Distinct Patters of Associations Between Cognitive Performance and Alzheimer’s Disease Biomarkers in a Multinational Cohort of Clinically Normal Older Adults

AbstractBackgroundThere is growing evidence of early cognitive changes associated with Alzheimer’s disease (AD) biomarker burden. While changes in CSF phosphorylated tau (p‐tau) and Aβ42 levels have been shown to precede onset of clinical symptoms by 15‐20 years, preclinical cognitive changes remain poorly understood, particularly in multinational cohorts. In this study, we leveraged the data from the multisite European Prevention of Alzheimer’s Dementia (EPAD) consortium (France, Netherlands, Spain, United Kingdom) to investigate cross‐sectional and longitudinal associations between cognitive performance and gold standard AD CSF biomarkers (p‐tau/Aβ42 ratio).MethodParticipants were 811 clinically normal older adults (age: 65.1±6.8; education: 14.4±3.7; 57% female) who completed a battery of digital cognitive tests of working memory, inhibitory control, and associative memory (TabCAT, University of California San Francisco) in addition to CSF Aβ42 and p‐tau‐181 (Roche Elecsys®). Additionally, 114 of these participants completed both cognitive and biomarker studies at 1‐year follow‐up (age: 65.4±5.9; education: 13.2±3.5; 54% female). Cross‐sectional associations between p‐tau/Aβ42 ratio and cognitive performance were examined using multiple linear regression models, and longitudinal associations were examined using linear mixed effects models. All analyses covaried for age, sex, education, hippocampal volume, and APOE ε4 status. Longitudinal analyses additionally covaried for time since baseline.ResultAt baseline, greater p‐tau/Aβ42 ratio was related to poorer performance on tasks of working memory (B=‐0.57, SE= 0.24, t=‐2.31, P=.02) and inhibitory control (B=‐0.45, SE=0.25, t=‐1.82, P=.06), but not on a task of associative memory (B=‐0.30, SE=0.26, t=‐1.13, P=.23). Longitudinal analyses showed that increases in p‐tau/Aβ42 ratio were significantly associated with decline in associative memory performance only (B=‐1.14, SE=0.52, t=‐2.20, P=.03).ConclusionIn summary, we found that greater AD biomarker burden was cross‐sectionally associated with poorer executive performance, while longitudinal increase in biomarker burden was related to greater decline in memory. Our findings contribute to the growing literature on the cognitive characteristics of preclinical AD and provide support for the hypothesis of an early impairment in attentional/executive processes, followed by a breakdown in memory functions as the pathological changes progress. A particular strength of our results is their potential generalizability in international cohorts and global studies of preclinical AD.