Objective subtle cognitive decline is associated with a more rapid increase in plasma phosphorylated‐tau181 levels over time

Abstract

AbstractBackgroundEarly identification of Alzheimer’s disease (AD) is imperative for early intervention and planning. Objectively‐defined subtle cognitive decline (Obj‐SCD) criteria, based on sensitive neuropsychological scores, is associated with AD biofluid and neuroimaging markers as well as progression to mild cognitive impairment (MCI) and dementia. However, the relationship between Obj‐SCD and newer plasma markers, such as plasma phosphorylated‐tau181 (p‐tau181), is unknown. Therefore, we examined baseline and longitudinal plasma p‐tau181 across CN, Obj‐SCD, and MCI groups.Method953 Alzheimer’s Disease Neuroimaging Initiative participants without dementia had plasma p‐tau181 data, which were log‐transformed prior to analyses. Participants were classified as CN (n=403), Obj‐SCD (n=200), or MCI (n=350) based on actuarial neuropsychological criteria. Baseline analyses compared p‐tau181 across groups. Linear mixed effects models, adjusting for age, sex, APOE e4 allele frequency, and pulse pressure, examined 4‐year p‐tau181 rate of change in Obj‐SCD and MCI participants relative to CN. Follow‐up analyses examined whether the group p‐tau181 x time trajectories differed by Aβ‐PET positivity status.ResultCN and Obj‐SCD groups had lower baseline plasma p‐tau181 than the MCI group and did not differ from one another (Figure 1). However, longitudinally, the Obj‐SCD group had the steepest increase in plasma p‐tau181 over four years and was the only group to differ from CN participants (Figure 2; b=.016, 95% CI: .003‐.018, p=.016). When groups were split by Aβ status, only the Aβ‐negative Obj‐SCD group showed a slightly faster increase in p‐tau181 relative to the Aβ‐negative CN group (b=.019, 95% CI: .001‐.037, p=.044).ConclusionBaseline plasma p‐tau181 did not differ between CN and Obj‐SCD; however, consistent with prior findings, Obj‐SCD was associated with future pathologic changes, including those measured by plasma p‐tau181, prior to frank impairment associated with MCI. Importantly, these results do not appear to be driven by Aβ+ Obj‐SCD participants. Despite the long‐held assumption that cognitive changes invariably follow biomarker changes, these findings suggest that early neuropsychological difficulties may emerge before or in tandem with measurable changes in plasma markers. Future work will examine the prognostic impact of combining Obj‐SCD and plasma markers, which both have the potential to be accessible early markers of future AD‐related declines.