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Friday, July 18, 2025
Dr. Brown: What Huntington’s teaches us about Alzheimer’s and other neurodegenerative diseases
"The lesson Huntington's teaches here is that this disease is biphasic. There’s a long asymptomatic period during which the number of CAG repeats rises slowly, during which treatment might be expected to be most effective in stopping the rise in the number of repeats," writes Dr. William Brown.

Huntington’s disease may be an uncommon cause of dementia, but at the cellular level has something important to teach us about other neurodegenerative diseases such as Alzheimer’s disease, frontotemporal degeneration and amyotrophic lateral sclerosis, commonly known as ALS.

Huntington’s is caused by a mutant gene which creates multiple repeats of a triplet of nucleotides: Cytosine, adenine and guanine. The number of repeats can vary in affected neurons from as few as twenty to several hundred.

Given that each CAG triplet codes for the amino acid glutamine, the result is that proteins coded by the Huntington’s gene become cluttered with far too many copies of the glutamine to function properly, and in the end, kill affected neurons.

That’s the story told by V. M. Rajagopal and Sarah Gelfman in their recent study “Accumulating gene errors drive Huntington’s disease,” in the March 20 issue of the journal Nature.

The authors suggest that Huntington’s disease begins with a long period lasting several decades during which the number of repeats in single brain cells remains less than 40 in patients even though they carry the abnormal Huntington’s gene.

However, much past 80 repeats, the number of repeats begins to rise steeply, and past 150 repeats, crosses a threshold beyond which the accumulating CAG repeats become toxic enough to kill brain cells.

The lesson Huntington’s teaches here is that this disease is biphasic. There’s a long asymptomatic period during which the number of CAG repeats rises slowly, during which treatment might be expected to be most effective in stopping the rise in the number of repeats.

However, once beyond the threshold for the number of repeats and treatment, however clever, might be too late.

That’s, of course, the argument for treating patients with Alzheimer’s disease as early as possible — when there are no clinical features of the disease, but biomarkers such as PET scans and assays for beta-amyloid and tau are positive.

However, treatment of Alzheimer’s by targeting accumulations of beta-amyloid and even tau proteins is controversial these days because the underlying amyloid hypothesis, which, guided the development of drugs for the last few decades, may be flawed and in need of a major rethink.

It’s not that monoclonal antibodies (mabs) designed to target accumulations of beta-amyloid don’t work — they do.

Almost all the drugs recently developed for Alzheimer’s manage to clear the brain of beta-amyloid well. The critical question centers on whether the accumulation of beta amyloid is a side show to a much more fundamental disorder affecting lysosomes in neurons as Professor Ralph Nixon of New York University suggests.

Controversial too is whether the current crop of drugs slows, never mind stops, cognitive decline in meaningful ways for patients with Alzheimer’s.

Compounding those key issues are growing questions about fraud in some of the clinical studies in Alzheimer’s, described in detail by Charles Piller in his 2025 book, “Doctored.”

These and problems highlighted by the New England Journal of Medicine about the manner in which some of these drugs were approved by the American Food and Drug Administration are serious enough to warrant review and hopefully prompt new hypotheses and treatments for Alzheimer’s.

The temptation to fib and fraud or even exaggerate claims isn’t new to medicine and science in general, but has become more common in recent years when pharmaceutical companies play outsized roles in designing, supervising and even writing the papers supporting their claims.

The reasons are clear: Developing new drugs is a very expensive business and companies stand to lose hundreds of millions, if not billions of dollars, if drugs fail in clinical trials.

Unfortunately, few physicians know enough about clinical trials design and analysis to critically review complex trials — hence the ceding of the heavy work to companies only too happy to lend a hand.

For much the same reasons, reviewing clinical trials requires a very professional review process, which takes a lot of time for the best journals to which manuscripts have been submitted for review.

The Huntington’s disease study was elegant, and the implications are important for other neurodegenerative diseases, such as Alzheimer’s disease, because the authors were able to show that at the cellular level, the impact of the disease was biphasic.

There is an initial long, slowly evolving course without symptoms, followed by a much shorter accelerated course associated with progressive cell death and symptoms and clinical progression.

That’s important because the window for successful treatment of neurodegenerative diseases is usually well before symptoms develop, and perhaps explains why treatments employed when the first symptoms develop may be too late to prevent progression of the disease.

Finally, given that the prevalence of diseases such as dementia reaches 30 to 50 per cent in the 80s and higher in the 90s, is the word disease even applicable, given that almost every system and organelle in cells begins to fail in late life?

Those failures are part of the cumulative wear and tear of life, and while the quality of life and even some longevity can be improved by lifestyle changes, in the end, there is an end.

No biological system is immortal — so far.

A good read on the subject of aging is the 2024 book, “Why We Die,” by Venki Ramakrishnan, who shared the Nobel Prize for work on the structure and function of ribosomes.

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. 

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