COMMENTARY

The Prevention of Alzheimer's Disease Probably Won't Come in a Pill Bottle

Michael Merzenich, PhD

Disclosures

September 19, 2022

Many exceptional scientists have dedicated their professional lives to understanding Alzheimer's disease. Numerous theories and research threads have been pursued, at great expense, on the path to an estimated 150-300 failed drug interventions. My bet is that our triumph over Alzheimer's will come in the next decade, but not from a pill bottle.

Finding the Cause of Alzheimer's Disease

Michael Merzenich, PhD

The search for a cause began in earnest with the recognition of the true nature of "plaques" and "tangles," the signature pathologic markers of Alzheimer's. Plaques were found to comprise clumps of amyloid protein that disable, then "kill," nearby brain cells. Tangles, developed through the aberrant polymerization of a protein (tau), destroyed the functionality of brain connections. Scientists came to believe that we could "cure" the disease by preventing the formation of these plaques and tangles.

If it could only have been so simple.

Then came the immune response theories. Some argued that the aging brain, challenged by infectious agents or tissue breakdown, makes too much soluble amyloid. They pointed to a leaky blood-brain barrier, which allowed infectious agents to invade the brain tissues.

Still others believed that the core issue was an inadequate immune response. They cited studies showing that a key agent that regulates the immune response, noradrenaline, is in short supply in the brains of patients with Alzheimer's, contributing to the inadequate clearance of soluble amyloid.

But then the focus was on acetylcholine, a key modulator of brain plasticity that was also shown to decline in the brain of people with Alzheimer's. Other experts honed in on the greatly reduced coupling of blood flow to levels of brain activity — what scientists call "reactive hyperemia."

Are you exhausted yet? I haven't even discussed tangles in detail, or the genetic factors associated with Alzheimer's.

To add to the confusion, many of these pathologic markers only poorly relate to the behavioral deficits that characterize the disease. Some people with lots of plaques and tangles and other pathologic markers at autopsy were doing just fine at the time they died. Yet, others with few plaques and tangles turned out to be in serious trouble.

This leads us to a very important question: Which of these is the correct target for the development of novel therapeutic interventions?

The answer: Every single one of them and more.

This often-occurring, natural, programmed self-destruction of the brain that we call Alzheimer's disease is a result of broadly deteriorating organic brain health, and that's probably why drug development has been so hard. Treating just one piece of this multifaceted brain health deterioration is inadequate to arrest or reverse the decline.

The Role of Cognitive Reserve

But what about those people who have many biomarkers of brain health decline, yet don't express the behavioral symptoms of Alzheimer's? What's their secret?

Pathologists have a term for this mysterious factor that forestalls the development of Alzheimer's disease in some: They call it "cognitive reserve." I call it "organic brain health."

Growing your cognitive reserve and actively managing your organic brain health should be high on the list of Alzheimer's prevention strategies. How can you do that?

The most popular approaches aim to prevent this brain disease much as we now try to prevent heart disease — with a multimodal approach focused on modifiable behavioral risks. In the case of Alzheimer's research, those interventions tend to include brain training, physical exercise, and nutrition.

A Multimodal Approach

The FINGER study, from Finland, used a structured program of brain training, a brain-healthy diet, physical exercise, and vascular risk monitoring. The initial results were exciting. FINGER showed a 25% larger cognitive improvement in the treatment group compared with a control group receiving general health advice. A similar multimodal behavioral intervention study conducted in in Australia found a clinically significant reduction on a well-validated dementia risk scale.

These studies enrolled people at risk for dementia, raising the possibility that clinically validated treatment protocols using only behavioral interventions may be the most promising for dementia prevention — and perhaps even treatment.

A next generation of FINGER-like studies are now underway all over the world, including the US POINTER Study.

Virtually all of these studies include brain training, which has been a primary focus of my own scientific work for the past 25 years.

Brain Training

Brain training directly improves the organic health of the brain. Stronger brain activation and improved functional connectivity across brain regions are seen on functional MRI studies after brain training, and EEG studies show improved information processing speed.

The ACTIVE study, which tracked more than 2800 older adults for 10 years, found that those in the brain training arm showed a 29% reduction in dementia risk compared with the control group. This was with a miniscule 10-18 hours of brain training in total over the decade, on a particularly important type of exercise (so-called "speed of processing" training). Those who trained more than others had still larger reductions in dementia incidence.

This explosion in research on modifiable risk factors for Alzheimer's is a blessing. The Lancet Commission estimates that 40% of dementia cases could be prevented or delayed by addressing 12 known lifestyle risk factors. I believe that this greatly understates the potential benefits of more complete and controlled management of brain health in older adults.

Finally…

You may have detected my frustration over our long, expensive journey to halt Alzheimer's with a myopic focus on finding a magic molecule to address plaques, tangles, or the laundry list of potential causes.

That frustration is not directed toward the well-intentioned researchers involved in those efforts. It is addressed to the devastating disease itself. Like most of you reading this column, I have lost loved ones to it, including my mother.

It's an exciting time now in Alzheimer's research. Finally, there is a growing appreciation that there will not be a single silver bullet. It will take an integrated approach to actively manage our brain health with evidence-based interventions. And the faster we get there, the better.

Michael Merzenich, PhD, is often credited with discovering lifelong plasticity, with being the first to harness plasticity for human benefit (in his co-invention of the cochlear implant), and for pioneering the field of plasticity-based computerized brain exercise. He is professor emeritus at UCSF and a Kavli Laureate in Neuroscience, and he has been honored by each of the US National Academies of Sciences, Engineering, and Medicine. He may be most widely known for a series of specials on the brain on public television.

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