Genetic Architecture of Aging-Related TDP-43 and Mixed Pathology Dementia

Grants and Contracts Details


ABSTRACT (This grant is responsive to RFA NOT-AG-21-045.) Aging-related dementia is highly heritable, yet a large proportion of this genetic risk remains unexplained. In >30% of aged individuals with clinical dementia, autopsy reveals TDP-43 pathology—an enormous and under-appreciated public health problem. A term for this prevalent non-Alzheimer’s amnestic dementia was recently proposed: limbic predominant age-related TDP- 43 encephalopathy (LATE). There is great clinical and pathologic heterogeneity among individuals with LATE. Some affected individuals have a rapid and devastating clinical course whereas others have relatively subtle TDP-43 pathology with benign symptoms. Both the severity of TDP-43 pathology, and the presence of comorbid pathologies, appear to be key determinants of clinical outcomes in LATE. There is highly-incomplete understanding of the genetic determinants of LATE and associated pathologies. To address this knowledge gap, we will develop a robust analysis pipeline (leveraging extensive prior work) that includes data-driven classification methods, and novel statistical methods to analyze genetic risk/protective factors. Exciting preliminary data indicate distinct genetic risk factors for LATE and associated pathologies. AIM 1: Assemble multimodal data sets for testing novel hypotheses about LATE pathogenesis, including clinical and genetics data, and develop rubrics for “pure” and “mixed” subtypes of pathology We will leverage extensive data processing resources to derive and test a pathological classification system optimal for research at the nexus between genetic risk and neuropathologic endophenotypes. Key endophenotypes included in the data set will include digital neuropathologic assessment of pathologies. These studies will aim to gather and curate clinical, genetic, and pathological information on diverse populations. AIM 2: Identify genetic regions associated with aging-related TDP-43 pathology in brain, i.e., LATE-NC We will employ genome-wide and targeted association testing, predicted quantitative trait loci (QTL) detection, and subsequent colocalization. Preliminary results demonstrate this is broadly feasible. A set of LATE risk factor genes has been discovered by us and others,1-5 including proof-of-concept: a LATE neuropathology gene previously linked to clinical AD (WWOX).6 AIM 3: Identify genetic regions and biologic pathways associated with LATE-associated neuropathologic endophenotypes: coexisting hippocampal sclerosis, arteriolosclerosis, and Alzheimer’s disease We will test the hypotheses that comorbid LATE-related phenotypes share genetic predisposition and can be treated as subtypes, and that underlying pathways are discoverable with multivariate, individual-specific network methodologies. We will expand our understanding of the genetic risk factors, disease-associated pathways, and the potential for modifying those pathways. We will develop and employ mutual exclusivity, clustering, and individual-specific network methods to infer pathways driving LATE-related pathologic phenotypes.
Effective start/end date4/15/233/31/26


  • National Institute on Aging: $1,714,473.00


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