APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging

Objective: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging. Methods: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta₄₂ (Aβ₄₂), tau, and phosphorylated tau (ptau;_181;). All individuals were genotyped for APOE. Results: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Aβ₄₂ appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Aβ₄₂ with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Aβ;_42; levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau₁₈₁. Interpretation: Increasing cerebral Aβ deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Aβ deposition may first be lowered CSF Aβ₄₂, followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.