Investigating regional and cellular vulnerabilities to tau pathology in young-onset Alzheimer's disease

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PROJECT SUMMARY/ABSTRACT Development of cognitive problems at any age is devastating, but development of cognitive problems in working-age people with dependents represents a major public health concern. Young-onset Alzheimer's disease (YOAD) is defined as individuals who present before age 65 and lack mutations known to cause Alzheimer's disease (AD) pathology. Neuropathology and neuroimaging studies demonstrate greater tau accumulation in YOAD who often present with atypical, non-amnestic syndromes. Our preliminary data demonstrates that tau accumulation occurs through progressive maturity levels in tangle-bearing neurons, which disproportionately affects cortical more than limbic structures in YOAD. Moreover, we show younger age onset is associated with greater tangle accumulation and neuronal loss in nucleus basalis of Meynert (cholinergic hub) and locus coeruleus (noradrenergic hub) – two neuromodulatory hubs implicated in early stage of disease. As stereotypic amyloid-β plaque patterns are robustly observed regardless of age, and comorbid neuropathologies are less frequent in YOAD, this cohort is ideally suited for a targeted investigation of selective vulnerabilities to tangle pathology in AD. Regional vulnerabilities to advanced tangle maturity levels in corticolimbic structures and neuromodulatory hubs are hypothesized to underlie the syndromic heterogeneity observed in YOAD. The overall goal of this grant is to uncover signatures of regional and cellular vulnerabilities underlying syndromic heterogeneity in YOAD by investigating what modifies patterns of tangle accumulation and microglial activation. Our preliminary data from single-cell RNA sequencing underscores the importance of considering disease heterogeneity and the utility of quantitative neuropathology for validating gene expression changes. This proposal seeks to shift current research in AD by focusing on younger-aged individuals and demonstrating how regional variability can inform cellular biology even in the context of end-stage disease. To accomplish our goals and facilitate stratification by atypical and typical (amnestic) clinical syndromes, the MPI team has combined expertise and resources to amass one of the largest documented YOAD cohorts totaling 558 brains with available tissue for study. The goal of the grant is to test the following hypotheses: 1) Modifiers of the neuropathologic patterns of tau pathology in YOAD brains differ between cases stratified by atypical vs. typical (amnestic) clinical syndromes, 2) The most vulnerable neuronal populations to AD-tau share a similar molecular signature across corticolimbic regions reflective of syndromic heterogeneity in YOAD, and 3) Corticolimbic microglial activation patterns differ in the brains of YOAD cases stratified by atypical vs. typical (amnestic) clinical syndrome. Completion of this project will identify specific cell populations vulnerable to regional AD-tau pathology and identify modifiers of microglial activation patterns corresponding to aggressive tau accumulation in YOAD.