What Causes Alzheimer's? Scientists Are Rethinking the Answer

'After decades in the shadow of the reigning model for Alzheimer's disease, alternative explanations are finally getting the attention they deserve,' writes Quanta magazine — in a 10,000-word update on where we are now:

Three decades ago, scientists thought they had cracked the medical mystery of what causes Alzheimer's disease with an idea known as the amyloid cascade hypothesis. It accused a protein called amyloid-beta of forming sticky, toxic plaques between neurons, killing them and triggering a series of events that made the brain waste away.... Decades of work and billions of dollars went into funding clinical trials of dozens of drug compounds that targeted amyloid plaques. Yet almost none of the trials showed meaningful benefits to patients with the disease....

A stream of recent findings has made it clear that other mechanisms may be at least as important as the amyloid cascade as causes of Alzheimer's disease.... The emerging new models of the disease are more complex than the amyloid explanation, and because they are still taking shape, it's not clear yet how some of them may eventually translate into therapies. But because they focus on fundamental mechanisms affecting the health of cells, what's being learned about them might someday pay off in new treatments for a wide variety of medical problems, possibly including some key effects of aging.... While these alternate ideas were once hushed and thrown under the rug, now the field has broadened its attention.

The article explores the theory — derived from research on genetically-engineered mice — that neurons bulging with toxic accumulations of proteins and molecules could be mistaken for classic amyloid plaques outside cells. (But in fact 'the extracellular amyloid plaques weren't killing the cells — because the cells were already dead.') Scientists are now also investigating lysosomes, cholesterol metabolism, and even the immune system.

To say that the amyloid hypothesis is dead would be overstating it, said Donald Weaver, a co-director of the Krembil Brain Institute in Toronto, but 'I would say that the amyloid hypothesis is insufficient....'
By 2017, 146 drug candidates for treating Alzheimer's disease had been deemed unsuccessful. Only four drugs had been approved, and they treated the symptoms of the disease, not its underlying pathology. The results were so disappointing that in 2018, Pfizer pulled out of Alzheimer's research. A 2021 review that compared the results of 14 of the major trials confirmed that reducing extracellular amyloid did not greatly improve cognition....
The hypothesis took another hit last July when a bombshell article in Science revealed that data in the influential 2006 Nature paper linking amyloid plaques to cognitive symptoms of Alzheimer's disease may have been fabricated. The connection claimed by the paper had convinced many researchers to keep pursuing amyloid theories at the time.

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