Amyloid Hypothesis & the Treatment of Alzheimer's Disease

Few scientific hypotheses have achieved more press than the “Amyloid Hypothesis” in the last decade, with headlines ranging from “hoax” to “breakthrough.” Did the media report on the science in such a way as to build it up just to tear it down like Hollywood fame, or is this a coming-of-age story of a theory withstanding scrutiny?

Alzheimer’s Disease (AD) originates from a case presented in 1906 at the Congress of Psychiatrists of Southern Germany by Dr. Alois Alzheimer, a rare ~at least for the early 1900s~ psychiatrist-pathologist hybrid specialist. In the presentation, Dr. Alzheimer told the story of a 50-year-old woman suffering from worsening sleep and memory disturbances, aggressive outbursts, and confusion until her death five years later. Her autopsy (by Dr. Alzheimer) noted distinctive, abnormal “clumps” (now identified as amyloid plaques), “tangled bundles” of fibers (now called neurofibrillary or tau tangles), and “adipose saccules” (lipid droplets) in the brain under a microscope. Several follow-up cases in the decade thereafter demonstrated rough parallels between abnormal microscopic brain findings and the symptoms previously described, and both were associated with advanced age for that time (>40 years old). Today, over a century later, the diagnostic criteria for Alzheimer’s disease are still generally based on the same correlations identified by Dr. Alzheimer in 1906. Worldwide life expectancy, however, has dramatically increased from ~45 to ~73 years old, empowering the age-associated progression of the devastating disease to play out global, widespread scale.

Demographic aging has driven and will continue to drive the ever-increasing disease burden, particularly in developed countries. Most estimates of the total Alzheimer’s drug market fall between $6-9 billion dollars. By 2050, the number of Americans living with Alzheimer’s is expected to reach 12.7 million, bringing the total economic burden to nearly $1 trillion yearly. Clearly, the clinical need and market are there. To that end, it's not so much uncertainty around the light at the end of the tunnel for biotechnology/pharmaceutical companies but rather the vast graveyard of failed drugs and hazy disease mapping along the path that has deterred pursuit by pharmaceutical and biotechnology companies. What they find most daunting is the uncertain underlying root cause of the disease. Although Dr. Alzheimer described the correlation of disease symptoms with the plaques, tangles, and droplets, the observational studies didn’t evaluate which, if any, of these features was a causal driver of disease. Could they be true, true but unrelated? To some degree, the current state of classification still resembles the ambiguity of its origin.

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The “amyloid hypothesis” of Alzheimer’s Disease (AD) is just that – a hypothetical proposition, albeit the leading hypothesis, made based on a limited collage of evidence suggesting that the relationship between amyloid accumulation and cognitive decline is causal. The rest of the disease process is proposed to result from amyloid accumulation stemming from an imbalance between amyloid production and amyloid- clearance.

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In 2006, the amyloid hypothesis took center stage after a series of experiments conducted in the 2000s, led by, Lesné and his colleagues’ Nature?publication, demonstrated that a particular amyloid derivative (Aβ*56) impairs memory/cognitive function independently of plaques or neuronal loss characteristic of AD in mice models. This drove further academic and commercial investment into this hypothesis over those competing.

Then, in 2014, Biogen reported data from the phase 1b (dose escalation) PRIME trial for its newest anti-amyloid antibody, aducanumab, that enhanced the clearance of amyloid from the brain. The study demonstrated a dose-dependent reduction in brain amyloid burden measured by amyloid imaging scans accompanied by a slowing of cognitive decline among those receiving the highest dose of the drug.

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The amyloid hypothesis soon fell out of favor with Biogen’s follow-on large phase III trials, ENGAGE and EMERGE. On the planned interim futility analyses review, the ENGAGE study was “unlikely to meet primary endpoints,” but the EMERGE study was “trending positive.” However, because they had specified in their statistical analysis plan that both studies had to meet their primary objectives to be considered successful, both trials were stopped to save time and money. After the trials were stopped, no new patients were enrolled, but those who were already randomized were allowed to continue therapy if they wanted.

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But there's more… months later and seemingly out of the blue, Biogen announced that further analysis had revealed a positive signal in the EMERGE study and was seeking regulatory approval from the FDA. Patients receiving the highest drug dose demonstrated a significant reduction in amyloid burden. Ultimately, they met the primary endpoint of clinical efficacy with a modest slowing of cognitive decline by clinical assessment.

This resurgence of the amyloid hypothesis has been tempered by the disputes rooted in the unconventional approval of aducanumab according to a biomarker that lacks consensus regarding its causal role in AD. The cost of the drug has also been a point of controversy. Combining questionable reliability with top-dollar prices is a surefire way to spark fuss in any industry, including healthcare.

Furthermore, Lesné’s 2006?Nature?paper that supported the basis of this causal claim had been brought into question regarding its scientific integrity regarding allegations of image tampering. Of note, these recent events don’t necessarily debunk the amyloid hypothesis but decrease our degree of certainty in its claims for establishing causality between amyloid and cognitive decline.

Overall, more than 10 different anti-amyloid agents have failed in large phase 3 trials, while dozens more have failed in smaller trials. There are several potential explanations for these failures. One is the drugs themselves, as none of these early agents showed the ability to effectively remove amyloid plaques, and several had serious side effects. Another is trial designs, as these studies enrolled patients without evidence of amyloid pathology and targeted patients with more advanced symptomatic AD, which is perhaps too late for intervention. Finally, these failures could suggest that that amyloid is not an ideal therapeutic target for symptomatic AD. All in all, the roller coaster ride of the amyloid hypothesis has had its ups and downs, but each hypothesis iteration, in theory, brings us closer to the truth.

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Jordan Baechle?is a physician-scientist and post-doctoral fellow at the?Buck Institute for Research on Aging?focused on bridging scientific discovery and innovation to patient and consumer care in aging, Biotechnology?Foresight?Fellow, and Go-to-market Scientific Advisor at?Jung

*This is not medical or investing advice.