Do Grinches hold back Hope in Alzheimer therapeutics? Is that why there are so few medications available? More on that later…
The prevailing Alzheimer’s Disease theory is that abnormal amyloid beta aggregates in the brain are the main culprit. Recently, a comprehensive molecular amyloid review was published, Hampel et al.: Nature Mol Psych Aug 2021, almost 400 citations. The abstract itself says “…the detailed molecular mechanisms…leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation…” [implying there’s still a lot to learn, or perhaps some uncertainty].
Hampel et al. reviewed scores of studies, from genetics to protein processing, including many in animal models, very compelling. It includes ideas about amyloid beta’s normal role, its toxicity, its soluble and plaque forms, interactions with tau, the APOE, cholinergic and glutamate systems, the possible role of glymphatic (waste processing) problems, and inflammation. There still seems to be a correlation issue, though, between finding amyloid in the brain and the expression of specific brain function problems (hippocampal atrophy is mentioned).
Single cause fallacy aside, others are questioning whether amyloid is the whole story. AD does not seem monogenic, like Spinal Muscular Atrophy. Despite the success of demonstrating findings at the molecular level, what is the bigger picture of how human clinical symptoms happen and progress? Are the amyloid beta findings a downstream issue? (The reviewers consider it upstream of neurodegeneration).
Compared to other conditions, there still seem to be a lot of questions about its initiation or on-going causality / pathophysiology, and this has garnered published skepticism. (Herrup: How Not to Study a Disease, MIT Press, Oct 2021, book review in Science Oct 2021; Nature paper 2015.)
Herrup does not dispute the amyloid science, but questions the primacy attributed to the “amyloid cascade hypothesis” (ACH), along with the focus on amyloid to the detraction of other ideas. In his 2015 review and opinion paper, with its 100 citations: “… Simply stated, you cannot produce an Alzheimer’s-like dementia by exposing a mammalian [mouse] brain to amyloid deposits…” [like a Koch’s postulate?]. He called for rejecting the ACH, and moving on.
Some have written that there must be some unknown factors for resilience, or resistance, (beyond the putative protection associated with some APOE alleles) against amyloid to account for the correlation problem; perhaps the protein tau, found tangled within neurons, is actually the critical factor in clinical symptoms. This implies that tackling tau might prevent clinical manifestations (therapeutics in this arena have failed so far). To some extent, these notions are also addressed by Hampel. But what drives the amyloid beta problem in the first place, and how / why does it spread as depicted in article?
Perhaps the most direct recent skepticism about the ACH appeared in an unsigned Sept 2021 editorial in EClinicalMedicine: “AD: Still in Need of a Cure!” It states “…molecular imaging based on [beta] amyloid plaques or tau tangles but not clinical symptoms, shows that patients tend to get diagnosed 3 times more often with AD but only a third will ever show any symptoms. This discrepancy sheds doubt on the involvement of [beta] amyloid plaques or tau tangles in the clinical manifestation, cause, and progression of AD.”
The editorial addresses the aducanumab FDA approval in June 2021. It basically dismisses the purported clinical effectiveness, presented to the FDA with statistical controversy; that approval lead to the resignation of several members of the expert advisory committee. British dementia researchers Liu and Howard wrote their opinion in Nature Sept 2021. They provide a timeline of the approval process. Another skeptical opinion in the popular literature: Drs. George and Whitehouse, “Alzheimer’s Inc:…Too Big to Fail”, Scientific American Aug 2021.
In support of the approval, Drs. Dunn, Stein and Cavazzoni of FDA leadership also wrote an editorial about the process, JAMA, July 2021. Some non-profits have supported the FDA approval. A board member at Us Against Alzheimer’s compared medical skeptics (some of whom have devoted their careers to solving AD) to the Grinch Who Stole Christmas, Sept 2021. He suggests skeptics are robbing Hope.
AlzGadfly understands how that writer might feel frustrated. This whole Gadfly blog is about the lack of real progress in Alzheimer therapeutics, especially compared to cancer and other areas of medicine. On the other hand, oncologists have to worry about giving patients false hope, and giving chemotherapy that could actually make things worse near the end, rather than better. And any pediatric oncologist (like old AlzGadfly) knows what it’s like to be considered a Grinch during the holidays, when making hard decisions with families.
Science usually creates some back and forth controversy, so that’s not at all unusual. Whether that energy can be harnessed for the greater good of persons living with dementia, with significant clinical impact, and soon, remains to be seen. So we may not need a Cindy Lou Who to save AD therapeutics, but more convincing approaches would be great.
