Nat Med

Study confirms APOE4 homozygosity = distinct genetic form of Alzheimer's

May 8, 2024

New research suggests that individuals with two copies of the APOE4 gene—about 2% to 3% of the general population—may have a distinct, genetically determined form of Alzheimer's disease (AD), suggesting the need for individualized prevention strategies, clinical trials, and treatments.

ApoE4 has long been known to increase the risk of developing Alzheimer’s, with two copies conferring greater risk than one. Now researchers conclude that such persons are almost guaranteed to develop Alzheimer’s if they live long enough, and are likely to develop Alzheimer’s earlier than people without this gene variant.

Dr. Juan Fortea of the University of Barcelona and colleagues studied more than 3,000 donated brains from the U.S. National Alzheimer's Coordinating Center, as well as biological and clinical data on more than 10,000 individuals from three countries.

Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared with APOE3 homozygotes.

By age 65, nearly all people with two copies of APOE4 had abnormal amyloid levels in their cerebrospinal fluid, and 75% had positive brain scans for amyloid.

Also, the age of symptom onset, beginning at approximately age 65, was earlier in people with two copies of APOE4, with a narrower 95% prediction interval than APOE3 homozygotes.

A key limitation of the study is that it involved mostly people of European ancestry.

Sources:

Fortea J, et al. (2024, May 6). Nat Med. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/38710950/

Steenhuysen, Julie. (2024, May 6). Reuters. People with two copies of a risk gene have genetic form of Alzheimer's, scientists say. https://www.reuters.com/business/healthcare-pharmaceuticals/people-with-two-copies-risk-gene-have-genetic-form-alzheimers-scientists-say-2024-05-06/