A growing body of research indicates that variations in the APOE gene may be responsible for a far greater proportion of Alzheimer’s disease (AD) cases than previously estimated. Researchers suggest that if everyone carried the most favorable ε2 variant of APOE, the incidence of Alzheimer’s could be reduced to just a tenth of current levels.

APOE, a gene involved in cholesterol transport and metabolism, has been linked to brain immune cell (microglia) dysfunction, which plays a critical role in neurodegenerative diseases. Dysfunctional microglia become increasingly inflammatory with age, potentially accelerating the development of Alzheimer’s pathology. While therapies targeting microglia are not yet available, promising laboratory and animal studies suggest potential pathways for future clinical trials.

The recent analysis drew on data from four major studies, including the UK Biobank, FinnGen, the A4 Study, and the Alzheimer’s Disease Genetics Consortium (ADGC), encompassing hundreds of thousands of participants. Researchers examined clinically diagnosed AD, Alzheimer’s neuropathology, all-cause dementia, and cerebral amyloidosis.

Key findings include:

• In the ADGC, 92.7% of Alzheimer’s cases were attributable to the common APOE ε3 and ε4 variants.
• In the FinnGen cohort, APOE ε3 and ε4 accounted for 71.5% of AD cases.
• In the A4 Study, 85.4% of cerebral amyloidosis was linked to these risk alleles.
• Across UK Biobank and FinnGen, nearly half of all dementia cases were associated with APOE ε3 and ε4.

“These findings suggest that without the risks associated with APOE ε3 and ε4, nearly all cases of Alzheimer’s and a significant portion of all dementia would not occur,” said the study authors. “Targeting APOE presents a major opportunity for prevention and intervention in dementia.”

The study emphasizes the urgent need to prioritize therapies aimed at APOE and microglial function to reduce the global burden of Alzheimer’s disease.