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Planning the First Primary Prevention Trial for Alzheimer’s Disease

Series - Alzheimer's Association International Conference 2017:

Is it time for the first primary prevention trial for Alzheimer’s pathology? Observational studies have made clear that amyloid accumulation begins more than two decades before symptoms appear, creating a huge window for intervention. Armed with better biomarkers for detecting early accumulation, researchers have pushed treatment to ever-earlier stages of the disease, and secondary prevention trials are underway to see if anti-amyloid drugs can stave off cognitive decline in preclinical disease populations. But what about stopping the disease process before it even gets a foothold?

Such was the goal discussed at a working meeting among leading clinician-researchers in the field, held in conjunction with the Alzheimer’s Association International Conference that took place July 16-20 in London. The assembled researchers agreed that all necessary pieces have finally fallen into place to allow them to tackle primary prevention of the central Alzheimer’s pathogenic pathway. These pieces include a trial-ready population of people certain to develop Alzheimer’s, detailed knowledge of how the disease progresses in this group, biomarkers that can track early amyloid accumulation, and drugs that prevent accumulation and are safe and cheap enough for long-term use. In a July 13 Nature commentary, Eric McDade and Randall Bateman of Washington University in St. Louis argued that now is the right time to begin this endeavor.

“We are at a point where a primary prevention trial makes sense. It’s time to move forward and truly test the amyloid hypothesis,” McDade told the working group. McDade helps direct the Dominantly Inherited Alzheimer Network trials unit (DIAN-TU). He described to the assembled scientists plans for a prevention trial in this population. In a lively discussion, the working group debated the issues surrounding how to implement such a trial.

DIAN participants come from families who carry pathogenic mutations in APP, PS1, or PS2 (see Nov 2008 news series; Aug 2016 news). All of these mutations cause the brain to produce more Aβ42 than normal, leading to early amyloid accumulation and plaque formation. Mutation carriers develop symptoms at around the same age their affected parent did. In many cases, this occurs in the mid-40s, meaning that the first insidious buildup of plaques in their brains probably begins in their 20s.

Because the disease starts so early in this group, DIAN researchers will enroll amyloid-negative carriers and noncarriers as young as 18. Noncarriers will be included so that participants will not have to find out their mutation status, although they will have the option to do so, McDade told Alzforum. On average, participants will be 22 years away from their estimated age of symptom onset.

The trial will test whether BACE inhibitors can slow the growth of plaques, as seen by amyloid PET, over the course of four to five years. Either one-third or one-half of participants will receive placebo.

The researchers are focusing on BACE inhibitors because these drugs can suppress production of Aβ42 and Aβ40 by 80 to 90 percent (Mar 2013 conference news; Oct 2014 news; Apr 2015 conference news). About half a dozen BACE inhibitors are currently in Phase 2 or 3 trials. So far, no serious side effects have cropped up in these multiyear studies, suggesting the drugs might be safe enough for long-term use. Because they are small molecules taken orally, they would be cheaper and more feasible for long-term use than antibody infusions, the scientists noted.

The working group largely supported the choice of BACE inhibitors, but voiced some cautions. Some noted that these drugs, unlike antibody therapies, have yet to demonstrate any slowing of cognitive decline in later AD. Mathias Jucker of the University of Tübingen, Germany, saw potential for antibodies to benefit young mutation carriers. Animal studies indicate that very few pathogenic seeds are present at early disease stages, hence mopping up those seeds could delay disease for a long time, Jucker suggested. But most researchers thought BACE inhibitors represented the most practical option for people in the early stages of familial AD.

“The case for BACE inhibitor treatment in this population is extremely strong. It would be unethical not to try it,” said Paul Aisen of the University of Southern California, San Diego.

To determine if the inhibitors work, the researchers will examine changes in the trajectory of plaque growth by PiB PET, McDade said. The goal is to slow amyloid accumulation compared to the placebo group, ideally keeping plaques below the threshold for amyloid positivity. The working group endorsed amyloid PET as the only feasible outcome measure for people at this early stage of AD pathogenesis. Reisa Sperling of Brigham and Women’s Hospital, Boston, noted that the brains of young mutation carriers do not harbor tau pathology yet. Nor have synapses begun to degenerate at this early stage, she added. Aβ in cerebrospinal fluid, while it detects very early signs of amyloidosis, does not track progression as well as amyloid PET, according to biomarker experts.

The greatest debate at the meeting centered around the size of this trial. DIAN researchers calculate that a cohort of 80 to 100 mutation carriers will provide 90 percent power to detect a 50 to 80 percent slowing of amyloid accumulation. Bateman noted that this calculation is based on analyses of extensive observational data that delineate the rates of change in the PiB PET signal for people carrying various mutations. The researchers will exclude people carrying the Arctic or Dutch mutations from the trial, due to the unique effects of these variants on amyloid, Bateman said.

Other scientists, such as Aisen and Sperling, urged the DIAN leaders to go bigger. Sperling pointed out that the calculation assumes a best-case scenario for BACE inhibitor performance, and makes no allowances for unexpected variability. Although researchers know something about how different mutations affect accumulation, it remains unknown how slashing the levels of Aβ monomer would affect the amyloid accumulation curve for each mutation, Sperling said. Moreover, other genes may influence the rates of amyloid buildup among different individuals, potentially muddying the results. A larger starting population would also help buffer against the expected attrition over a long trial, Sperling added. She recommended doubling the size to 100 people per arm to increase the odds of seeing a positive outcome. Cost, and caution about how many young adults to expose to an investigational drug were the counterpoints on this question. In the end, the discussion persuaded DIAN leaders to raise their enrollment goal to 140–180 mutation carriers.

Maintaining the trial population will be crucial, because the researchers have long-term plans for them. If the initial four- to five-year study does show a slowing of plaque growth, then the researchers will switch all participants to drug and follow them for several more years to try to detect a cognitive benefit. This phase of the trial will not include non-carriers. Researchers have not yet settled on a cognitive outcome measure, but several composites that detect change in preclinical populations have now been developed. These include the Preclinical Alzheimer Cognitive Composite (PACC), the Cognitive Function Instrument (CFI), ADCOMS, and a cognitive composite used in DIAN (Jun 2014 news; Mar 2015 news; Wang et al., 2016; Aug 2016 conference news). The researchers will compare cognitive change in this cohort to historical data from DIAN to look for any slowing of the trajectory. They will also analyze whether people initially on drug maintain their abilities better than those who started on placebo.

Exposing young, outwardly healthy people for so many years to experimental drugs raises ethical issues. Participants will be asked not to get pregnant during the trial, because what BACE inhibitors might do to a developing fetus is not yet known. Animal studies demonstrate a much bigger role for BACE in the developing than in the adult brain (Oct 2016 news). This requirement might represent a significant sacrifice for people in their prime child-bearing years, especially for noncarriers who run no risk of passing on the disease to their child, some researchers argued. McDade noted, however, that participants might be able to take a “drug holiday” for a year to have a child, and then resume dosing. Others noted that these issues must be spelled out clearly during the consent process.

A final conundrum concerns whether findings in the autosomal-dominant AD population will translate to sporadic disease. The latter involves impaired clearance, not overproduction, suggesting the findings might not be directly applicable to late-onset disease, noted José Luis Molinuevo of Barcelonaβeta Brain Research Center in Barcelona, Spain. Sperling agreed that if the study is successful, it will need to be repeated in the sporadic AD population. Such a trial would have to be larger, perhaps 250 people per arm, she suggested. A previous, negative, trial of ginkgo biloba pills demonstrated that a large prevention study can be done in sporadic AD, with the majority of the 3,000 elderly participants staying with the regimen for six years (Nov 2008 news). But for a mechanism-based, anti-amyloid drug such as a BACE inhibitor, an ADAD trial is a crucial first step to show efficacy, the researchers concurred.

McDade noted that the families involved in DIAN are eager to participate in this. At the DIAN Family Conference held in conjunction with AAIC, they expressed strong support for the trial, with some pressing to start treatment earlier than age 18. “The stakes are extraordinarily high. If successful, a primary prevention treatment could avert the loss of memories, thoughts, and independence for a significant proportion of the world’s older population,” wrote McDade and Bateman in their Nature commentary.—Madolyn Bowman Rogers

Comments

  1. A line of evidence suggests that a contributing factor to sporadic Alzheimer’s disease, that may potentially influence amyloidogeneis upstream of amyloid accumulations, is abnormally elevated activity in default mode network (DMN) neurons during cognitive resting state conditions (Raichle et al., 2001; Buckner et al., 2005, 2008; Cirrito et al, 2005; and Bero et al., 2011).

    Like Paul Aisen and Reisa Sperling, I agree in the prudence of expanding the first primary prevention trial for Alzheimer’s disease, not just by increasing the sample size, but also by weighing the evidence of abnormal DMN activity along with the amyloid hypothesis, and the suggestions in the 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease (Fargo et al., 2014 https://www.ncbi.nlm.nih.gov/pubmed/25341459), which include commencing trials utilizing combination therapy and the repurposing of medications. DIAN leaders should consider creating small cohorts within this trial, and evaluating the combination of BACE inhibitors with low-dose repurposed medications in the cohorts to target DMN activity, to also measure whether amyloidogenesis and progression of disease can be altered by influencing the DMN.

    There are currently existing medication candidates available (Bakker A. et al. 2015, Musaeus CS et al. 2017, Gerhard T. et al. 2015, Mertens J. et al. 2015, Stern S. et al. 2017), which could target abnormal network activity, which have a known safety profile, which are inexpensive, which could be monitored, which could be ethically and safely administered at low doses for extended periods of time to DIAN participants; and which are reasonable candidates to test alongside, and in combination with, BACE inhibitors in long-term prevention trials.

    References:
    Alzheimer's Association National Plan Milestone Workgroup et al. 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease. Alzheimers Dement. 2014 Oct;10(5 Suppl):S430-52. PubMed: 25341459.

    Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015 Feb 21;7:688-98. PubMed: 25844322.

    Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 Jun;14(6):750-6. PubMed: 21532579.

    Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. PubMed: 16120771.

    Buckner RL, Andrews-Hanna JR, Schacter DL. The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008 Mar;1124:1-38. PubMed: 18400922.

    Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed: 16364896.

    Gerhard T, Devanand DP, Huang C, Crystal S, Olfson M. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry. 2015 Jul;207(1):46-51. 2015 Jan 22. PubMed: 25614530.

    Mertens J et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015 Nov 5;527(7576):95-9. Erratum in: Nature. 2016 Feb 11;530(7589):242. PubMed: 26524527.

    Musaeus CS, Shafi MM, Santarnecchi E, Herman ST, Press DZ. Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1065-1076. PubMed: 28527204.

    Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):676-82. PubMed: 11209064.

    Stern S et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. Mol Psychiatry. 2017 Feb 28. PubMed: 28242870.

    View all comments by James Wallace

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References

Series Citations

  1. DIAN: International Network to Chart AD Preclinical Decade

News Citations

  1. At Age 8, DIAN Is Churning Out Data and Growing into a Movement
  2. BACE Inhibitors Barrel Forward—Next Hurdles: Safety, Efficacy
  3. Research Brief: New BACE Inhibitor Joins the Fold
  4. At AD/PD Meeting, New BACE Inhibitor Struts Its Stuff
  5. Test Battery Picks Up Cognitive Decline in Normal Populations
  6. Test Tracks Preclinical Functional Decline
  7. DIAN Longitudinal Data Say Cognition Goes Earlier Than Previously Thought
  8. What Exactly Does BACE Do in Adults?
  9. Big Ginkgo Prevention Trial Comes Up Negative

Mutations Citations

  1. APP E693G (Arctic)
  2. APP E693Q (Dutch)

Paper Citations

  1. Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. Epub 2016 Mar 23 PubMed.

Further Reading

Primary Papers

  1. McDade E, Bateman RJ. Stop Alzheimer's before it starts. Nature. 2017 Jul 12;547(7662):153-155. PubMed.

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