Association of β-Amyloid Accumulation With Executive Function in Adults With Unimpaired Cognition

Background and Objectives The neuropathologic changes underlying Alzheimer disease (AD) start before overt cognitive symptoms arise, but it is not well-known how they relate to the first subtle cognitive changes. The objective for this study was to examine the independent associations of the AD hallmarks beta-amyloid (A beta), tau, and neurodegeneration with different cognitive domains in cognitively unimpaired (CU) individuals. Methods In this cross-sectional study, CU participants from the prospective BioFINDER-2 study were included. All had CSF biomarkers (A beta 42 and phosphorylated tau [p-tau]181), MRI (cortical thickness of AD-susceptible regions), A beta-PET (neocortical uptake), tau-PET (entorhinal uptake), and cognitive test data for memory, executive function, verbal function, and visuospatial function. Multivariable linear regression models were performed using either CSF A beta 42, p-tau181, and cortical thickness or A beta-PET, tau-PET, and cortical thickness as predictors of cognitive function. The results were validated in an independent cohort (Alzheimer's Disease Neuroimaging Initiative [ADNI]). Results A total of 316 CU participants were included from the BioFINDER-2 study. Abnormal A beta status was independently associated with the executive measure, regardless of modality (CSF A beta 42, beta = 0.128, p = 0.024; A beta-PET, beta = 0.124, p = 0.049), while tau was independently associated with memory (CSF p-tau181, beta = 0.132, p = 0.018; tau-PET, beta = 0.189, p = 0.002). Cortical thickness was independently associated with the executive measure and verbal fluency in both models (p = 0.005-0.018). To examine the relationships in the earliest stage of preclinical AD, only participants with normal biomarkers of tau and neurodegeneration were included (n = 217 CSF-based; n = 246 PET-based). Again, A beta status was associated with executive function (CSF A beta 42, beta = 0.189, p = 0.005; A beta-PET, beta = 0.146, p = 0.023), but not with other cognitive domains. The results were overall replicated in the ADNI cohort (n = 361). Discussion These findings suggest that A beta is independently associated with worse performance on an executive measure but not with memory performance, which instead is associated with tau pathology. This may have implications for early preclinical AD screening and outcome measures in AD trials targeting A beta pathology.

Automated summary

This study found independent associations between neuropathologic changes in Alzheimer's disease and different cognitive domains. Beta-amyloid was associated with executive function, while tau was associated with memory. Cortical thickness was also associated with cognitive function. These findings have implications for early screening of Alzheimer's disease and treatment targeting beta-amyloid pathology.