Success of anti-amyloid therapy answers few but raises many questions

The success of anti-amyloid mono-clonal antibodies (MAB) in Alzheimer’s disease (AD) is a remarkable breakthrough in research in neurodegenerative disorders and offers hope for millions of sufferers. It establishes the role of protein aggregation as the prime-mover of neurodegeneration. The ‘amyloid-cascade hypothesis’was criticized because amyloid plaques were omnipresent in post-mortem brain in cognitively healthy individuals, and no correlation was demonstrated with distribution and load of plaque with pattern and severity of cognitive impairment. Opponents also argue that there are several other patho-mechanisms including tau hyperphosphorylation, oxidative stress, inflammation, defective cerebral glucose metabolism, vascular pathology, mitochondrial dysfunctions, etc. which also play some role in disease pathogenesis. However, clinical improvement through Alzheimer’s Disease Assessment Scale (ADAS-Cog13) and ADCS-iADL (the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory) in tandem with plaque removal with use of donanemab,[1] suggests that amyloid lowering in the earlier stages of the disease is likely to produce clinical benefit and also establishes the role of amyloid in the orchestration of Alzheimer’s pathogenesis. In the Traiblazer-Alz 2 study donanemab significantly slowed clinical progression at 76 weeks in early symptomatic AD and amyloid and tau pathology in those with low/medium tau and in the combined low/medium and high tau pathology population.[2] There were several setbacks before the first success with aducanumab in 2023. Pharmaceutical industries invested several million USD to get a breakthrough and amyloid was their best bet. The fascinating hypothesis, with amyloid as the primary culprit was chased by several companies before being successful in clinical trials. However, Alzheimer’s drug discovery was marred with unprecedented controversies.[3] While many anti-amyloid MABs have failed, a few have succeeded in clinical trials and this has been linked to the rate and degree of amyloid removal from the brain.[4] The Clarity AD study for lecanemab[5] and Traiblazer-Alz 2 for donanemab[2] showed clear benefit for patients with early symptomatic AD and these two drugs received full approval from US FDA. They are currently being used in several countries including USA and Japan. These drugs are yet to be available in India and many other countries in low and medium income countries (LMICs) where majority of the AD patients live. Cost is one of the limiting factors for the use in these countries, apart from the availability of biomarkers which are essential to immunotherapy. Beside these, there are several other problems for regular use of anti-amyloid MABs in clinical practice. The agents were used in subjects with clinical diagnosis of mild cognitive impairment (MCI) and early AD who were biomarker positive. Here lies the problem of using these agents, since image-based biomarkers are not widely available and lumbar puncture for testing cerebrospinal fluid (CSF) biomarkers is difficult for many elderly individuals. Efforts to replace these with more easily accessible plasma-based biomarkers are currently being explored. For this, plasma-based biomarkers need to undergo further studies in diverse ethnic populations for determining cut-off level to discriminate diseased from healthy individuals. Amyloid-related imaging abnormalities (ARIA), the adverse effect encountered in all anti-amyloid MABs are linked to several factors including ApoE4 carriers, cerebral amyloid angiopathy, and presence of microhemorrhages[6] and also in African descends in some earlier clinical trials. Another issue of MABs regular use in subjects of AD lies the unavailability of randomized controlled trials of these agents in diverse ethnic populations. Testing in all racial and ethnic populations is essential to prove the effectiveness as well as safety of these agents and to provide confidence to the clinician to use them across the globe. In clinical practice, many individuals carry mixed pathologies in their brain, e.g. alpha-synuclein, TDP-43 and vascular pathologies often coexist with amyloid plaques. It would also be interesting to know how these anti-amyloid MABs do in such patients. These MABs have been tested in selected individuals with late-onset typical AD. However, around 20-30% of AD subjects can have atypical clinical phenotype, and it is argued that these individuals carry pure AD pathologies in their brain.[7] Anti-amyloid antibodies also need to be tested in these atypical AD subjects. The success of anti-amyloid MABs was based with the strong determination that removal of amyloid from brain would result in clinical improvement. This came from changes in our concept of AD pathogenesis. In 2007, the International Working Group (IWG) revised the 1984 diagnostic criteria for AD and was the first to propose that the diagnosis of AD in patients with cognitive deficits could be anchored around the presence of biomarkers to support more accurate and earlier disease diagnosis.[8] The biological construct of the disease came from prospective study of disease biology along with cognitive changes in dominantly inherited Alzheimer’s network (DIAN) coupled with discoveries of image-based and fluid-based biomarkers.[9] It is said that AD pathology start growing in the brain decades before symptom onset, and amyloid (A) deposition is the primary and initial event, followed by deposition of tau (T) and subsequent neurodegeneration (N), the basis for ATN framework. To accommodate the contribution of other factors, an X is added to this framework that signifies all others including neuroimmune dysregulation, synaptic dysfunction and blood-brain barrier alterations, etc.[10] Since amyloid is not the only agent involved in disease pathogenesis, we expect more effective pharmaceutical agents targeting these diverse patho-mechanisms in the near future for treating the disease. As in many other diseases like infection, cancer, etc. multiple agents with different targets would be an effective treatment strategy in future. In the logical conclusion of this framework, it is now argued that AD is a continuum from presymtomatic stage to clinically overt dementia. The biological construct gave the strong foundation to test anti-amyloid MABs in early symptomatic individuals. This also justifies the logic of preserving cognition before much of neurodegeneration happens. However, while it is important to ‘catch those young’ the proposition is going far beyond that, making an AD diagnosis in asymptomatic individuals. This however raises several questions, which would be difficult to address. Logically, an elderly might carry amyloid and tau pathology in his brain without throwing an iota of symptoms. Can we ethically label them having Alzheimer’s disease? This carries the risk of social discrimination for employment, promotion, and insurance with additional psychological stress, notwithstanding. There is more dilemma for the physicians, how to treat them. Removing amyloid and tau from brain are justified to prevent inevitable neurodegeneration. But, to prove that removal would be beneficial, prospective interventional studies are needed. Some of these questions hopefully, may be answered in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study and a companion to the ground-breaking Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.[11] We will be eagerly waiting how things will unfold in next few years. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.