Neuronal Distribution of Tau Pathology, Microglial Gene Expression Trajectories, and Resilience to Alzheimer disease

ImportanceSome individuals are capable of tolerating Alzheimer disease neuropathological changes (ADNC) without manifesting clinical symptoms. Elucidating the neuropathological, and molecular mediators may facilitate the identification of more accurate in vivo biomarkers and inform the development of targeted therapeutic strategies. ObjectiveTo investigate cellular distribution of tau pathology, microglial responses, and gene expression profiles associated with divergent clinical outcomes (dementia vs. no dementia) in individuals exhibiting comparable ADNC. Design, Setting and ParticipantsWe analyzed postmortem brain tissue from 97 participants from the ROSMAP study:49 with high likelihood of AD (25 demented [demented AD] and 24 cognitively normal [resilient]), and 48 with low likelihood (22 demented [impaired-other (IMP-O)] and 26 cognitively normal [control]). Cases were matched for age, gender, and co-pathologies. Main outcomes and measuresAmyloid-{beta} plaques, phospho-tau pathology (tangles and tau-positive neurites), tau oligomers in synaptic-fractions, tau seeding activity, neurons, synapse density, and astrocyte and microglia activation were quantified. The relationships with bulk and microglia-specific RNA-sequencing were also examined. Statistical analyses employed ANOVA with Tukeys HSD/Bonferroni corrections for pathological and clinical variables, and the Wald test for differential gene expression ResultsDemented AD and resilient brains exhibited comparable tau tangle and amyloid-{beta} plaques; however, demented AD showed higher total pTau burden (tangles and tau-positive neurites) (Mean[SD], 27.39%[21.89%] vs. 10.60%[14.71%]; p= 0.0004) and elevated pTau oligomer levels in synaptic-enriched fractions (0.48[0.52] vs. 0.16[0.19]; p=0.0010). Both demented AD (0.21x107[0.14x107]; p<0.0001) and IMP-O (0.62x107 [0.42x107]; p<0.0001) showed greater synaptic loss than resilient (1.54x107[0.55x107]; p=0.0008) and controls (2.92x107[1.13x107]). CD68+ microglia burden was increased in demented (1.14%[0.27%]; p<0.0001) and IMP-O (0.97%[0.36%]; p<0.0001) but not in resilient (0.72% [0.17%]; p=0.2835) compared to controls (0.59%[0.17%]). Synaptic pTau oligomers and CD68+ microglia were the strongest correlates with antemortem cognition. Resilient brains exhibited downregulation of neuroinflammation-related genes and possessed a distinct microglial subpopulation supporting resilience, characterized by overexpression of CD83, DUSP1, and NAMPT. Conclusion and relevanceOur findings suggest that aberrant accumulation of tau in neurites and synapses, rather than tangles within neuronal soma, may trigger a microglial pro-inflammatory activation linked to synaptic loss and impaired cognition. Cell-specific transcriptomic analysis identified a distinct microglial cell subpopulation associated with resilience to ADNC.