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Glenner GG, Wong CW.
Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein.
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Selkoe DJ.
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The scientific evidence in favor of amyloid-β being part of the AD mechanism is, in my opinion, very clear. It is crucial that this hypothesis be fully tested in the clinic.
The discussion on cause and consequence of amyloid is not entirely dissimilar to the question years ago of whether the HIV virus was responsible for AIDS.
I would like to add two elements to the discussion:
1. When to treat? This critically depends on how the amyloid peptide contributes to the disease process. I refer to the different scenarios we discussed recently in an ARF Webinar based on Karran et al., 2011). If amyloid peptide acts as a trigger, only very early treatment (primary prevention) will be effective; if it is a driver, then later interventions (but still before major neuronal loss) would be good.
2. How to convince industry to continue investing in trials? I agree that collaboration among industry, academia, and government will be necessary. I also think that we should give longer patent protection for drugs that need such long clinical trials before showing efficacy. The companies that do the long walk should be sure they get a reward at the end that is sufficient to take this risk.
References:
Karran E, Mercken M, De Strooper B.
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.
Nat Rev Drug Discov. 2011 Sep;10(9):698-712.
PubMed.
This is an interesting conversation among highly respected scientists. I'll just add one additional perspective.
Clinico-neuropathological correlation data, although complex, are compatible with the hypothesis that "something" (genetics plus environment) leads to amyloid-β plaques, and these spark a process of cortical tangles that contribute to the synapse elimination and cell loss that correlate with cognitive status. As many different studies have found, NFTs in neocortex in the presence of plaques are the pathological feature linked most specifically and strongly to cognitive status in AD patients, but one does not observe numerous cortical NFTs without amyloid plaques or FTLD (1).
An interesting recent development from both in-vivo and tissue culture studies across different (excellent) labs indicates that once NFTs are developing in the cortex, the process of tau deposition may auto-propagate (2-5). If this is true, it adds credence to Dr. Sperling's thesis that the timing of therapy (before the auto-propagating horse has left the barn) is critical.
References:
Nelson PT, Head E, Schmitt FA, Davis PR, Neltner JH, Jicha GA, Abner EL, Smith CD, Van Eldik LJ, Kryscio RJ, Scheff SW.
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This article well summarizes a current consensus that has been emerging in the field based primarily on clinical trial failures. We need to be cautious, since it is not clear whether these treatments would work even if started early. Nevertheless, for some therapies, a rationale for early treatment can be made.
For example, for Aβ immunotherapy, one can speculate that plaques may act to sequester therapeutic antibodies from more important pools of Aβ. Concurring with most of the comments, cumulative data continues to point to β amyloid as being involved. Even the suggestion that presenilin mutations may act independent of β amyloid has only looked at one pool of Aβ when concluding that Aβ generation is not affected.
Emerging brain imaging supports amyloid-related effects on cognition even in the cognitively normal. One needs also to be aware of limitations in calling elderly individuals “normal." The elderly cannot run as fast as when they were young, while most justifiably are still classified as normal. Immunoelectron microscopy shows that all aggregated amyloid, including diffuse plaques, is associated with brain damage, and not all neuropathology presents with obvious symptoms.
I concur with the comment by Hardy that the major challenge remains that we still do not understand enough about the underlying disease process. Aging synapses are not an easy system to understand. We need to bridge our understanding of the biochemical and biological pathways connecting the various participants, including ApoE, tau, Aβ, and aging, among many others.
I commend the authors for asking for input. More discussion, particularly between basic and clinical scientists, might contribute to better clinical trials in the future.
The thoughtful commentary by Sperling, Jack, and Aisen focused on their third hypothesis, i.e., that AD trials have failed because the drugs are being administered at the wrong stage of the disease. They examined this hypothesis exclusively from the amyloid perspective. I do not wish to enter into discussion about that perspective, but rather to agree with their view that drug trials should target as early a stage in the disease process as is feasible.
Sperling et al. say, “Perhaps the most daunting challenge is to identify a clinically relevant change that defines the stage at which an individual tips from cognitively normal to subtly abnormal….” Biomarker studies cannot do this yet, and anyway, they are largely based upon the amyloid hypothesis. What is needed is some clinical marker that is predictive of future cognitive decline. In the OPTIMA cohort, we have been studying volunteer control subjects for more than 20 years, and some of these have now developed MCI and a few have progressed to AD. Examining the results of yearly cognitive tests revealed that, as well as age, two particular tests were predictors of subsequent conversion to MCI: verbal expression and learning (1). Using interval-censored survival analysis, we found that it was possible to predict not only that the people would convert to MCI, but precisely at what time they would convert within the period of up to 10 years after the testing. Thus, if we were to reveal these predictions to people, they might well agree to enter a clinical trial of a disease-modifying treatment. Clearly, more research on this approach is needed, but, at least in principle, this method provides one answer to the challenge thrown up by Sperling et al.
At present, the earliest stage that treatments can be given is MCI because at this stage, there is a measurable cognitive impairment that the subjects themselves are aware of. MCI might be considered too late for amyloid-modifying therapy, but it is not too late for other approaches to be successful. I will give three examples here.
First, exercise: Its beneficial effect on cognition is supported by many observational studies and animal experiments (2). A well-designed randomized trial in people with MCI or subjective memory complaints showed a beneficial effect on ADAS-Cog following 24 weeks of enhanced physical activity (3).
Second, omega-3 fatty acids: A trial of docosahexaenoic acid in people with memory impairment showed improvements in memory scores after 24 weeks (4).
Third, B vitamins to lower homocysteine: An 18-month trial of folic acid, B6, and B12 in patients with AD was negative overall, but it is noteworthy that in a subgroup with mild AD, the B vitamin treatment did slow cognitive decline over 15 months (5). A more striking result was obtained when these three B vitamins were given at an earlier stage in the disease process. In a two-year trial in MCI, the B vitamins led to a slowing in the rate of brain atrophy by up to 53 percent (6), and to a slowing in cognitive decline and an actual improvement in the global CDR score in the MCI subjects with high baseline homocysteine (7). The last results are consistent with a disease-modifying effect of the B vitamins, which was further supported by analysis of the loss of regional grey matter: The regions where loss of grey matter in MCI was slowed by B vitamin treatment were the same as those which show atrophy in AD (8).
I suggest that MCI is the stage of choice to test disease-modifying drugs.
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Having been involved in many clinical trials in AD from both the academic (investigator) and industry (sponsor) perspective, this is a long overdue and necessary debate. As many have pointed out, the poor track record of clinical trials aimed at modulating amyloid has come to bite all of us. This can be seen by the exodus of big pharma from this area and the increasing difficulty for smaller companies to obtain funding for innovative research.
At the risk of sounding contrarian, one of the topics that does not seem to be transparently discussed here is that the putative failures of these amyloid-directed compounds may have nothing to do with the stage of the disease, but rather with the compound itself.
I would like to make at least two points:
1) Investigational compounds are routinely tested in transgenic models that are poorly representative of sporadic AD and whose response to treatment is neither qualitatively nor quantitatively generalizable to sporadic AD.
2) Most of these compounds were progressed into phase III trials on the back of either flimsy or completely negative phase II studies. Commercial analyses probably suggested that the risk-adjusted net present value (NPV) of a project was still positive even with a 95 percent probability of failure, and that was used as the rationale for entry into phase III. The lack of dose-response relationships, robust effects on biomarkers and reliance on post-hoc sub-group analyses are strong predictors of study failure in almost every therapeutic area.
There is some merit to the notion that we would like to intervene as early as we practically can. However, it seems to me that the argument that these compounds are failing because we are treating too late sounds like a convenient excuse rather than being the result of properly designed studies that have failed.
If we want to restore credibility, then lets take a compound that has a strong scientific rationale, targets a clear aspect of AD pathology, has failed in a sufficiently large study of patients with mild-moderate AD dementia and test it in patients with amnestic MCI.
Reisa Sperling Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
Posted:
It is heartening to see that our recent commentary has sparked a spirited discussion among a group of esteemed AD researchers. We would like to address a few of the points raised in the previous Alzforum comments.
Many of the comments have focused on the “amyloid-o-centricity” of the article, but in fact, both the table and the figure suggest a large number of non-amyloid targets that would be ideal for future prevention trials. It is the case, however, that the most clearly defined “at-risk” groups for secondary prevention trials—autosomal dominant mutation carriers, ApoE4 homozygotes, and biomarker positive older individuals—do all share amyloid-β accumulation as a common risk factor. Ideally, we would try combinations of amyloid and non-amyloid-based therapies in secondary prevention trials. Unfortunately, we do not yet have non-amyloid-based therapies with evidence of target engagement in humans and adequate safety data to support the three- to five-year-duration secondary prevention trials that will be needed to detect evidence of slowing clinical decline at the preclinical stages of AD.
We were a bit surprised that many of the comments still focus on the basic science debate on whether Aβ is an important factor in AD pathobiology. We must stop wasting time arguing about whether Aβ accumulation is “the” cause of AD, as amyloid is likely to be only one of several factors underlying the condition we recognize as AD dementia. Amyloid, indeed, may be “necessary but not sufficient.” Even if it is not “necessary,” most scientists acknowledge that amyloid plays at least “a” role in the pathophysiological process of AD. It is our understanding that the cardiovascular field had “cholesterol wars” for many years before the field reached consensus that cholesterol was “a” factor in heart disease. At this point, some cardiologists are bemoaning the fact that cholesterol lowering in asymptomatic individuals has only resulted in a 25-30 percent attributable reduction in cardiac morbidity and mortality. Just imagine if we could achieve a 25 percent reduction in the rate of progression to AD dementia with an anti-amyloid therapy by treating early enough in the disease process.
Furthermore, these clinical trials will provide a key piece of evidence regarding the role (or lack thereof) of Aβ in the progression of AD. As the currently available mouse models of AD do not manifest significant neuronal loss, it is critical to determine the link among Aβ, neurodegeneration, and neuronal loss in humans. Natural history studies will only provide a piece of the necessary scientific evidence, as we are not able to control many of the other factors that may influence clinical progression in patients. A clinical trial prior to significant atrophy is needed to support (or refute) the hypothesis that lowering Aβ will alter downstream neurodegeneration and neuronal loss in AD.
As we mention in the commentary, it may, indeed, be the case that some of the previous trials have failed because the therapeutic agents were not hitting their intended targets, or that the clinical trial protocols were poorly designed or executed. We are thrilled that the field is already moving towards earlier intervention at the stage of MCI/prodromal AD. However, if, as the accumulating data suggest, the neurodegenerative process is already well entrenched by the stage of MCI, it may be difficult for an anti-amyloid therapy in isolation to fully alter the clinical course of disease. We now have several biologically active anti-amyloid agents, albeit with some risk, but at least a reasonably well-defined safety profile that will allow well-informed consent, and we have the tools to identify asymptomatic individuals at risk for AD dementia who might benefit from these therapies. As we wrote in the commentary, there are many challenges ahead in conducting these secondary prevention trials, as we do not yet have all of the answers, but we must move forward. The alternative of waiting another decade to begin these prevention initiatives is simply not tenable, given the looming public health crisis of an ever-growing population of AD dementia patients.
Comments
Oregon Health Sciences University
I agree with Dr. Sperling's assessment that we now have the tools for a more definitive assessment of the amyloid hypothesis than has been possible previously, and I agree that a "secondary prevention" trial should be a high priority for our field. At the same time, though, we should not give up on the possibility of finding disease-modifying treatments for our patients with established dementia. Patients with early dementia are capable of a very good quality of life if we can prevent progression to more dependent and ultimately vegetative phases of the disease.
The currently active Phase 3 bapineuzumab trial is expected to demonstrate clear-cut effects on cerebral amyloid, so the clinical outcomes will tell us whether an anti-amyloid approach is a viable treatment strategy at the stage of symptomatic dementia. If not, then we may conclude that anti-amyloid approaches are futile after the diagnosis of dementia, but that should not be interpreted to mean that meaningful treatment is impossible at that point. Instead, we should investigate other candidate mechanisms that may be independent of amyloid at later stages, such as "calcium dyshomeostasis, tau-mediated neurodegeneration, and mitochondrial dysfunction" cited by Dr. Sperling, and plan appropriate treatment trials targeting those mechanisms.
Dr. Sperling's analogy with heart failure may be revisited here: Certainly prevention is preferable to treatment, but heart failure is now a remarkably treatable condition due to efforts targeting the right mechanisms at the right time.
University of Melbourne
This commentary is very germane. A few major issues deserve further elaboration.
Testing the Aβ theory of AD (rather than the “amyloid hypothesis”) still has not been accomplished. The challenges are formidable. While the “right” target may not have been identified, we would suggest that it is the toxic oligomeric species of Aβ, which, in the human brain, are still poorly defined. The “right” drug will then turn on its ability to target these toxic species. Very few drugs or biologics in current clinical development can claim to act on these species. The “right” stage for intervention is clearly the presymptomatic one, but rather than talk of secondary prevention, it might be more realistic to initially aim for delay of onset, say by five years. How to demonstrate to the regulators that such an approach is feasible will also be a formidable challenge.
Finally, the authors have “rightly” identified the ethical issues of disclosing to presymptomatic individuals their biomarker status. We need to debate and resolve this issue urgently, as any intervention aimed at the presymptomatic stage will require this disclosure.
University of Southampton
Is Prevention Better Than Cure?
The paper by Sperling and colleagues is a thought-provoking review of where we are presently with respect to Alzheimer's disease therapy, with the emphasis on treating patients earlier in the course of the disease. By the time someone presents with dementia, or even with MCI, the AD process is in full flow: with Aβ aggregation in the form of plaques, cerebral amyloid angiopathy (CAA) and oligomers; intraneuronal tau in the form of tangles, neuropil threads, and dystrophic neurites; activation of microglia and astrocytes; and neuronal and synaptic dysfunction and loss. It is, perhaps, expecting rather a lot to think that removing the trigger from the disease at this stage might halt or even reverse the multiple facets of the pathology. Many of the therapeutic avenues discussed in the paper are focused on the Aβ hypothesis, including the immunotherapy approach. As the authors point out, it has been shown that Aβ immunotherapy can result in plaque removal from the Alzheimer's brain, but that even when complete, this does not seem to halt the cognitive decline (Holmes et al., 2008). Possible reasons for this apparent self-perpetuation of the neurodegeneration in the absence of Aβ plaques include: persistent or increased soluble Aβ as plaques are disrupted; persistent inflammation; prion-like properties of tau; increased CAA; and finally, of course, the possibility that Aβ is the wrong target.
The seminal work of Dale Schenk and colleagues, which kicked off the whole Aβ immunotherapy field, was essentially two different experiments (Schenk et al., 1999). First, they immunized aged APP transgenic mice, which had brains full of plaques, and demonstrated that there was some removal of plaques in established disease—this is essentially what the studies in humans now show. In the second experiment, they immunized mice at a very early age, before any plaques had formed, and found a complete prevention of plaque formation during aging. To us, the really intriguing question at the moment in the immunotherapy field is, What would happen if you immunized humans at an early stage in life? Could it be done safely, without side effects? On the one hand, we happily routinely immunize our children against microorganisms to which they may never be exposed, but on the other hand, there is a niggling suspicion that Aβ, and perhaps even Aβ oligomers, have a physiological function. Secondly, would early immunization prevent the formation of Aβ plaques and oligomers during aging? Judging by the close parallels between the immunotherapy studies in aged animals and humans, it seems likely. If so, immunization before the disease begins (i.e., before the formation of any plaques) will avoid the side effects which appear to be associated with removing amyloid from the brain (Boche et al., 2010). Thirdly, if early immunotherapy were to prevent Aβ aggregation, would this then prevent the whole AD process: tau accumulation, glial pathology, neuronal and synaptic damage—and prevent the dementia? This would be the real test of the amyloid cascade hypothesis.
References:
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999 Jul 8;400(6740):173-7. PubMed.
Boche D, Denham N, Holmes C, Nicoll JA. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 2010 Sep;120(3):369-84. PubMed.
Maastricht University; VU University Medical Centre
Reisa Sperling and colleagues have written a thoughtful commentary on the future of trials in AD. They describe the pros and cons of primary, secondary, and tertiary prevention trials and conclude that secondary prevention trials (i.e., prevention of cognitive impairment in subjects with amyloid pathology) are likely the best option for the moment. But, as they note, secondary prevention trials have their problems, and, in particular, clinically relevant endpoints will be difficult to reach within a reasonable trial duration and with a manageable sample size. Moreover, we do not exactly know what drives AD pathology in the preclinical stage of the disease. Any secondary prevention trial is therefore not only a proof of efficacy of a treatment but also an experiment, which tests assumptions on the underlying AD pathophysiology.
How to proceed from here? One strategy may be to test treatments considered for secondary prevention trials in a two-step approach. First, treatments may be tested in intermediately sized two-year studies with a range of biomarkers as an outcome, including biomarkers that reflect the target of the drug and biomarkers for neurodegeneration such as brain atrophy, synapse loss, disconnectivity, or tau in CSF. If these results look promising, large-scale trials with a longer duration may be performed with clinical endpoints. A minor comment on the paper is that the authors consider trials with carriers of autosomal-dominant AD mutations or ApoE4 homozygotes as candidates for secondary prevention trials. However, some of these subjects may not have yet developed AD pathology, and trials in such subjects could be considered as primary prevention trials.
Icahn School of Medicine at Mount Sinai
To answer the rhetorical question presented by Sperling et al., "Why do we keep testing drugs aimed at the initial stages of the disease process in patients at the endstage of the illness?", it is because prevention trials are almost too daunting to consider, especially in these days of diminishing resources. However, the figure of 20 years of presymptomatic cerebral amyloidosis shown by the DIAN study earlier this year fulfilled our worst nightmares about when we should begin to intervene. Along the way, it is likely that amyloid imaging will be used off-label to create a new class of anxious pre-patients (or pre-escapees). Things are bad enough for our patients and their families with currently approved drugs that are almost universally disappointing and frustration-inducing without quadrupling, or more, the number of worried as well. But maybe that is the price of progress.
The first challenge is raising the $100 million-plus required to pay for the first prevention trial. I would argue that we should get on with raising the funds and get the trials going. It is likely that the first trial will not be definitive, and it is also likely that we will think most seriously about whom to include and exclude, and what parameters to follow once we are actually committed and involved. In other words, "There is nothing like a hanging to focus the mind."
The trial should be as adaptive as possible, because new data will come in over the many years that the trial will require, and we should be able to adjust to incorporate new information. The prevention cohort should include some subjects who have positive amyloid scans and perfect cognition, as well as some who may have positive scans and who are also already one standard deviation off. There is no obvious way to choose between these two groups, so I would say just commit to both from the get-go. The outcome with the latter group will be obvious sooner, but that could mean more disappointment.
Just last week, I attended an Alzheimer's event chaired by one of the world's pre-eminent cardiologists. According to this expert, cardiologists the world over are ready to embrace Alzheimer's as a cardiovascular disease and get on with taking the Framingham/cholesterol/statin approach to the problem. Seems to me that we should get off the dime and take serious steps toward prevention trials. Otherwise, the heart docs might just plow ahead and solve Alzheimer's while we are wringing our hands...!
Case Western Reserve University
Sperling et al. have put forward a now familiar argument (also proposed by others; 1-4) that amyloid-based therapies of the past decade have failed not because they were targeted at the wrong pathophysiological mechanism, but rather because the intervention came too late. Here they present cogent arguments that we should begin secondary prevention trials in asymptomatic individuals who are at a high risk for developing Alzheimer’s disease (AD).
No one can argue with the sensibility of the argument that a therapy has a greater chance of success if started early in the disease process. So there is some merit in advocating continuation of this approach. Also, as a practical matter, and having invested so heavily in amyloid-based therapeutic strategies, the field finds it difficult to walk away from this approach, especially since no alternative seems to be on the immediate horizon. Yet the complacent thinking that we must be on the right track and will have a successful treatment if we begin treatment earlier is dangerous. It also happens to be flawed for the following reasons.
First, neither Sperling et al. nor the other purveyors of this argument (1-4) define what "early" is. Suppose, having started the secondary prevention trial at an "early" enough time point and continuing it for a sufficient period, there are still no clinical benefits (biomarkers moving in the right direction is of little solace to an AD patient or a caretaker if cognition continues to deteriorate). Would this situation lead to further arguments that we should have started even earlier, or would it be enough to finally invalidate the amyloid-based approach?
Second, it is indeed advisable to identify at-risk populations and, as the authors have done, group them into those carrying familial AD (FAD) mutations, being homozygous for the ApoE4 allele, or being older amyloid-positive individuals as subjects for secondary prevention trials. However, to assume that all three risk groups develop AD through the same pathophysiological mechanism, that the therapeutic intervention being tested targets this mechanism, and that the same mechanism is responsible for the majority of cases of sporadic AD, is extremely risky and runs contrary to emerging evidence (5-8).
Finally, the amyloid hypothesis is still a "hypothesis," and despite a decade of failed clinical trials based on this hypothesis, there is reluctance to ask hard questions regarding the validity of many of its suppositions. Is the dominantly inherited FAD, where the amyloid hypothesis has a better chance of being correct, the same as sporadic AD, which afflicts 98 percent of AD patients? Autopsy studies (9-11), which are the gold standard for neuropathological observations, have provided impeccable evidence that in brain parenchyma, tau pathologies precede amyloid abnormalities, which is contrary to the currently favored view (12) that amyloid abnormalities occur prior to tau abnormalities. Historically, the presence of amyloid plaques has been considered a prerequisite for an AD diagnosis. With the knowledge that a third of the elderly population is PIB-positive and cognitively healthy, and that there is a growing number of cases of PIB-negative dementia patients (13), is the traditional definition of AD still consistent in terms of underlying mechanisms?
We all agree with the authors that "...the cost of caring for an ever-expanding number of AD dementia patients..." will be astronomical "...if we do not find a successful disease-modifying therapy." However, not fundamentally altering the course of our thinking about AD pathogenesis may prove to be even more expensive in the long run.
References:
Golde TE, Schneider LS, Koo EH. Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron. 2011 Jan 27;69(2):203-13. PubMed.
Selkoe DJ. Resolving controversies on the path to Alzheimer's therapeutics. Nat Med. 2011 Sep;17(9):1060-5. PubMed.
Holtzman DM, Morris JC, Goate AM. Alzheimer's disease: the challenge of the second century. Sci Transl Med. 2011 Apr 6;3(77):77sr1. PubMed.
Hyman BT. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol. 2011 Aug;68(8):1062-4. PubMed.
Pimplikar SW. Reassessing the amyloid cascade hypothesis of Alzheimer's disease. Int J Biochem Cell Biol. 2009 Jun;41(6):1261-8. PubMed.
Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. J Neurosci. 2010 Nov 10;30(45):14946-54. PubMed.
Herrup K. Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010 Dec 15;30(50):16755-62. PubMed.
Shen J, Kelleher RJ. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9. PubMed.
Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transm Suppl. 1998;53:127-40. PubMed.
Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.
Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.
Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.
Shimada H, Ataka S, Takeuchi J, Mori H, Wada Y, Watanabe Y, Miki T. Pittsburgh compound B-negative dementia: a possibility of misdiagnosis of patients with non-alzheimer disease-type dementia as having AD. J Geriatr Psychiatry Neurol. 2011 Sep;24(3):123-6. PubMed.
Former Duke University Professor
The assumptions are that amyloid deposition is the instigating event and thus the right target, that drugs that reduce amyloid accumulation in the brain may be the right drugs, and that performing drug trials in normal people can be safe and reasonable. I have a long record of disagreeing with the first two assumptions, but I believe that pursuing the right target with appropriate drugs for which there are established safety records may delay the onset of mild cognitive impairment (MCI) symptoms and also delay the onset of dementia.
For decades, we have used the neuropathology of amyloid deposition as the Holy Grail of academic Alzheimer’s disease (AD) research, frankly at the expense of support for any new directions by the peer review system. Hypothesis testing has taken a back seat to the belief of many (who want grant support over a career in AD research) that amyloid deposition is the root cause for the development of AD. The rationale that amyloid is the “right” target is based on the pathological presence of amyloid in brains of AD patients, and by the fact that less than 1 percent of patients carrying rare mutations in amyloid-related genes develop the early onset form of AD. Linguistically, this is a false syllogism. Everyone thought the Earth was flat once upon a time as well. Majority belief systems do not replace hypothesis testing.
The authors introduce three hypotheses for the failure of the recent AD clinical trials—I favor the first two—that “we are targeting the wrong pathophysiological mechanisms” and “the drugs do not engage the right targets in patients.” The third hypothesis is partially correct: that “the drugs are hitting the right targets but are doing so at the wrong stage of the disease.” The authors implicitly accept that targeting amyloid-β is the right way to proceed. However, the fact that “the majority of clinical trials target brain amyloid-β” does not validate the target. A drug target is validated after its modulation produces a clinical effect. The authors postulate that the failure of recent trials, which were originally so highly touted, was because the treatment came too late, not because the target was wrong. I believe part of that argument is true. Treatment should begin early.
There is a solution. Let’s redefine the prevailing definition of the disease, focusing on a stage before symptoms appear rather than the time after death when brain autopsies can be performed. The argument that amyloid deposition in the brain precedes AD symptoms is supported, but no prospective studies that begin with cognitively normal adults have provided positive and negative predictive values for AD risk as a result of amyloid deposition. This lack of hypothesis testing continues despite available technologies for imaging amyloid plaques. Instead, most amyloid proponents have proceeded based on belief in a hypothetical “scheme of the proposed stages of AD” like that shown in Figure 1 of the Commentary. These constructions may be used in the future to make predictions for real subjects who would be entered into clinical trials. And note—these are subjects, not patients, as the people in the proposed prevention studies are asymptomatic. Defining subjects by amyloid testing as suitable candidates for a secondary prevention study is fine, but at this point in time, defining them as presymptomatic patients is questionable.
At this stage, it will be more useful to shift resources and inquire: Are there adequate prognostics of AD in asymptomatic subjects that could be useful in designing primary prevention studies? Prognosis-based enrichment designs can usher the possibility of testing truly preventive measures. Twenty years ago (this week, coincidentally), we determined that ApoE was an important constituent of the disease, and that it binds to amyloid and is found in plaques (1-3). For several years after the papers were published, the field said, “Aha, then it is amyloid.” Now the rest of the field suddenly (from my viewpoint) is proposing clinical trials stratified by ApoE genotypes. But over the years, we have investigated alternative mechanisms and researched whether the genetic predisposition data are due to ApoE or other polymorphic markers within the region of linkage disequilibrium (4,5). We now hypothesize that we have markers that can predict the relative risk for onset of symptoms in the next five years in normal individuals within the older age range, when AD becomes common (6). For Caucasians at least, a polymorphic poly-T tract (“523”) in TOMM40 defines variability in age of disease onset for ApoE3 and ApoE2 carriers.
Early experiments are, in general, supportive of our findings, with some exceptions (7,8). While we have questions about some technical aspects of these publications (the ascertainment heterogeneity for age of onset in the ADNI series in one, and methods for determining the poly-T length in the other), it is right to test the hypothesis. Similar to the history of testing ApoE, there will be some important naysayers. That is science. We will test the hypothesis using rational and adequately powered experimental designs, with clinically relevant endpoints. One way to test the suitability of the genetic data, or any biomarker for that matter, for predicting which individuals are at greatest risk of developing clinical symptoms of MCI will be to prospectively qualify the biomarker, or a multi-component biomarker algorithm composed of age, ApoE allele status, and TOMM40-523 genotype. This same experiment might also be used to measure the relative positive and negative predictive values of amyloid deposition over a practical time frame for a clinical trial. That is, there may well be a way to test the scheme that is republished as Figure 1 in the Commentary.
At the end of our planned five-year study, which will include periodic clinical neuropsychological testing, there will be data with which we calculate the positive and negative predictive values for the genetic algorithm. Simultaneously, the efficacy of a drug to delay the onset of cognitive impairment of the Alzheimer’s type will be tested within the high-risk group in a Phase 3 study. The drug, pioglitazone, targets a number of pathogenic pathways that have been implicated in the development of AD, most notably the mitochondrial pathogenic pathway that is supported by an extensive body of literature. This might be the right drug used in the right subjects at the right time. Pioglitazone has been used for more than 22 million human-years and has an extensively studied risk profile. A sister drug, rosiglitazone, had a positive clinical effect at three different doses in a Phase 2B monotherapy trial after stratification for ApoE genotype (9). But ApoE-stratified, Phase 3 trials in mild to moderate AD “failed”(10).
There is no doubt that ApoE has an isoform-specific role in disease pathogenesis, but perhaps this is mediated by differential interaction with mitochondrial Tomm40. Based on our current data for the distribution of TOMM40 alleles in different populations, we suggest that the large proportion of Far Eastern patients in those trials have a different risk algorithm than do Caucasians. That is, in contrast to the Phase 2B Caucasian-only study, the patient population was heterogeneous with respect to risk. If this is true, the Phase 3 trials performed in a mixed ethnic group had no chance to succeed because we did not account for the contribution of TOMM40-523 to the genetic risk.
Putting all these pieces together, the biomarkers of Figure 1 of the Science Translational Medicine Commentary, including amyloid deposition, must be evaluated so that positive and negative predictive values can be calculated. The context for the biomarker validation could be a delay-of-onset, clinical study similar to that which is proposed for pioglitazone. Amyloid deposition may be an effect, not a cause, of the disease process, and it may also be a later accelerant of clinical pathogenesis. Removing amyloid may be valuable. However, testing amyloid-directed drugs, which have an uncertain risk profile, in normal people seems premature and perhaps dangerous, especially in the absence of hard, quantitative, prospective data for amyloid deposition as a biomarker.
The best way to uncover the causative events culminating in AD is to perform clinical trials that measure neuropsychiatric endpoints adequate for detecting changes in normal, aging subjects. We have embarked on one such study and hope the field will shift its efforts accordingly.
Note: This comment was invited by the Alzheimer Research Forum.
References:
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PubMed.
Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8098-102. PubMed.
Roses AD, Gilbert J, Xu PT, Sullivan P, Popko B, Burkhart DS, Christian-Rothrock T, Saunders AM, Maeda N, Schmechel DE. Cis-acting human ApoE tissue expression element is associated with human pattern of intraneuronal ApoE in transgenic mice. Neurobiol Aging. 1998 Jan-Feb;19(1 Suppl):S53-8. PubMed.
Lai E, Riley J, Purvis I, Roses A. A 4-Mb high-density single nucleotide polymorphism-based map around human APOE. Genomics. 1998 Nov 15;54(1):31-8. PubMed.
Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm MG, Feldman HH, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung GY, Johnson J, Kelly DD, Keren R, Kertesz A, King KS, Lovestone S, Loy-English I, Matthews PM, Owen MJ, Plumpton M, Pryse-Phillips W, Prinjha RK, Richardson JC, Saunders A, Slater AJ, St George-Hyslop PH, Stinnett SW, Swartz JE, Taylor RL, Wherrett J, Williams J, Yarnall DP, Gibson RA, Irizarry MC, Middleton LT, Roses AD. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008 Jan;65(1):45-53. PubMed.
Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, Huentelman MJ, Welsh-Bohmer KA, Reiman EM. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 2010 Oct;10(5):375-84. Epub 2009 Dec 22 PubMed.
Chu SH, Roeder K, Ferrell RE, Devlin B, Demichele-Sweet MA, Kamboh MI, Lopez OL, Sweet RA. TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. Neurobiol Aging. 2011 Dec;32(12):2328.e1-9. PubMed.
Cruchaga C, Nowotny P, Kauwe JS, Ridge PG, Mayo K, Bertelsen S, Hinrichs A, Fagan AM, Holtzman DM, Morris JC, Goate AM, Alzheimer's Disease Neuroimaging Initiative. Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Arch Neurol. 2011 Aug;68(8):1013-9. PubMed.
Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD, . Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54. PubMed.
Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamägi U, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131-46. PubMed.
Washington University School of Medicine
I am unaccustomed to posting comments in an online scientific debate, in this case regarding the challenge posed by Reisa Sperling, Clifford Jack, and Paul Aisen to conduct clinical trials of potential Alzheimer's therapies in the preclinical (presymptomatic) stages of the illness. Hence, I am sure to find myself in way over my head. Nevertheless, I here offer mild rebuttals to some previous comments about the paper by Sperling et al.
Sanjay Pimplikar rightly notes that the amyloid hypothesis remains unproven, and that its basis rests largely on genetic forms of Alzheimer's disease (AD) caused by dominantly inherited mutations or Down's syndrome. The exact causative mechanisms of Alzheimer's disease remain unknown, and whether changes in amyloid-β, tau, or other molecules are primary, secondary, or unrelated still must be determined. There also is little argument that molecular pathologies other than amyloid-β dysregulation contribute to the clinical syndrome of AD and clearly deserve investigation and treatment efforts. However, Dr. Pimplikar supports his comment by observing that tau pathologies precede amyloid pathologies in AD. This is only partially correct. Based on neuropathological evidence, it is known that tau abnormalities, manifested by neurofibrillary tangles, form in limbic structures in virtually everyone as they age. This process is independent of amyloid deposition in the form of cerebral cortical plaques. Plaques, however, do not occur in everyone as they age. When plaques do develop, the age-related tauopathy is accelerated and tangles begin to appear in the cerebral cortex. Thus, the initial and ubiquitous formation of tangles with age is both spatially and temporally independent from that of amyloid deposits (1) and does not represent the earliest stage of AD, as it is unassociated with detectable neuronal loss (2,3), at least during current life spans. In the presence of amyloid deposition, the age-related limbic tauopathy is converted into widespread tauopathy, which is associated with neuronal loss, with tangles, and neuritic pathology now present in cerebral cortex. Thus, Dr. Pimplikar is accurate in stating that tau pathologies occur first, but only the age-related limbic tauopathy that does not result in AD. The AD-related tauopathy occurs after amyloid is deposited in cerebral cortex. These neuropathological observations do not refute the amyloid hypothesis.
Allen Roses also makes cogent arguments against the amyloid hypothesis. One argument, that there is no evidence that cognitively normal persons with evidence of amyloid deposition progress to symptomatic Alzheimer's disease, again is only partially correct. It is true that there are no definitive studies, with positive and negative predictive values, demonstrating that such individuals are at greatly increased risk for converting from preclinical AD to symptomatic AD, because there still is insufficient longitudinal follow-up of such individuals. However, the available preliminary data in cognitively normal older adults do indicate that preclinical AD, defined either by abnormal cerebrospinal fluid levels of amyloid-β and tau or by amyloid imaging, indeed is associated with increased risk of progression to symptomatic AD within five years (4,5).
Alzheimer's disease caused by mutations in PSEN1, PSEN2, and APP genes is characterized by overproduction of amyloid-β, and late-onset “sporadic” AD is characterized by under-clearance of amyloid-β (6). Almost certainly it is too simplistic to attribute an illness as complex as AD solely to amyloid dysregulation, but nonetheless, it would be a serious mistake to dismiss testing anti-amyloid therapeutic strategies when toxic amyloid-β species appear and amyloid deposition begins—that is, in preclinical AD, prior to the onset of neurodegeneration and the cascade of associated pathologies that characterize symptomatic AD. Initiating “secondary prevention” studies in asymptomatic individuals who are destined to develop AD dementia by virtue of their inheritance of a deterministic mutation for AD is the current focus of the Dominantly Inherited Alzheimer Network (DIAN) as well as for other programs. The DIAN Therapeutic Trials Unit, led by my colleague Randall J. Bateman, M.D., is developing the infrastructure to launch these trials, hopefully within months, in the DIAN cohort. The results of such trials, even if clinical benefit is unrealized, will provide extremely valuable information about the mechanisms underlying AD and further inform the debate about the role of amyloid dysregulation. Ideally, of course, these trials will demonstrate efficacy and provide long-awaited optimism that truly effective therapies for AD one day will be available.
References:
Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.
West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet. 1994 Sep 17;344(8925):769-72. PubMed.
Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol. 2001 Sep;58(9):1395-402. PubMed.
Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. Epub 2007 Jan 8 PubMed.
Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, Mintun MA. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009 Dec;66(12):1469-75. PubMed.
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. PubMed.
Universitat Autònoma de Barcelona
I think that there is consensus about moving preclinical, but we should globally agree on the design of the clinical trials at presymptomatic stages: number of participants, criteria for enrollment, duration, treatments, and endpoints. Considering the large number of treatments that need to be tested, and the phenomenal expense and effort that go into clinical trials, we should aim at designing a universal model of inexpensive, minimalistic trials that give the maximum information in the shortest time. This should be, I believe, a priority for the Alzheimer's field.
Mount Sinai School of Medicine, NYU
The commentary by Sperling and colleagues is thought provoking and a welcome addition to a longstanding and important scientific debate. Regardless of the disappointing results of the clinical trials of anti-amyloid drugs, however, there are strong rational arguments against the amyloid cascade hypothesis of AD elaborated well before any clinical trials of anti-amyloid drugs were initiated (1). Thus, the negative results of these trials are not surprising. I agree, however, with the careful arguments of John Morris that it would be a mistake to dismiss all anti-amyloid drug testing. Although amyloid may not be the primary etiological agent of AD, there is a good chance that amyloid depositions cause secondary damage to neurons.
I'd like to clarify an important point in John’s arguments. His assertion that “Alzheimer's disease caused by mutations in PSEN1, PSEN2, and APP genes is characterized by overproduction of amyloid-β…” has been challenged by experimental data showing that many PS FAD mutations do not increase production of Aβ (for recent review, see reference 2 below and references therein). The Swedish APP mutation that affects the β-secretase cleavage rather than PS activity is among the few FAD mutations that cause a clear and robust increase in Aβ. Interestingly, this was the first increase in Aβ caused by an FAD mutation to be identified (3). Others followed. It is curious, though, that this mutation that increases in-vitro Aβ42 (often more than 10 times) precipitates AD at a later age than the London mutations that hardly cause any increase in Aβ. Thus, I consider it highly probable that PS and APP FAD mutations cause neurodegeneration by mechanisms independent of Aβ.
References:
Neve RL, Robakis NK. Alzheimer's disease: a re-examination of the amyloid hypothesis. Trends Neurosci. 1998 Jan;21(1):15-9. PubMed.
Robakis NK. Mechanisms of AD neurodegeneration may be independent of Aβ and its derivatives. Neurobiol Aging. 2011 Mar;32(3):372-9. PubMed.
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672-4. PubMed.
Barrow Neurological Institute
Sperling and colleagues suggest that brain amyloid deposition drives the clinical sequelae associated with AD, and that anti-amyloid-based therapies continue to be the most promising treatment for the disease. They argue that a reason for the failure of numerous clinical trials employing anti-amyloid intervention is not due to targeting the wrong pathologic substrate, but rather that the time of the intervention was too late. The authors go on to present a series of cogent arguments that the field should begin secondary prevention trials in asymptomatic individuals who are at a high risk for developing Alzheimer’s disease (AD) using amyloid interventions.
Such trials would most likely be cases with familial AD (FAD) or even those with Down’s syndrome. However, there is evidence of different types of amyloid plaques found in FAD (“wooly”) compared to sporadic AD (1). Despite these differences and possibly other yet unknown variances across disorders, the amyloid cascade hypothesis of AD remains the dominant paradigm that is assumed will lead to an eventual therapeutic strategy.
However, the question still remains as to whether the amyloid hypothesis has run its course, and that the AD field should initiate a paradigm shift. An argument for such a shift could be based on the lackluster track record for anti-amyloid-based clinical trials, and that amyloid pathology may not define the substrate underlying the onset of AD. The observations that many aged people without cognitive impairment, and even those with mild cognitive impairment (MCI), a prodromal stage of AD, exhibit a similar degree of Aβ deposition based upon postmortem brain tissue (2) as well as in-vivo amyloid imaging studies (3) limits the use of these lesions as a true pathologic marker for the distinction between normal aging and preclinical AD. In this regard, cortical insoluble Aβ40 and Aβ42 levels were found to correlate with neuropathologic AD status (CERAD and Braak staging), but were not predictive of a clinical diagnosis of MCI (4).
The observation that extensive reduction of amyloid plaques following Aβ vaccination therapy failed to prevent further cognitive decline in people with a clinical diagnosis of early AD (5) suggests a lack of efficacy for this type of treatment. Although it is argued that treatment was not started early enough to alter the course of cognitive decline, these findings do suggest that solely targeting this protein for the treatment of dementia may be incorrect once the disease is initiated, which may occur some 20 years prior to clinical symptoms.
I would argue that we still do not know what component of amyloid, if any, to target. On the other hand, Aβ may normally function as an antimicrobial peptide in the innate immune system in response to clinically relevant pathogenic microorganisms (6) or activate neuroprotective properties (7). Therefore, its removal may result in increased vulnerability to infection and continued brain dysfunction during all disease phases. This would suggest that the field requires a paradigm shift that goes beyond the problems of Aβ protein cleavage, processing, and aggregation.
A more parsimonious treatment approach for AD, at any stage of the disease, must take into account the fact that the neuropathologic substrate(s) of AD are diverse. It may include amyloid pathology, but there is also molecular, cellular, and synaptic dysfunction, as well as the initiation of neuroplastic (positive or negative) events (8), which may be triggered by an increase in amyloid production. Data are emerging to suggest that the disease process may be initiated via a trans-synaptic neuron-to-neuron disconnection syndrome affecting multiple levels throughout the central nervous system (9), which may be independent of amyloidosis but related to hominoid evolutionary pressures placed upon the human brain during the expansion of the limbic cortex and neocortex in response to higher cortical cognitive function.
At this time in the history of the etiology of AD, an argument can be made that there is no “silver bullet” to target, which best fits the diverse pathologic, molecular, and cellular constellation of events that occurs years prior to clinical AD. The field should look forward and seriously consider alternative therapeutic strategies, or we may be in the same place as we are now but 10 years down the road without any drugs to treat this devastating neurologic disease. In the end, a poly- and not just a mono-pharmaceutical treatment approach is most likely to be the most effective treatment strategy, which would include anti-amyloid drugs as one component of a treatment cocktail.
References:
Shepherd C, McCann H, Halliday GM. Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol. 2009 Jul;118(1):37-52. PubMed.
Price JL, McKeel DW, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009 Jul;30(7):1026-36. PubMed.
Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, Dekosky ST, Halligan EM, Klunk WE. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008 Nov;65(11):1509-17. PubMed.
Forman MS, Mufson EJ, Leurgans S, Pratico D, Joyce S, Leight S, Lee VM, Trojanowski JQ. Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis. Neurology. 2007 Mar 6;68(10):757-63. PubMed.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD. The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010 Mar 3;5(3):e9505. PubMed.
Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G, Smith MA. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis. 2009;18(2):447-52. PubMed.
Mufson EJ, Binder L, Counts SE, Dekosky ST, Detoledo-Morrell L, Ginsberg SD, Ikonomovic MD, Perez SE, Scheff SW. Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol. 2012 Jan;123(1):13-30. PubMed.
Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.
Yale University School of Medicine
Alzheimer’s dementia is a human problem that is still woefully under-supported and underinvestigated. But investing so heavily in multibillion-dollar clinical trials based on current knowledge should not be the only solution. The costs, societal and economic, are too great for us to wait for the results of decades-long clinical trials to test our current notions as to what causes the disease. The confusing disagreements as to how amyloid contributes to disease masks our ignorance of the basic pathological mechanisms that begin the disease process.
The amyloid hypothesis is a valuable contribution to understanding dementia, but it has not been properly explored, since we know little about what might trigger the earliest events. Basically, we have no idea when AD starts, how it starts, and where it starts. These are difficult questions that have not been addressed by current animal models, nor will they be answered by focusing so many research dollars and investigator efforts on the study of advanced stages of the disease. These are questions that deserve at least as high a priority as the plans that have been proposed in this essay.
Institute of Neurology, UCL
Sperling and colleagues cite three possible reasons why amyloid-targeted therapies may not yet have shown efficacy: 1) wrong mechanism, 2) right mechanism, but drug not hitting target, and 3) right mechanism, right target, but too late. That pretty much covers it.
Surprisingly, given their expense, most of the trials which have been run have been severely flawed and do not allow us to distinguish these (Golde et al., 2011). These heated discussions reflect that, while everyone has opinions, there are very few facts. I think all that it is safe to say at this point (based on the immunization trial) is that this is not a miracle cure.
The evidence for the amyloid hypothesis is, of course, genetic (see Glenner’s abstract in Glenner and Wong, 1984 for its first explicit statement). Given this, clearly the evidence that it contains some truth is strongest in mutation carriers, and yet these individuals (and Down's syndrome individuals) have been excluded from clinical trials. In my view, both for moral and scientific reasons, this omission needs to be corrected, and the DIAN study (led by Dr. Morris) and similar studies such as the Alzheimer's Prevention Initiative for the Colombian E280K families have to be priorities.
It is worth noting that the amyloid hypothesis was conceived on the basis of APP triplication in Down’s and APP mutations (Hardy and Higgins, 1992; Selkoe, 1991). Higgins and I, and separately Selkoe, predicted that other risk factors would impinge on the same pathway. This prediction was spectacularly borne out by St. George-Hyslop’s work identifying presenilins, and then by the work of De Strooper and Wolfe showing that this was the enzyme involved in Aβ formation, as well as by Roses’ groundbreaking identification of ApoE as the major brain-expressed and genetically variable Aβ-binding protein (Strittmatter et al., 1993). Given this history, I am constantly surprised by Dr. Roses' implicit rejection of his biggest contribution to the Alzheimer's field.
The amyloid hypothesis remains the only hypothesis which explains the genetic data: The only other which comes close is the presenilins inhibition hypothesis of Sambamurti et al., 2011 and Shen (Shen and Kelleher, 2007; see also ARF Live Discussion). This, of course, does not mean it is right, but clearly it deserves proper testing. My two concerns are, first, not so much that the amyloid hypothesis is wrong, but rather that because we do not know the function of APP or Aβ, we are missing why the protein is deposited in those individuals who do not have dominant mutations (Hardy, 2009), and second that drug trials will be abandoned before a clear answer is reached. So I offer three explicit (not original) suggestions: Do prevention trials in mutation carriers. Work out the function of APP and whether Aβ has a function.
References:
Golde TE, Schneider LS, Koo EH. Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron. 2011 Jan 27;69(2):203-13. PubMed.
Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984 Aug 16;122(3):1131-5. PubMed.
Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184-5. PubMed.
Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron. 1991 Apr;6(4):487-98. PubMed.
Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8098-102. PubMed.
Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C, Bhat NR, Kindy MS, Lahiri DK, Pappolla MA. Targets for AD treatment: conflicting messages from γ-secretase inhibitors. J Neurochem. 2011 May;117(3):359-74. PubMed.
Shen J, Kelleher RJ. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9. PubMed.
Hardy J. The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J Neurochem. 2009 Aug;110(4):1129-34. PubMed.
UK Dementia Research Institute@UCL and VIB@KuLeuven
The scientific evidence in favor of amyloid-β being part of the AD mechanism is, in my opinion, very clear. It is crucial that this hypothesis be fully tested in the clinic.
The discussion on cause and consequence of amyloid is not entirely dissimilar to the question years ago of whether the HIV virus was responsible for AIDS.
I would like to add two elements to the discussion:
1. When to treat? This critically depends on how the amyloid peptide contributes to the disease process. I refer to the different scenarios we discussed recently in an ARF Webinar based on Karran et al., 2011). If amyloid peptide acts as a trigger, only very early treatment (primary prevention) will be effective; if it is a driver, then later interventions (but still before major neuronal loss) would be good.
2. How to convince industry to continue investing in trials? I agree that collaboration among industry, academia, and government will be necessary. I also think that we should give longer patent protection for drugs that need such long clinical trials before showing efficacy. The companies that do the long walk should be sure they get a reward at the end that is sufficient to take this risk.
References:
Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011 Sep;10(9):698-712. PubMed.
University of Kentucky
This is an interesting conversation among highly respected scientists. I'll just add one additional perspective.
Clinico-neuropathological correlation data, although complex, are compatible with the hypothesis that "something" (genetics plus environment) leads to amyloid-β plaques, and these spark a process of cortical tangles that contribute to the synapse elimination and cell loss that correlate with cognitive status. As many different studies have found, NFTs in neocortex in the presence of plaques are the pathological feature linked most specifically and strongly to cognitive status in AD patients, but one does not observe numerous cortical NFTs without amyloid plaques or FTLD (1).
An interesting recent development from both in-vivo and tissue culture studies across different (excellent) labs indicates that once NFTs are developing in the cortex, the process of tau deposition may auto-propagate (2-5). If this is true, it adds credence to Dr. Sperling's thesis that the timing of therapy (before the auto-propagating horse has left the barn) is critical.
References:
Nelson PT, Head E, Schmitt FA, Davis PR, Neltner JH, Jicha GA, Abner EL, Smith CD, Van Eldik LJ, Kryscio RJ, Scheff SW. Alzheimer's disease is not "brain aging": neuropathological, genetic, and epidemiological human studies. Acta Neuropathol. 2011 May;121(5):571-87. PubMed.
de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, Hyman BT. Caspase activation precedes and leads to tangles. Nature. 2010 Apr 22;464(7292):1201-4. PubMed.
Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009 May 8;284(19):12845-52. PubMed.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.
Guo JL, Lee VM. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. 2011 Apr 29;286(17):15317-31. Epub 2011 Mar 3 PubMed.
Lund University
This article well summarizes a current consensus that has been emerging in the field based primarily on clinical trial failures. We need to be cautious, since it is not clear whether these treatments would work even if started early. Nevertheless, for some therapies, a rationale for early treatment can be made.
For example, for Aβ immunotherapy, one can speculate that plaques may act to sequester therapeutic antibodies from more important pools of Aβ. Concurring with most of the comments, cumulative data continues to point to β amyloid as being involved. Even the suggestion that presenilin mutations may act independent of β amyloid has only looked at one pool of Aβ when concluding that Aβ generation is not affected.
Emerging brain imaging supports amyloid-related effects on cognition even in the cognitively normal. One needs also to be aware of limitations in calling elderly individuals “normal." The elderly cannot run as fast as when they were young, while most justifiably are still classified as normal. Immunoelectron microscopy shows that all aggregated amyloid, including diffuse plaques, is associated with brain damage, and not all neuropathology presents with obvious symptoms.
I concur with the comment by Hardy that the major challenge remains that we still do not understand enough about the underlying disease process. Aging synapses are not an easy system to understand. We need to bridge our understanding of the biochemical and biological pathways connecting the various participants, including ApoE, tau, Aβ, and aging, among many others.
I commend the authors for asking for input. More discussion, particularly between basic and clinical scientists, might contribute to better clinical trials in the future.
University of Oxford
The thoughtful commentary by Sperling, Jack, and Aisen focused on their third hypothesis, i.e., that AD trials have failed because the drugs are being administered at the wrong stage of the disease. They examined this hypothesis exclusively from the amyloid perspective. I do not wish to enter into discussion about that perspective, but rather to agree with their view that drug trials should target as early a stage in the disease process as is feasible.
Sperling et al. say, “Perhaps the most daunting challenge is to identify a clinically relevant change that defines the stage at which an individual tips from cognitively normal to subtly abnormal….” Biomarker studies cannot do this yet, and anyway, they are largely based upon the amyloid hypothesis. What is needed is some clinical marker that is predictive of future cognitive decline. In the OPTIMA cohort, we have been studying volunteer control subjects for more than 20 years, and some of these have now developed MCI and a few have progressed to AD. Examining the results of yearly cognitive tests revealed that, as well as age, two particular tests were predictors of subsequent conversion to MCI: verbal expression and learning (1). Using interval-censored survival analysis, we found that it was possible to predict not only that the people would convert to MCI, but precisely at what time they would convert within the period of up to 10 years after the testing. Thus, if we were to reveal these predictions to people, they might well agree to enter a clinical trial of a disease-modifying treatment. Clearly, more research on this approach is needed, but, at least in principle, this method provides one answer to the challenge thrown up by Sperling et al.
At present, the earliest stage that treatments can be given is MCI because at this stage, there is a measurable cognitive impairment that the subjects themselves are aware of. MCI might be considered too late for amyloid-modifying therapy, but it is not too late for other approaches to be successful. I will give three examples here.
First, exercise: Its beneficial effect on cognition is supported by many observational studies and animal experiments (2). A well-designed randomized trial in people with MCI or subjective memory complaints showed a beneficial effect on ADAS-Cog following 24 weeks of enhanced physical activity (3).
Second, omega-3 fatty acids: A trial of docosahexaenoic acid in people with memory impairment showed improvements in memory scores after 24 weeks (4).
Third, B vitamins to lower homocysteine: An 18-month trial of folic acid, B6, and B12 in patients with AD was negative overall, but it is noteworthy that in a subgroup with mild AD, the B vitamin treatment did slow cognitive decline over 15 months (5). A more striking result was obtained when these three B vitamins were given at an earlier stage in the disease process. In a two-year trial in MCI, the B vitamins led to a slowing in the rate of brain atrophy by up to 53 percent (6), and to a slowing in cognitive decline and an actual improvement in the global CDR score in the MCI subjects with high baseline homocysteine (7). The last results are consistent with a disease-modifying effect of the B vitamins, which was further supported by analysis of the loss of regional grey matter: The regions where loss of grey matter in MCI was slowed by B vitamin treatment were the same as those which show atrophy in AD (8).
I suggest that MCI is the stage of choice to test disease-modifying drugs.
References:
Oulhaj A, Wilcock GK, Smith AD, de Jager CA. Predicting the time of conversion to MCI in the elderly: role of verbal expression and learning. Neurology. 2009 Nov 3;73(18):1436-42. PubMed.
Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011 Sep;86(9):876-84. PubMed.
Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008 Sep 3;300(9):1027-37. PubMed.
Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N, Stedman M, . Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010 Nov;6(6):456-64. PubMed.
Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ, . High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. PubMed.
Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244. PubMed.
de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2011 Jul 21; PubMed.
Douaud G, Refsum H, de Jager CA, Bradley K, Jacoby RS, Smith AD. Disease-modification in MCI with homocysteine-lowering B vitamins slows atrophy of particular brain regions: the VITACOG trial. J Nutr Health Aging. 2011;15:S12.
AbbVie
Having been involved in many clinical trials in AD from both the academic (investigator) and industry (sponsor) perspective, this is a long overdue and necessary debate. As many have pointed out, the poor track record of clinical trials aimed at modulating amyloid has come to bite all of us. This can be seen by the exodus of big pharma from this area and the increasing difficulty for smaller companies to obtain funding for innovative research.
At the risk of sounding contrarian, one of the topics that does not seem to be transparently discussed here is that the putative failures of these amyloid-directed compounds may have nothing to do with the stage of the disease, but rather with the compound itself.
I would like to make at least two points:
1) Investigational compounds are routinely tested in transgenic models that are poorly representative of sporadic AD and whose response to treatment is neither qualitatively nor quantitatively generalizable to sporadic AD.
2) Most of these compounds were progressed into phase III trials on the back of either flimsy or completely negative phase II studies. Commercial analyses probably suggested that the risk-adjusted net present value (NPV) of a project was still positive even with a 95 percent probability of failure, and that was used as the rationale for entry into phase III. The lack of dose-response relationships, robust effects on biomarkers and reliance on post-hoc sub-group analyses are strong predictors of study failure in almost every therapeutic area.
There is some merit to the notion that we would like to intervene as early as we practically can. However, it seems to me that the argument that these compounds are failing because we are treating too late sounds like a convenient excuse rather than being the result of properly designed studies that have failed.
If we want to restore credibility, then lets take a compound that has a strong scientific rationale, targets a clear aspect of AD pathology, has failed in a sufficiently large study of patients with mild-moderate AD dementia and test it in patients with amnestic MCI.
Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
It is heartening to see that our recent commentary has sparked a spirited discussion among a group of esteemed AD researchers. We would like to address a few of the points raised in the previous Alzforum comments.
Many of the comments have focused on the “amyloid-o-centricity” of the article, but in fact, both the table and the figure suggest a large number of non-amyloid targets that would be ideal for future prevention trials. It is the case, however, that the most clearly defined “at-risk” groups for secondary prevention trials—autosomal dominant mutation carriers, ApoE4 homozygotes, and biomarker positive older individuals—do all share amyloid-β accumulation as a common risk factor. Ideally, we would try combinations of amyloid and non-amyloid-based therapies in secondary prevention trials. Unfortunately, we do not yet have non-amyloid-based therapies with evidence of target engagement in humans and adequate safety data to support the three- to five-year-duration secondary prevention trials that will be needed to detect evidence of slowing clinical decline at the preclinical stages of AD.
We were a bit surprised that many of the comments still focus on the basic science debate on whether Aβ is an important factor in AD pathobiology. We must stop wasting time arguing about whether Aβ accumulation is “the” cause of AD, as amyloid is likely to be only one of several factors underlying the condition we recognize as AD dementia. Amyloid, indeed, may be “necessary but not sufficient.” Even if it is not “necessary,” most scientists acknowledge that amyloid plays at least “a” role in the pathophysiological process of AD. It is our understanding that the cardiovascular field had “cholesterol wars” for many years before the field reached consensus that cholesterol was “a” factor in heart disease. At this point, some cardiologists are bemoaning the fact that cholesterol lowering in asymptomatic individuals has only resulted in a 25-30 percent attributable reduction in cardiac morbidity and mortality. Just imagine if we could achieve a 25 percent reduction in the rate of progression to AD dementia with an anti-amyloid therapy by treating early enough in the disease process.
Furthermore, these clinical trials will provide a key piece of evidence regarding the role (or lack thereof) of Aβ in the progression of AD. As the currently available mouse models of AD do not manifest significant neuronal loss, it is critical to determine the link among Aβ, neurodegeneration, and neuronal loss in humans. Natural history studies will only provide a piece of the necessary scientific evidence, as we are not able to control many of the other factors that may influence clinical progression in patients. A clinical trial prior to significant atrophy is needed to support (or refute) the hypothesis that lowering Aβ will alter downstream neurodegeneration and neuronal loss in AD.
As we mention in the commentary, it may, indeed, be the case that some of the previous trials have failed because the therapeutic agents were not hitting their intended targets, or that the clinical trial protocols were poorly designed or executed. We are thrilled that the field is already moving towards earlier intervention at the stage of MCI/prodromal AD. However, if, as the accumulating data suggest, the neurodegenerative process is already well entrenched by the stage of MCI, it may be difficult for an anti-amyloid therapy in isolation to fully alter the clinical course of disease. We now have several biologically active anti-amyloid agents, albeit with some risk, but at least a reasonably well-defined safety profile that will allow well-informed consent, and we have the tools to identify asymptomatic individuals at risk for AD dementia who might benefit from these therapies. As we wrote in the commentary, there are many challenges ahead in conducting these secondary prevention trials, as we do not yet have all of the answers, but we must move forward. The alternative of waiting another decade to begin these prevention initiatives is simply not tenable, given the looming public health crisis of an ever-growing population of AD dementia patients.
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