Domain‐specific subtle cognitive decline associations with cerebrospinal fluid and plasma β‐amyloid and p‐tau Alzheimer’s disease biomarkers in cognitively unimpaired individuals

Abstract

AbstractBackgroundPresence of Alzheimer’s disease (AD) core pathology, β‐amyloid (Aβ) and p‐tau, has been proven to impact cognitive function even in cognitively unimpaired (CU) individuals. Although the Aβ and p‐tau (AT) effect has been mainly associated with memory function, recent evidence (Tideman, P., 2022. Neurology) suggested that Aβ levels were associated independently of p‐tau with the cross‐sectional performance in executive functioning. The aim of the present study was to explore specific associations of cerebrospinal fluid (CSF) and plasma Aβ and p‐tau baseline levels with the longitudinal change in several cognitive domains in a sample of CU individuals at increased risk of AD.MethodWe analyzed the associations of baseline CSF Aβ42/40, and p‐tau181 as well as plasma Aβ42/40, and p‐tau231 levels, with domain‐specific cognitive changes 3 years after baseline in 337 CU participants from the ALFA+ study. We defined AT groups (A‐T‐, A+T‐, and A+T+) using CSF levels, and the A‐T‐ group’s baseline performance served as reference to compute z‐scores for Visual Processing, Semantic Fluency, Executive Functioning, Episodic Memory, and Attentional Processing. Delta scores were computed by subtracting baseline from follow‐up scores and then compared among AT groups by means of ANCOVAs. Multiple linear regressions were performed on the whole sample using CSF Aβ42/40, p‐tau181 and plasma Aβ42/40, p‐tau231 as predictors of change in cognitive function.ResultA+T+ individuals showed a significant decline in Executive Function (p = 0.005, Cohen’s d = 0.716), and Attentional Processing (p = 0.032, Cohen’s d = 0.563), but not in Episodic Memory (p = 0.334) when compared with A‐T‐ individuals. In the whole sample, CSF Aβ42/40 was associated independently of p‐tau181 with a decline in Semantic Fluency (β = 6.284, p = 0.013), Attentional Processing (β = 3.828, p = 0.020), and Episodic Memory (β = 3.513, p = 0.004). Plasma p‐tau231 levels were associated with a decline in Semantic Fluency (β = ‐0.413, p = 0.045). CSF p‐tau181 and plasma Aβ42/40 were not associated with cognitive changes.ConclusionExecutive Function and Attentional Processing were more sensitive than Episodic Memory in capturing the early subtle cognitive changes in CU individuals with underlying AD pathology. Attentional Processing was the only cognitive domain associated both with the status of AD biomarkers and with the effect of CSF Aβ levels independently of p‐tau.