APOE4homozygosity represents a distinct genetic form of Alzheimer’s disease

This study aimed to evaluate the impact of APOE4homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4homozygotes. The age of symptom onset was earlier in APOE4homozygotes at 65.1, with a narrower 95% prediction interval than APOE3homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.