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Among neurocognitive disorders, none looms larger in the public imagination than Alzheimer’s disease.

Despite enormous effort, progress in prevention and treatment has been modest at best.

Increasingly, researchers are exploring alternative explanations.

Some friends and I are discussing our favorite dishes. “What’s yours?” one asks me. I can feel the answer, hovering just beyond the horizon of my consciousness, but out of my reach. My heart begins to pound; my head starts to spin.

Anyone past the age of 50 has likely experienced a version of this predicament, euphemistically termed a “senior moment.” The more frequently it occurs, the more dread it triggers. The worry is widely shared. Among neurocognitive disorders, none looms larger in the public imagination than Alzheimer’s disease. Recent estimates suggest it may rank third after heart disease and cancer as a cause of death among older adults in North America.

Twenty years ago, a widely cited paper in the journal Nature argued that Alzheimer’s is driven by the accumulation of abnormal proteins, specifically sticky beta-amyloid that builds up into plaques outside of neurons and tau tangles, or misfolded proteins, within them. Together, they disrupt cell communication and cause cell death.

For the last two decades, the amyloid hypothesis has dominated the field, guiding countless clinical trials and drug-development programs. Yet the results have been disappointing. Despite enormous effort, progress in prevention and treatment has been modest at best. Increasingly, researchers are exploring alternative explanations, new ways of thinking about a disease that remains uncooperative to understanding.

By some estimates, 40 percent of dementia cases (Alzheimer’s included) worldwide are linked to risk factors that can, at least in principle,........

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