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Background: The pathological hallmarks of Alzheimer's disease such as amyloid plaques and neurofibrillary tau tangles are usually associated with the primary clinical manifestation of cognitive decline. Recent studies implicate that a subset of "resistant" individuals have high burden of AD pathology, yet do not exhibit dementia (cognitive decline). Here, we compared the publicly available gene expression profiles of these resilient individuals and susceptible individuals (showing both AD pathology and cognitive decline) in dorsolateral prefrontal cortex (DLPFC) brain tissue obtained from individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). Method: We conducted bulk RNA‐Seq analysis on data from the DLPFC of 239 individuals with differing AD pathological findings and clinical consensus diagnosis. This data set is available through the Synapse portal (AMP‐AD consortium). The patients were subdivided into four groups of control, weakly resilient, strongly resilient, and susceptible, according to their degree of pathology (Braak stage) and clinical cognitive diagnosis. The control group included individuals with no cognitive impairment and initial braak stages; 0 and 1. The weakly and strongly resilient groups included individuals with no and mild cognitive impairment with advanced Braak stages respectively, while the susceptible group comprised individuals with AD‐dementia and advanced tauopathy (Braak stage>4). We used DESeq2 between these groups with a multiple factor approach that corrected for sex and age of death. Result: Our findings provide insight into genes that may be attributable to weak or strong resilience in the presence of relatively advanced AD pathology. Some of these candidate genes, such as SERPINA5 and GIPR, have previously been associated AD pathology and other neurodegenerative diseases, but we also identified a set of less well‐characterized genes that may be involved in cognition specific contributions to AD resilience. Conclusion: Our study recapitulates genes with known associations with AD pathology, and also identifies new candidate genes and pathways worth pursuing further as potential therapeutic targets to mitigate cognitive decline associated with AD. As ongoing proteomics and snRNA‐seq data is generated, these candidates may be further refined through an integrative approach, yielding new insights into pathways involved in AD pathology‐mediated decline and cognitive resilience. [ABSTRACT FROM AUTHOR]

Background: Pathological tau is spread along anatomically connected networks, originating in areas containing particularly vulnerable cell populations. It is hypothesized that tau is released and spread as free tau, or via extracellular vesicles (EVs) that include exosomes (30‐150 nm), microvesicles (100‐1000 nm), and apoptotic bodies (1000‐5000 nM). While a variety of different EV tau species have been identified in tissue, cells, and bio‐fluids, EV tau has not yet been described from human post‐mortem tauopathy brain tissue. Method: Using a differential centrifugation and sucrose flotation method described by Perez‐Gonzalez et al., EVs were isolated from post‐mortem human frontal cortex tissue blocks from Alzheimer's Disease (AD), Corticobasal Degeneration (CBD), and Control cases (BA9, n=4/group). Result: Electron microscopy (EM) confirmed the presence of vesicles with characteristic shape and size of exosomes and microvesicles. As demonstrated by immunoblotting, EV tau from tauopathy cases contains very little full‐length tau, but is specifically enriched in tau fragments of 10‐15 and 30‐35 kDa. EVs from control cases contain low levels of full‐length tau, and no tau fragments. EV tau fragments are sarkosyl‐insoluble, protected by the lipid membrane of the vesicle, and are seed‐competent (RD‐tau biosensor FRET seeding assay, seeding of primary neurons, and significant spread of AT8+ tau in EV‐injected PS19 mouse hippocampi). Epitope mapping and mass spectrometry sequencing confirm the presence of C‐terminal tau fragments, and further proteomic analyses confirm the identity of EVs as secreted vesicles. Together, these data provide the first clues to tauopathy‐specific proteomic signatures of EVs, and identify exosome components derived from the most vulnerable cell populations. This work complements the biomarker literature showing that N‐terminal regions of tau are secreted into the cerebral spinal fluid, while C‐terminal regions are retained in the brain. Conclusion: The identification of a seed‐competent species encased in a vesicle that readily fuses with cell membranes confirms that EVs are likely a significant mediator of pathological tau spread in the human brain. Our continued investigation of EV tau cryo‐EM structure, and of EV tau‐containing vesicles will focus on identifying novel immunological targets for pathological tau, and the vesicles that facilitate its spread. [ABSTRACT FROM AUTHOR]