biostudies-literatureWuestefeld AVetenskapsrådetNIA NIH HHSStiftelsen För Gamla TjänarinnorDepartment of DefenseMultiPark - A Strategic Research Area at Lund UniversityBente Rexed Gerstedt FoundationNIH HHSe70511https://www.ebi.ac.uk/biostudies/studies/S-EPMC12290488biostudies-literatureUnknown21(7)<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Discussion</h4>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.<h4>Highlights</h4>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.Alzheimer's & dementia : the journal of the Alzheimer's AssociationTau, atrophy, and domain-specific cognitive impairment in typical Alzheimer's disease.PMC12290488RF1-AG056014P30-AG072979U01 AG0249042024-250W81XWH-12-2-0012U19-AG0249042022-00900R01-AG070592R01-AG069474Wisse LEMand for the Alzheimer's Disease Neuroimaging Initiativevan Westen DXie LMcGrew EPichet-Binette AMattsson-Carlgren NDas SRSpotorno NWolk DAYushkevich PAWuestefeld AfalseTau, atrophy, and domain-specific cognitive impairment in typical Alzheimer's disease.<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Discussion</h4>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.<h4>Highlights</h4>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.2025-01-01T00:00:00Z2025 Jul2026-03-15T17:10:47.122Z2025-08-13T03:04:36.579ZS-EPMC122904884070949410.1002/alz.70511