Plowey ED, Bussiere T, Rajagovindan R, Sebalusky J, Hamann S, von Hehn C, Castrillo-Viguera C, Sandrock A, Budd Haeberlein S, van Dyck CH, Huttner A. Alzheimer disease neuropathology in a patient previously treated with aducanumab. Acta Neuropathol. 2022 Jul;144(1):143-153. Epub 2022 May 17 PubMed.
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University of Southampton
University of Southampton, Faculty of Medicine
The anti-Aβ antibody aducanumab (Biogen), which binds aggregated species of Aβ, has recently been approved for clinical use in the U.S. by the FDA (as Aduhelm). This decision seems to have been largely based on an impressively reduced signal on amyloid PET scans for many patients. Despite thousands of patients having received aducanumab in the clinical trials leading up to this decision, knowledge of the corresponding changes in brain tissue has been lacking. This paper by Edward Plowey and colleagues from Biogen and Yale, published in Acta Neuropathologica, is the first to describe the neuropathological findings in a patient shown to have had a reduction in PET amyloid signal after treatment with aducanumab.
The patient studied was diagnosed clinically with AD, enrolled in the PRIME study and randomized to the placebo arm, but then received 32 monthly doses of aducanumab in a long-term extension of the trial. Amyloid PET scans showed extensive amyloid in her brain at initial screening, little change during the phase in which she received placebo, and then a substantial lowering of the amyloid signal after she was treated with aducanumab. MRI scans showed no evidence of amyloid-related imaging abnormalities (ARIA). She passed away four months after her last dose of aducanumab.
Postmortem studies confirmed the presence of AD neuropathological changes with significant phosphorylated tau (ptau) accumulation (Braak stage V, NIA/AA stage B3) and no comorbid neuropathology. However, the Aβ plaque density was markedly lower than in untreated AD cases (0.17 percent vs. 5 to 10 percent). In addition, there were morphological features consistent with substantial plaque removal including sparse residual Aβ plaques comprising predominantly dense cores that lacked surrounding non-compact Aβ, moth-eaten plaques, and reactive amoeboid microglia closely associated with residual plaques. Cerebral amyloid angiopathy was present even in cortical areas without remaining plaques. There was no evidence of Aβ-related angiitis or microbleeds, putatively the pathologies underlying ARIA.
Although neuronal ptau accumulation was extensive (Braak stage V/VI), the ptau burden was substantially lower than in untreated AD cases, in particular with a reduction in plaque-associated ptau-positive dystrophic neurites. This finding supports the amyloid cascade hypothesis of AD, which puts tau accumulation downstream of Aβ pathology.
Remarkably, as the authors point out, the changes described in this patient treated with aducanumab correspond very closely to the changes in patients actively immunized against Aβ with AN1792 in the first AD immunotherapy trial (Elan Pharmaceuticals). Any differences seem minor and could be due to the interval between the exposure to anti-Aβ antibodies and the neuropathological examination, other individual factors such as ApoE genotype, as well as the agent employed.
Comparison of neuropathological changes after treatment with aducanumab and AN1792
*Aβ within microglia was not described in the patient treated with aducanumab, although the presence of amoeboid-activated microglia clustered around residual plaques was interpreted as indicating that Fc-receptor-mediated phagocytosis is a significant clearance mechanism.
More neuropathological studies are needed to better understand the changes in AD pathology induced by Aβ immunotherapy. The best way to facilitate this would be to build a neuropathology component into the clinical trials allowing the participants the opportunity to consent. In particular, there is a need to clarify the pathological changes causing ARIA, which occurs frequently with aducanumab, and also to identify correlates of alterations in cognitive function. Better understanding of these and other factors is especially important now that treatment with aducanumab has been approved for clinical use in the U.S.
Despite plaque removal, both this aducanumab-treated AD patient and AD patients treated with AN1792 continued to progress in terms of cognitive decline. Although caution should be applied in drawing conclusions from small numbers of cases, we have suggested that this may be due to continued prion-like spread of tau through the cerebral cortex. If so, this implies that Aβ-targeted therapies would be best employed before there is significant cortical tau accumulation, which would necessarily be in asymptomatic subjects. It is difficult to envisage passive immunotherapy, requiring regular infusions or injections, being used in asymptomatic subjects for the prevention of AD. We therefore encourage further exploration of active Aβ immunization as prevention, before the onset of symptomatic AD.
Declaration: JN has received compensation as a consultant to Biogen in relation to AB immunization studies.
References:
Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol. 2006 Nov;65(11):1040-8. PubMed.
Zotova E, Holmes C, Johnston D, Neal JW, Nicoll JA, Boche D. Microglial alterations in human Alzheimer's disease following Aβ42 immunization. Neuropathol Appl Neurobiol. 2011 Aug;37(5):513-24. PubMed.
Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain. 2008 Dec;131(Pt 12):3299-310. PubMed.
Boche D, Donald J, Love S, Harris S, Neal JW, Holmes C, Nicoll JA. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease. Acta Neuropathol. 2010 Jul;120(1):13-20. PubMed.
Nicoll JA, Buckland GR, Harrison CH, Page A, Harris S, Love S, Neal JW, Holmes C, Boche D. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease. Brain. 2019 Jul 1;142(7):2113-2126. 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.
Washington University
In this paper, the authors assess the neuropathology of a woman who had received 32 monthly doses of Aducanumab after first being in the placebo arm of the Phase Ib study. Longitudinal amyloid imaging during life revealed that she initially had a very high SUVR, which changed over time following treatment to values that are considered amyloid-negative. At postmortem, the amount of Aβ immunoreactivity and fibrillar plaques were virtually absent, consistent with the amyloid imaging result.
What was perhaps more striking is that while her Braak (tau stage) was high (stage V), her anti-p-tau staining throughout the cortical neuropil was much lower than several other AD cases at Braak stage V. This is consistent with the idea that removing amyloid could also decrease downstream tau pathology to some extent.
Interestingly, and consistent with mouse studies and human studies with other anti-amyloid antibodies that are capable of removing plaques, there was still abundant CAA, suggesting that this type of anti-amyloid antibody is incapable of removing amyloid around arteries/arterioles. These results are very similar to what was reported by Nicoll and colleagues in 2006 when assessing the neuropathology of patients following active immunization with Aβ.
While clinical trials with several anti-amyloid antibodies in very mild to mild dementia due to AD are suggesting that there may be a modest slowing of decline in cognitive function, what is illustrated in the active and passive immunization studies is that at this stage of disease, even if one can remove amyloid, the neocortical tau phase has already started in many individuals. While these treatments may be able to lessen the progression/amount of tau pathology as illustrated here, they don’t appear to be able to remove it.
As tau pathology strongly correlates with neurodegeneration, this is important. These findings and a host of other data strongly suggest that active or passive immunization—or any therapy that can prevent or remove amyloid—will have a much better chance of having much greater effects in slowing/preventing neurodegeneration and cognitive decline if they are started before significant tau and other downstream pathologies are prominent.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School
In general, this sounds very much like the AN1792 effect on AD pathology and bodes well for biomarkers as good indicators of what is going on in the brain. It would be interesting to know if blood-based biomarkers also showed changes consistent with the pathology. Aβ was removed and some p-tau lowering was observed, especially in neuritic plaques, but CAA remained, possibly due to an ongoing Aβ removal process and/or lower affinity of the antibody for vascular amyloid?
These data support the idea that Aβ deposition occurs first and is followed later by p-tau pathology. Therefore, it makes sense to start an anti-amyloid therapy before the p-tau ball starts rolling if one wants to see a stronger clinical benefit, as p-tau is a closer correlate of cognitive decline.
I completely agree that these results, together with the AN1792 results, suggest AD prevention may be possible if anti-amyloid immunotherapy is given during the preclinical stage of AD, prior to p-tau accumulation (Lemere and Masliah, 2010). Primary and secondary prevention trials underway in people with early onset familial AD due to a mutation in APP or PSEN will hopefully answer this question.
Would an anti-amyloid mAβ be useful for prevention, i.e., in this early preclinical phase of A+T-N- or even earlier, before Aβ deposition? I lean more toward active immunization for prevention, as it is less costly, easier to administer, requires much less frequent dosing, and will generate an array of polyclonal anti-amyloid antibodies. Also, I believe ARIA will be much less likely to occur in someone with no or very little amyloid in their brain. Thus, the side effects would likely be lower.
Over the past 20 years, our group and others have found ways to improve the safety of an anti-amyloid active vaccine by targeting the B cell epitope and avoiding an Aβ-specific T cell epitope. Several active vaccines are currently under development or in testing, e.g., AC Immune’s ACI-24, Michael Agadjanyan’s DNA vaccine, and Thomas Bayer’s neoepitope Aβ vaccine that generates antibodies to pGlu3 Aβ and Aβ starting at residue 4.
If there was a cheaper, easier way to administer an anti-amyloid antibody, maybe by gene therapy, and if it was specific to a particular pathogenic form, such as a pGlu3 Aβ “seed,” it might be suitable for prevention, too, and might have the advantage of only lowering pathogenic species, not all forms of Aβ. To my knowledge, such an antibody treatment does not yet exist.
For decades, I have stated that I can see, someday in the future, people going to their doctor at 40 years of age to get their anti-amyloid vaccine. In my opinion, that is how we are going to prevent AD. By that I do not mean all types of dementia; other causes of dementia will not be affected by such a vaccine.
Going forward, I agree with Drs. Nicoll and Boche that we need to better understand the pathology underlying ARIA. We are working on this now in animal models, but human pathology studies are going to be very important. Also, finding fluid biomarker changes associated with ARIA may help us to understand the mechanism(s) of its occurrence.
References:
Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy?. Nat Rev Neurol. 2010 Feb;6(2):108-19. PubMed.
Dementia Reserch Center
Given the tremendous and persistent commitment of patients and their families in these trials—repeated infusions, MRI, PET scans, LPs, etc.—and the huge investment of money and time, it is important that efforts are made to understand fully the effects of therapies, including the histopathological effects, as reported here by Plowey and colleagues. It feels a wasted opportunity that we so often lack this valuable data.
It is remarkable to think that it is over 25 years since the first-ever demonstration that the pathology of Alzheimer’s disease could be modified—and yet we have relatively few pathological reports. In the first 100 years after Alzheimer’s first description of plaques and tangles, the relentless course of pathological accumulation just ran its unmodified course in countless patients.
Then, with the AN1792 vaccination studies, pioneered by Dale Schenk and others, we saw that amyloid immunotherapy could at least achieve “target engagement” with in vivo evidence of titer-dependent brain volume changes and the “meningoencephalitis” that halted the trial. This was followed by detailed neuropathological studies that demonstrated patchy amyloid clearance described by James Nicoll, Delpine Boche and colleagues (Nicoll et al., 2003). This clearly was modification of pathology, albeit in a variable, uncontrolled manner and without evidence of clinical benefit.
Over the last decades, this modification of pathology has been repeatedly shown with amyloid and tau PET and with fluid biomarkers. Judging by amyloid PET fibrillary amyloid pathology, at least, can effectively be “cleared,” and by several therapies, e.g. donanemab, lecanemab, gantenerumab etc.
“Alzheimer pathology” is modifiable and we can “see” the time course.
While demonstration of clinical benefit is the key arbiter, wouldn’t it be valuable to have more pathological examination of the effects of therapy on the brain with linked clinical and dosing data. Perhaps particularly in early phase studies to guide later phase design.
Interpretation would be much more powerful if we had results from reasonable numbers of treated and untreated cases, and could facilitate comparisons between different therapies. These studies could help understand the mechanism and routes by which amyloid is cleared. Autopsies from those in active treatment might help characterize ARIA or other effects.
Families certainly recognize the importance of brain donation and of pathological examination, and would want to maximize the information that can be gained from their involvement in trials.
References:
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
Michigan State University
The study by Plowey et al., albeit limited to a single case, is highly suggestive that the processes observed in mice treated with anti-Aβ antibodies was predictive of the response in humans. The “therapeutic” studies, starting treatment in mice with already well-established amyloid deposits, of amyloid immunotherapy demonstrated considerable clearance of amyloid, with opsonization and microglia phagocytosis playing a significant role (Morgan, 2011; Wilcock et al., 2004).
One difference in Plowey et al. from preclinical work is the absence of evidence for increased vascular deposits derived from cleared parenchymal plaques. This suggests that the titration dosing regimen may have been successful in avoiding enhanced angiopathy in this individual.
Perhaps most remarkable are the striking reductions in p-tau staining, not only of perikarya, but most dramatically in the neuropil staining. Anti-tau actions were rarely studied in mice because little tauopathy was evident in the amyloid models.
The recent plasma biomarker studies for aducanumab and donanemab are consistent with this reduction. If true, this is counter the perspective that tauopathy, once initiated, might become self-propagating independent of amyloid. Additionally, this would imply that tauopathy is reversible, like amyloid.
A final comment regards the continued cognitive decline. Recent work from the ROSMAP studies at Rush indicate that amyloid only accounts for 35 percent of the variance in cognitive decline in older adults (Boyle et al., 2019). Thus, a slowing, not arrest, of cognitive decline may be exactly what we should expect from successful anti-amyloid therapy.
References:
Boyle PA, Yu L, Leurgans SE, Wilson RS, Brookmeyer R, Schneider JA, Bennett DA. Attributable risk of Alzheimer's dementia attributed to age-related neuropathologies. Ann Neurol. 2019 Jan;85(1):114-124. Epub 2018 Dec 19 PubMed.
Morgan D. Immunotherapy for Alzheimer's disease. J Intern Med. 2011 Jan;269(1):54-63. PubMed.
Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004 Dec 8;1(1):24. PubMed.
Vice President, The Institute for Molecular Medicine
This interesting paper on the study participant passively vaccinated with aducanumab, and published results on AN-1792 trials elegantly outlined by Nicoll and Boche, further supports the modern version of the amyloid-cascade hypothesis, suggesting that accumulation of pathological Aβ precedes tau pathology and cognitive decline by decades. These data, along with other Aβ immunotherapy clinical studies using brain and fluid biomarkers, demonstrated that accumulation of pathological tau, but not Aβ, correlates with the onset of clinical symptoms, progression, and severity of disease. Importantly, accumulated evidence indicates that Aβ and tau do not act in isolation. Instead, there is significant crosstalk between these two molecules, with most studies demonstrating that Aβ pathology can accelerate hyperphosphorylation and accumulation of pathological tau and onset of the disease.
Thus, Plowey et al.'s data, along with clinical results from other passive vaccination and the AN-1792 trials, support our long-standing tenet that effective anti-Aβ antibodies should be used as a preventive measure in cognitively unimpaired people rather than as a treatment for MCI subjects and AD patients. However, I need to mention that AN1792 vaccine responders had anti-Aβ antibody titers of ≥1:2200 (a few had titers of 1:10000 or more). That is much less than after passive administration of aducanumab (6 mg/kg per each injection and a cumulative dose of 186 mg/kg).
Remarkably, even these relatively low anti-AN-1792 antibody titers were sufficient for reduction of Aβ and keeping people plaque-free for up to 14 years after vaccination. Hence, an immunogenic active vaccine inducing steady long-term production of antibodies and, as we should expect, memory B cells specific to pathological amyloid, is more effective than frequent (monthly) intravenous administrations of high concentrations (6-10 mg/kg each time) of very expensive fully human or humanized monoclonal antibodies in a large population of cognitively unimpaired people at risk of AD.
In sum, an immunogenic Aβ vaccine, like most approved human vaccines, will likely be effective as a prophylactic measure rather than a therapeutic treatment. Immunizations of asymptomatic people at risk of AD with such a safe vaccine could inhibit aggregation of Aβ, and delay the accumulation of pathological tau and the onset of AD. This strategy, based on the amyloid hypothesis and Dale Schenk's pioneering study, may also open the window of opportunity for the preventive tau vaccine or Aβ/tau dual vaccine aiming to slow down further tau propagation/accumulation in the brains of cognitively unimpaired people and AD progression.
Implementation of such a strategy that might delay, but not fully prevent, disease onset, requires accurate prognostic/predictive plasma biomarkers based on the measurement of pathological soluble forms of Aβ/tau (e.g., C2N and Quanterix antigenic assays) or antibody concentrations (different immunoassays) against these molecules.
TrueBinding
These are interesting findings. Investigating therapeutic efficacy either by active or passive immunization of Aβ using transgenic mouse models is different than comparing in humans. Nine years ago, we published that systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice (Rasool et al., 2013).
Aducanumab binds aggregated forms of Aβ, and dose-dependent incidences of ARIA were reported from the trials, highest in ApoE ε4 carriers (Sevigny et al., 2016; Salloway et al., 2022). However, many investigational therapies currently or previously investigated in clinical studies of AD are anti-Aβ drugs, mostly mAbs targeting accumulation of Aβ peptide. All these trials failed to meet clinical efficacy endpoints, although some have shown efficacy in patient subtypes and demonstrated an acceptable safety and tolerability profile (Panza et al., 2019; Van Dyck, 2018). The first immunotherapy for AD by Elan's AN-1792 was halted as 6 percent of patients suffered from various side effects.
Going forward, the most valuable point is how to avoid auto-inflammatory side effects like microhemorrhage or meningoencephalitis.
References:
Rasool S, Martinez-Coria H, Wu JW, Laferla F, Glabe CG. Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice. J Neurochem. 2013 Aug;126(4):473-82. PubMed.
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.
Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, Suhy J, Forrestal F, Tian Y, Umans K, Wang G, Singhal P, Budd Haeberlein S, Smirnakis K. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. 2022 Jan 1;79(1):13-21. PubMed.
Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019 Feb;15(2):73-88. PubMed.
van Dyck CH. Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise. Biol Psychiatry. 2018 Feb 15;83(4):311-319. Epub 2017 Aug 24 PubMed.
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