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.