Last week, I highlighted the biphasic nature of the course of Huntington’s disease. There is an initial long asymptomatic period, which lasts several decades.

This is followed by the development of symptoms and signs, and steady progression thereafter to death. Such a course suggests a long period during which dysfunctional changes and losses of neurons accumulate, before passing a threshold beyond which pathophysiological changes accelerate and can no longer be masked by surviving nerve cells. 

In the peripheral nervous system, clinical findings related to motor nerve cell losses suggest that losses of motor nerve cells of up to 50 per cent may be masked by compensatory changes in the remaining cells in, for example, amyotrophic lateral sclerosis, known as ALS.

Translated, that means that by the time symptoms first develop in ALS affecting, for example, hand muscles, roughly half the related motor nerve cells may have been lost — irretrievable by any treatment. Roughly similar correspondence between cell numbers and symptoms probably holds true in Parkinson’s disease and affected systems in other neurodegenerative diseases. 

Clearly, the best way to treat neurodegenerative diseases would be as early as possible, before significant cell dysfunction changes and losses of neurons develop. That’s become the recent rationale for treating Alzheimer’s disease as early as possible, even well before the first symptoms and findings become evident.

The latter goal has become possible with the use of positron emission tomography (PET), measurement of biomarkers in the cerebrospinal fluid and genomic studies, especially for patients with family histories of dementia. But there’s a hitch.

It sounds great to treat as early as possible, but the drug had better be not only effective, but safe and free from troublesome side effects in patients who are clinically well. That’s a high bar to achieve.  

The trouble is that for decades, Alzheimer’s has been stuck with the amyloid hypothesis. In this model, the primary cause of the disease is thought to be the accumulation of toxic breakdown products of amyloid precursor protein (APP), such as beta-amyloid, with until recently, little attention paid to the accumulation of tau protein within nerve cells.

Instead, almost all the effort in the last few decades has gone into the amyloid wing of the hypothesis and the development of monoclonal antibodies designed to target beta-amyloid but not tau.

Since 2021, three drugs designed to target beta-amyloid were approved. The first aducanumab (2021) was mired in controversy and the other two, lecanemab (2023) and donanemab (2024), were marked by lacklustre clinical performance.

They certainly cleared the brains of affected patients of much of their beta-amyloid, but the sticking point was whether lecanemab and donanemab slowed clinical progression of their dementia in ways that were clinically obvious. 

Charlotte Teunissen, a neuroscientist at the Amsterdam University Medical Center, was quoted recently in Nature as stating, “A 30 per cent decline (in the rate with which cognition declined) does mean something — the difference between being able to have meaningful conversations with your children about their lives, or not.” 

Maybe so, but the results of the cognitive studies were not impressive and reason enough for many to be skeptical of the claims and more than sufficient reason to develop more promising approaches. 

One obvious approach is to treat patients with antibodies to not only beta-amyloid but tau as well. That’s a long overdue and promising approach and the subject of ongoing trials are also underway to treat people with laboratory but no clinical evidence of Alzheimer’s. That also makes sense to me. 

More promising may be clean sheet approaches based, for example, on the hypothesis that the accumulation of beta amyloid is an epiphenomenon of the disease, not the cause. 

For example, Ralph Norris, a New York University professor, suggests that Alzheimer’s disease may be caused by dysfunction of lysosomes in neurons. Lysosomes are cytoplasmic organelles responsible for enzymatically digesting food taken up by the cell and breaking down worn-out components in the cell, such as amyloid protein. 

Dogging the field on Alzheimer’s disease are recent claims of fraud by Charles Piller in his 2025 book, “Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s” and the related book review by Carl Elliot in the highly regarded journal Science, entitled “A scientific field, misled: Fraud undermines Alzheimer’s disease research.”

These are not easy days in Alzheimer’s disease, and such a tragedy if the accusations turn out to be even partially right. 

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.