Associations of [ ¹⁸ F]PI-2620 Binding with Memory and Phosphorylated Tau 217 in Cognitively Unimpaired Older Adults

[¹⁸F]PI-2620 is a second-generation tau PET tracer that may detect early tau accumulation in aging. We investigated whether temporal lobe [¹⁸F]PI-2620 binding is associated with age, sex, genetic Alzheimer disease (AD) risk, plasma biomarkers of AD (plasma phosphorylated tau 217 [p-tau₂₁₇], Aβ_1–42/Aβ_1–40), astrogliosis (glial fibrillary acidic protein), and domain-specific cognition in cognitively unimpaired (CU) older adults. <b>Methods:</b> In this study, 166 CU older adults (mean age, 72 ± 7 y; females, 46%; apolipoprotein ϵ4 [APOE4] carriers, 23%) and 13 young adults underwent extensive cognitive testing, blood sampling, MRI, and dynamic [¹⁸F]PI-2620 PET (0–60 min postinjection). Associations of regional [¹⁸F]PI-2620 distribution volume ratio (DVR) with age, sex, APOE4 genotype, and plasma biomarkers were examined using region-of-interest and voxelwise analyses. Additional imaging markers of age-related pathology included hippocampal volume, medial temporal lobe thickness, white matter (WM) hyperintensities, perivascular spaces, and hippocampal perfusion (R1-derived maps). Associations among temporal lobe DVR, other imaging markers, and domain-specific cognitive performance (from factor analysis) were tested. <b>Results:</b> In older adults, temporal [¹⁸F]PI-2620 binding was higher in women (β = 0.543, <i>P</i> &lt; 0.001) and APOE4 carriers (β = 0.395, <i>P</i> = 0.030) and was positively associated with plasma p-tau₂₁₇ (β = 0.22, <i>P</i> = 0.008). Voxelwise analyses showed age-related increases in basal ganglia signal, whereas WM signal was higher in younger adults. In a multiple regression model, higher temporal DVR (β = −0.36, <i>P</i> = 0.003) and lower hippocampal volume (β = 0.22, <i>P</i> = 0.007) predicted worse episodic memory and, together with demographic factors, explained approximately 30% of the variance. <b>Conclusion:</b> Temporal [¹⁸F]PI-2620 binding is associated with genetic AD risk, plasma p-tau₂₁₇, female sex, and episodic memory deficits in CU older adults, supporting its sensitivity to early tau pathology, while highlighting the need to consider potential WM binding.