Longitudinal cognitive change in older adults with elevated tau PET signal in the absence of amyloid

Abstract

AbstractBackgroundMost theoretical frameworks for Alzheimer’s disease (AD) pathogenesis propose amyloid as the primary pathologic process, whereas tau in the absence of amyloid (A‐/T+) is considered a “non‐AD pathologic change” (Jack et al., 2018). Previous research has demonstrated AD‐like characteristics of the A‐/T+ biomarker profile, including poorer memory and language performance and entorhinal thinning (Weigand et al., 2022; Yoon et al., 2022). Assessment of domain‐specific longitudinal cognitive decline in this group, however, has not yet been addressed. Our study sought to evaluate 1‐year memory, language, and attention/executive function trajectories of A‐/T+ older adults.MethodWe included 756 older adults at baseline across the AD clinical continuum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of whom 359 had 1‐year follow‐up cognitive data. Four A/T groups were classified based on cortical amyloid‐beta and medial temporal tau positron emission tomography positivity. Linear mixed effects models examined 1‐year trajectories of each baseline A/T group in domains of memory, language, and attention/executive function. Both statistical significance and effect size estimates were evaluated.ResultThe following proportions of A/T groups were observed at baseline: 47.0% A‐/T‐, 13.2% A‐/T+, 13.4% A+/T‐, and 26.4% A+/T+. Only the A+/T+ group exhibited a statistically significant decline in language and attention/executive function domains relative to the A‐/T‐ group. Examination of effect sizes, however, revealed that the A‐/T+ group had a quantitatively similar degree of decline as the A+/T+ group in memory (A‐/T+ and A+/T+ bs = ‐0.13), and an intermediate degree of decline between the A‐/T‐ and A+/T+ groups for language (A‐/T+ b = ‐0.17) and attention/executive function (A‐/T+ b = ‐0.19). Similar patterns were observed when examining cognitively unimpaired participants only.ConclusionOlder adults with the A‐/T+ biomarker profile demonstrate a degree of cognitive decline across multiple domains consistent with a possible AD trajectory. The systematic exclusion of these individuals from AD clinical trials may hinder early intervention efforts to attenuate the cognitive decline observed in this biomarker group, and an expansion of our conceptualization of the AD continuum to include A‐/T+ individuals may offer improved insight into the pathologic and cognitive changes that occur in the context of preclinical AD.