Sex and cerebral small vessel disease‐specific longitudinal trajectories of amyloid, tau, and neurodegeneration

Abstract

AbstractBackgroundThe AT(N) model of Alzheimer’s disease (AD) posits a temporal evolution of β‐amyloid (Aβ) accumulation followed by tau then neurodegeneration. We investigated whether longitudinal relationships of these pathologies varied by sex and cerebral small vessel disease burden (cSVD), hypothesizing stronger associations in women and those with high baseline cSVD.MethodParticipants included 37 non‐demented older adults (mean 74 y/o at inclusion; 59% female; 89% white; 29% APOE4+). Tau was measured once at time 0 using 18F‐AV‐1451 in an AD composite region of interest. Global amyloid and cerebral metabolism in lateral temporal lobe (neurodegeneration) were measured at repeated annual visits (8 years before tau‐PET to 2 years after), using 11C‐PiB and 18F‐fluorodeoxyglucose (FDG)‐PET. cSVD at study inclusion was characterized by high or low white matter hyperintensity (WMH) volume on MRI. We calculated individual slopes of Aβ and cerebral metabolism up to the tau‐PET visit (time ‐8 to 0) using linear mixed effects models. Using age‐adjusted linear regression models, we examined associations of Aβ slope, tau, and cerebral metabolism slope or metabolism at the final visit (time≥0). We tested effect modification by sex and WMH using interaction terms and stratified analyses when interaction p<0.10.ResultAssociations of Aβ slope with tau varied by sex (p‐interaction=0.007) but not WMH. Greater increase in Aβ slope was associated with greater tau in women (β=3.5, p=0.004), but not men (β= ‐1.2, p=0.34). Tau did not predict cerebral metabolism at the final FDG visit (β=0.10, p=0.67), but increasing Aβ slope predicted hypometabolism at the final FDG visit (β= ‐2.1, p=0.01). Neither of these relationships varied by sex or WMH. Associations of cerebral metabolism slope with tau varied by sex (p‐interaction=0.08), but not WMH. Decreasing cerebral metabolism slope was associated with greater tau in women (β= ‐16.3, p=0.05), but not men (β=4.7, p=0.59). Further adjustment for APOE4 (N=31) did not appreciably alter results.ConclusionIn non‐demented older adults, we found that associations of Aβ and cerebral hypometabolism with later increased tau were stronger in women than men; cSVD did not modify these associations. Tau did not predict later cerebral metabolism, while Aβ did.