Abstract
AbstractBackgroundThe medial temporal lobe (MTL) is affected in aging and dementia. Aging, small vessel disease, β‐amyloid, tau pathology, and inflammation are hypothesized to play a role in neurodegeneration, but their interplay is still unclear. We investigate potential MTL atrophy mediators of (1) Aβ‐related effects in cognitively normal older adults and (2) aging effects in a β‐amyloid negative (A‐) subgroup.Method401 adults (41‐91 years) from the Swedish BioFINDER‐2 study were included ([mean±SD] 65.5±11.7 years; A‐ n=274, 62.7±11.8 years). Using the Automated Segmentation for Hippocampal Subfields for T1‐ and T2‐weighted MRI, hippocampal subfield volumes (dentate gyrus (DG), subiculum (Sub), cornu ammonis (CA) 1) and thickness of entorhinal cortex (ERC), Brodmann areas (BA) 35/36, and parahippocampal cortex (PHC) were obtained. [18F]RO948‐ and [18F]Flutemetamol‐PET standard uptake value ratios were calculated for mean MTL tau (excluding hippocampus; partial volume corrected (PVC)) and global Aβ (with and without PVC). White matter lesions (WML; log‐transformed) to estimate small vessel disease and cerebrospinal fluid (CSF) Glial fibrillary acidic protein (GFAP) to estimate neuroinflammation were analyzed. Both global Aβ‐PET and CSF Aβ‐42/40 ratio determined amyloid‐β status.ResultAll predictors were negatively associated with Sub volume and BA35/PHC thickness in the whole sample, with roughly similar results for the A‐ subgroup (Table 1, Fig. 1). PVC global Aβ‐PET showed similar results. Mediation analyses therefore focus on these three regions. In the whole sample, MTL tau‐PET and GFAP fully mediated the associations between global Aβ‐PET and Sub/BA35/PHC (Fig. 2). When including age in the model only MTL tau‐PET, not GFAP, remained a significant mediator for Sub.In the A‐ group, MTL tau‐PET partially mediated the age‐Sub/BA35 associations. These mediations survived adjusting for Aβ, except for BA35 (p=.054). Global WML partially mediated the age‐PHC association (Fig. 3). No other predictors were significant mediators.ConclusionAs expected, global Aβ‐PET‐associated neurodegeneration is mediated by MTL tau pathology, but, interestingly, also potentially by inflammation.MTL tau pathology and small vessel disease seemingly drive age effects on the MTL, but in different MTL regions. The mediating effect of MTL tau is supportive of a role for Primary Age‐Related Tauopathy in age‐related neurodegeneration.
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