Impact of sex and ApoE4 on the longitudinal association of plasma ptau‐181 and NFL with cognitive decline in non‐demented older adults

Abstract

AbstractBackgroundAPOE4 is a strong genetic risk factor for Alzheimer’s disease (AD). Sex‐dependent differences has been shown in AD pathophysiology and clinical course. Here, we aim to assess the association between longitudinal changes in ptau‐181 and neurofilament light protein (NfL) and concurrent changes in cognitive measures in non‐demented individuals and to evaluate if this association is impacted by sex and ApoE4 status.MethodParticipants (N = 738) were non‐demented (cognitively unimpaired or mild cognitive impairment) older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 738) with up to 4ys of longitudinal data. Linear Mixed Effects (LME) models were used to study the effect of ptau‐181 and NFL on cognition as measured by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐cog11; Range 0‐70) and Clinical Dementia Rating, sum of boxes (CDR‐SB). Sex by time and APOE4 by time interactions were assessed in the models for the entire sample. Analyses was repeated after separately stratifying sample by sex and APOE4.ResultAt baseline, both ADAS‐11 and CDRSB values correlated with plasma p‐Tau181 and NfL measures (Table 1). The longitudinal change in plasma p‐Tau181 correlated only with baseline CDR‐SB while that of NfL correlated with baseline ADAS‐11. The APOE4*time interaction, but not sex‐time interaction, were significant in LME models of both p‐Tau181 and NFL (Table 2). When stratified by sex, in females longitudinal increase in p‐Tau181 was associated with cognitive decline measured by both ADAS‐11 and CDR‐SB. In males, longitudinal increase in p‐Tau181 was associated with increase in ADAS‐11 scores and NfL was associated with cognitive decline on both outcomes. When stratified by APOE4 status, longitudinal changes in plasma biomarkers were only associated with cognitive decline in the APOE4+ subsample.ConclusionPlasma NfL and pTau increase during early AD and can be used to monitor disease progression. The relationship between increase in plasma ptau‐181 and NFL levels and worsening of cognition is affected by APOE4 status.