September 28, 2023
Michael Merzenich, PhD

he antiamyloid drug lecanemab was recently approved by the US Food and Drug Administration for treating early-stage Alzheimer’s disease (AD). In trials of both lecanemab (Leqembi) and the investigational antiamyloid donanemab, a long-held neuropharmacologic dream was realized: Most amyloid plaques — the primary pathologic marker for AD — were eliminated from the brains of patients with late pre-AD or early AD.

Implications for the Amyloid Hypothesis

The reduction of amyloid plaques has been argued by many scientists and clinical authorities to be the likely pharmacologic solution for AD. These trials are appropriately viewed as a test of the hypothesis that amyloid bodies are a primary cause of the neurobehavioral symptoms we call AD.

In parallel with that striking reduction in amyloid bodies, drug-treated patients had an initially slower progression of neurobehavioral decline than did placebo-treated control patients. That slowing in symptom progression was accompanied by a modest but statistically significant difference in neurobehavioral ability. After several months in treatment, the rate of decline again paralleled that recorded in the control group. The sustained difference of about a half point on cognitive assessment scores separating treatment and control participants was well short of the 1.5-point difference typically considered clinically significant.

A small number of unexpected and unexplained deaths occurred in the treatment groups. Brain swelling and/or micro-hemorrhages were seen in 20%-30% of treated individuals. Significant brain shrinkage was recorded. These adverse findings are indicative of drug-induced trauma in the target organ for these drugs (ie, the brain) and were the basis for a black box warning label for drug usage. Antiamyloid drug treatment was not effective in patients who had higher initial numbers of amyloid plaques, indicating that these drugs would not measurably help the majority of AD patients, who are at more advanced disease stages.

These drugs do not appear to be an “answer” for AD. A modest delay in progression does not mean that we’re on a path to a “cure.” Treatment cost estimates are high — more than $80,000 per year. With requisite PET exams and high copays, patient accessibility issues will be daunting.

Of note, in my view, the trials of these drugs do not support the hypothesis that amyloid is the primary neuropathologic agent underlying the progressive neurobehavioral decline in AD. To the contrary, they add strong support for the counterargument that the emergence of amyloid plaques is an effect and not a fundamental cause of that progressive loss of neurologic function that we ultimately define as “Alzheimer’s disease.”

Time to Switch Gears

The more obvious path to winning the battle against this human scourge is prevention. A recent analysis published in The Lancet argued that about 40% of AD and other dementias are potentially preventable. I disagreeI believe that 80%-90% of prospective cases can be substantially delayed or prevented. Studies have shown that progression to AD or other dementias is driven primarily by the progressive deterioration of organic brain health, expressed by the loss of what psychologists have termed “cognitive reserve.” Cognitive reserve is resilience arising from active brain usage, akin to physical resilience attributable to a physically active life. Scientific studies have shown us that an individual’s cognitive resilience (reserve) is a greater predictor of risk for dementia than are amyloid plaques — indeed, greater than any combination of pathologic markers in dementia patients.

Building Up Cognitive Reserve

It’s increasingly clear to this observer that cognitive reserve is synonymous with organic brain health. The primary factors that underlie cognitive reserve are processing speed in the brain, executive control, response withholding, memory acquisition, reasoning, and attention abilities. Faster, more accurate brains are necessarily more physically optimized. They necessarily sustain brain system connectivity. They are necessarily healthier. Such brains bear a relatively low risk of developing AD or other dementias, just as physically healthier bodies bear a lower risk of being prematurely banished to semi-permanent residence in an easy chair or a bed.

Brain health can be sustained by deploying inexpensive, self-administered, app-based assessments of neurologic performance limits, which inform patients and their medical teams about general brain health status. These assessments can help doctors guide their patients to adopt more intelligent brain-healthy lifestyles, or direct them to the “brain gym” to progressively exercise their brain in ways that contribute to rapid, potentially large-scale, rejuvenating improvements in physical and functional brain health.

Randomized controlled trials incorporating different combinations of physical exercise, diet, and cognitive training have recorded significant improvements in physical and functional neurologic status, indicating substantially advanced brain health. Consistent moderate-to-intense physical exercise, brain- and heart-healthy eating habits, and, particularly, computerized brain training have repeatedly been shown to improve cognitive function and physically rejuvenate the brain. With cognitive training in the right forms, improvements in processing speed and other measures manifest improving brain health and greater safety.

In the National Institutes of Health–funded ACTIVE study with over 2800 older adults, just 10-18 hours of a specific speed of processing training (now part of BrainHQ, a program that I was involved in developing) reduced the probability of a progression to dementia over the following 10 years by 29%, and by 48% in those who did the most training.

This approach is several orders of magnitude less expensive than the pricey new AD drugs. It presents less serious issues of accessibility and has no side effects. It delivers far more powerful therapeutic benefits in older normal and at-risk populations.

Sustained wellness supporting prevention is the far more sensible medical way forward to save people from AD and other dementias — at a far lower medical and societal cost.

Editor’s note: An earlier version of this article mistakenly stated that donanemab was FDA approved.

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. His current focus is BrainHQ , a brain exercise app.