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Can we prevent Alzheimer’s disease?

I know that most of my patients, and likely most anyone who’s thought about the last decades of life, are more frightened of Alzheimer’s disease (AD) than of death itself. Alzheimer’s, which contributes to an estimated 60-70% of all dementia cases world-wide, robs from the afflicted not only their cognitive acuity but their core sense of who they are. It’s a scenario that is especially alarming for people who carry a specific gene mutation, the APOE4 allele -- having one copy increases the AD risk two-to-three times, having both copies up to twelve times. Meanwhile, the latest AD drug candidate, aducanumab, was turned down by the FDA two times, and only squeaked through the approval process on the third try despite scant evidence it provided any significant benefit. It was only the latest disappointment in an unbroken string of over 300 failed Alzheimer’s drug trials. 

This cumulative failure adds up to nothing less than a refutation of what for decades has been the prevailing theory that AD is primarily caused by the build-up of an aberrant protein, amyloid-beta, which clumps inside the neurons. What followed was the singular game plan to develop drugs that shrink these clumps, or plaques, improving symptoms and ultimately achieving an end goal of outright cure. But the plan flopped, unsurprisingly given that autopsy studies have shown that some people with normal cognitive function had just as much plaque as AD sufferers, and that some people with pronounced AD symptoms didn’t show an abnormal amyloid burden. Surely there is an association between amyloid and AD but it’s becoming increasingly clear that it’s more of a bystander in the disease process, less a cause than an effect.


If, by now, you’re tempted to stop reading, please don’t -- there is a silver lining here.


The problem with the amyloid theory of AD – besides being wrong – is that it crowded out potentially more promising approaches. Call it the latest iteration of the “streetlight effect” – recall the story of the drunk searching for his car keys under the streetlight, not because that’s where he dropped them but because that’s where the light was the best. Researchers are now moving beyond amyloid in their efforts to puzzle out the mechanisms behind AD, shining light in new places which, it’s not too much to hope, will yield better therapies.

For example, a California bio-tech start-up, NeuroAge Therapeutics, is working to identify disease bio-markers that it hopes will lead to a drug that can reprogram neurons to make them 'younger,' less susceptible to dysfunction and cell death."  

Likely, the most ambitious such effort places AD in the larger context of the biology of aging. Author and theorist Dr. Michael Fossel has proposed what he calls a “unified model of dementias.” He and a handful of like-minded researchers work “upstream” from AD, all the way back to the progressive shortening of our telomeres, one of the “hallmarks of aging.” Telomeres, you may recall, are the tips of our chromosomes which limit cell division in “mitotic” cells that divide frequently, including the glial cells protecting our neurons (which don’t divide). When their telomeres get too short, glial cells stop dividing and  become   senescent – that is, decrepit and dysfunctional – spitting out inflammatory molecules and/or altering gene expression (the turning on and off of specific  genes). This sets in motion the neurological changes that culminate in AD and, Fossel believes, other neurodegenerative diseases like Lewy body dementia and Parkinson’s.


Another fresh approach looks at AD as, at least in part, a metabolic disorder. The circumstantial evidence is abundant, for instance, type 2 diabetics have an over 50% greater risk of developing AD. The theory is that insulin resistance effectively starves the brain of the glucose fuel it needs to function, triggering the cascade of bad things that we know are associated with the disease: inflammation, oxidative stress, mitochondrial dysfunction. We can think of this metabolic perspective as a first cousin to vascular explanations of dementia emphasizing compromised blood flow in the brain. (In theory, so-called “vascular dementia” and AD are distinct diagnostic categories. In practice, they overlap.)   


The real world pay-off here is that we already know how to enhance metabolic and vascular health. In the absence of some wonder drug not currently on the horizon, the most powerful thing we can do to take care of the brain – and reduce our chances of developing Alzheimer’s or any other disabling form of cognitive impairment -- is to take care of the rest of the body. The prescription shouldn’t surprise you: plenty of exercise, a diet low in refined carbs and high in “good” fats and non-starchy vegetables, good sleep, keeping a lid on chronic stress. While all these elements are important, I can’t think of any “intervention” that offers more neuro-protective bang for the buck than exercise, including resistance exercise.   

Dr. Dale Bredesen, author of the best-selling The End of Alzheimer’s, has had an outsize influence promoting a “multi-modal” preventive health approach to the general public. Many in the medical establishment take issue with his broad claims and lack of methodological rigor (it’s not easy doing randomized clinical trials of lifestyle changes). But it is inarguable that the better you take care of yourself, the better positioned you’ll be to take advantage of a more efficacious generation of AD drugs when they do finally arrive.


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