Tau, atrophy, and domain-specific cognitive impairment in typical Alzheimer's disease

Abstract

INTRODUCTION: A granular understanding of the mechanisms linking tau pathology to cognitive decline in Alzheimer's disease is crucial. We investigate mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration on tau-induced domain-specific cognitive impairment in amyloid-beta (Aβ) positive cognitively normal and impaired adults. METHODS: We assessed magnetic resonance imaging–derived MTL and neocortical volume/thickness and 18F-Flortaucipir positron emission tomography in 319 Aβ-positive individuals. Cognitive functions across six domains were isolated by adjusting for other cognitive measures. RESULTS: MTL tau correlated with memory subdomains, neocortical tau with executive function, and both with semantic fluency. Specific structural measures partially mediated these tau–cognition associations: Brodmann area 35 mediated tau–immediate and tau–delayed recall, posterior hippocampus tau–recognition, and inferior temporal cortex tau–semantic fluency associations. DISCUSSION: Our findings provide a nuanced understanding of region-specific macrostructural atrophy as one pathway of tau-induced cognitive changes, aligning with known tau spread patterns. Additionally, isolating cognitive functions is a promising approach for future research. Highlights: Medial temporal lobe tau was related to memory domains; neocortical tau to executive function. Both tau positron emission tomography measures were associated with semantic fluency. Specific regional atrophy partially mediated tau-induced cognitive changes. Other mechanistic links between tau and cognitive subdomains require investigation. Isolated cognitive domains should be explored as future avenues of research.