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INTRODUCTION: Little is known about plasma phosphorylated tau 217 (p-tau217) in individuals without a clinical diagnosis of Alzheimer's disease (AD). We studied associations of plasma p-tau217 with age, sex, education, and genetic risk; estimated the heritability; and conducted a genome-wide association study (GWAS).METHODS: A population-based biobank recall study of 65- to 85-year-old twins ( = 697, mean [SD] age 76.2 [4.6] years; 53% women, 154 full pairs) excluding those with AD based on health registry data.RESULTS: Higher p-tau217 level and likelihood of AD neuropathologic change (p-tau217 > 0.42 pg/mL; evident in 39%) were associated with higher age and having an apolipoprotein E () ε4 allele. Heritability was 0.56 (95% confidence interval [CI]: 0.36-0.79) and GWAS indicated 45 single nucleotide polymorphisms (SNPs) (< 5 × 10) centered around the locus.DISCUSSION: Our results elucidate the characteristics and genetic associations of p-tau217 in a population-based setting. We found many 65- to 85-year-olds without a clinical diagnosis of AD to have AD neuropathologic change based on plasma p-tau217.HIGHLIGHTS: Plasma phosphorylated tau 217 (p-tau217) is a promising biomarker of Alzheimer's disease (AD).We studied plasma p-tau217 in a population-based sample of 65- to -85-year-olds.We excluded those with a clinical diagnosis of AD.Older age and having an apolipoprotein E () ε4 allele were associated with higher plasma p-tau217.Heritability of p-tau217 was 56% and a genome-wide association study (GWAS) implicated genes around the region.