Rethinking Alzheimer’s Causes: Beyond the Amyloid Hypothesis

Alzheimer’s will affect 11 million people in the United States by 2040. The amyloid hypothesis holds that sticky plaques and other so-called amyloid-beta proteins build up in the brain and prompt changes that cause Alzheimer’s disease’s cruel decline, gradually stealing a person’s mastery of everyday life, cherished memories, and, finally, their sense of self. But are we sure?

In Alzheimer’s disease, brain cells that process, store, and retrieve information degenerate and die. Although scientists do not yet know the underlying cause of this destruction, they have identified several possible culprits.

One prime suspect is a microscopic brain protein fragment called beta-amyloid, a sticky compound that accumulates in the brain, disrupting communication between brain cells and eventually killing them. Some researchers believe that flaws in the processes governing the production, accumulation, or disposal of beta-amyloid are the primary cause of Alzheimer’s. This theory is called “the amyloid hypothesis.”

Supporters of the amyloid hypothesis cite three main lines of evidence:

-In a few hundred extended families worldwide, scientists have identified rare genetic mutations that virtually guarantee an individual will develop Alzheimer’s. These mutations occur in any of three genes. Each of these genes involves biological processes associated with beta-amyloid production or accumulation. Only an estimated 1 percent of people with Alzheimer’s disease have one of these mutations.

-Scientists have developed mice genetically engineered to carry some of these genetic mutations. The mice develop amyloid plaques, have difficulty remembering their way through mazes, and develop other symptoms that mimic human Alzheimer’s.

– Individuals with Down syndrome who have three copies of the chromosome carrying the APP gene instead of the standard two almost invariably develop amyloid plaques by age 40. Not all people with Down syndrome develop Alzheimer’s disease, but studies suggest that about 75 percent of those older than age 65 have Alzheimer’s.

In the early 1990s, legions of researchers began to sign on to the idea that removing amyloid from the brain could stop or reverse that process. But anti-amyloid drugs failed time and again. Then, in 2006, an animal experiment published in the journal Nature identified a specific type of amyloid protein as the first substance found in brain tissue to cause symptoms associated with Alzheimer’s directly. Top scientists called it a breakthrough that provided a key target for treatments. The paper became one of the most cited in the field, and funds to explore similar proteins skyrocketed.

 Supporters of the amyloid hypothesis declared victory, including eminent scientists who have staked their careers on proving its accuracy. The F.D.A. also approved a look-alike competitor, Kisunla.

There are serious concerns about the new drugs. For tens of thousands of dollars per person annually—plus costly diagnostic scans—they offer benefits so slight that many neurologists say they may be imperceptible to patients and their loved ones.

These drugs also can cause dangerous brain swelling and bleeding. The F.D.A. required warnings of fatal side effects on each drug’s product label. The drugs also mysteriously shrink the brain much faster than Alzheimer’s itself, with unknown long-term effects.

In 2022, an investigation in Science showed evidence that the famous 2006 experiment that helped advance the amyloid hypothesis used falsified data. On June 24, after most of its authors conceded that technical images were doctored, the paper was finally retracted. Days later, a City University of New York scientist behind a well-financed, controversial Alzheimer’s drug was indicted on charges alleging research fraud.

But then, what exactly is the cause? Risk factors like diabetes, high blood pressure and cholesterol, obesity, depression, hearing loss, sedentary lifestyles, poor diets, and racial discrimination can be targeted. Miguel Arce Rentería, a neuropsychologist at Columbia University, argues that more accessible treatment that also addresses social issues may stave off the worst of Alzheimer’s for years. Although most research seeks an elusive remedy, the mood is shifting. Federal funding for studying care and prevention, like some of Dr. Arce Rentería’s research, has recently risen.

 Amyloid-beta proteins play a role in the complex mystery of Alzheimer’s, but they’re not the singular key to the cure that so many scientists imagine. If there were a universal source for Alzheimer’s, it would show up earlier in life and be more evident in everyone who suffers from the disease.

Lilly’s new Alzheimer’s drug costs over $32,000 a year and may or may not work. Is that too much to charge for hope, and can our healthcare system absorb the costs? Why not charge for a “pay for performance” model?

Ultimately, solutions to Alzheimer’s could arrive much faster if the amyloid hypothesis wasn’t reinforced with quasi-religious zeal by many of the field’s most powerful scholars.