Cohort Study: APOE4 Homozygosity as a Distinct Genetic Form of Alzheimer’s Disease with Early Biomarker Changes – Nat Med

This cohort study investigated the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by analyzing clinical, pathological, and biomarker data. The study utilized data from the National Alzheimer’s Coordinating Center and five additional large cohorts, comprising a total of 3,297 individuals for the pathological study and 10,039 for the clinical study. Results demonstrated that APOE4 homozygotes exhibited almost universal AD pathology and had significantly higher levels of AD biomarkers from age 55, compared to APOE3 homozygotes. By age 65, nearly all APOE4 homozygotes showed abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, indicating a high biological penetrance of AD. These individuals also exhibited an earlier onset of symptoms, around age 65.1, and the progression and predictability of biomarker changes paralleled those observed in autosomal dominant AD and Down syndrome. However, in the dementia stage, amyloid and tau positron emission tomography scans showed no differences across haplotypes. The study concludes that APOE4 homozygosity represents a genetically distinct form of AD, underscoring the importance of tailored prevention strategies and treatments.

Reference (link to abstract – $ for full-text):

Juan Fortea et al. (2024). APOE4 Homozygosity as a Distinct Genetic Form of Alzheimer’s Disease with Early Biomarker Changes. Nature Medicine. DOI: https://doi.org/10.1038/s41591-024-02931-w