TDP-43 Pathology, Cognitive Decline, and Dementia in Old Age

IMPORTANCE Cognitive decline is a leading cause of disability and death in old age but its neurobiological bases are not well understood. OBJECTIVE To test the hypothesis that transactive response DNA-binding protein 43 (TDP-43) is related to late-life cognitive decline. DESIGN, SETTING, AND PARTICIPANTS Longitudinal clinical-pathologic cohort study involving more than 40 Catholic groups across the United States. A total of 130 older Catholic nuns, priests, and monks underwent annual clinical evaluations, including detailed cognitive testing, for a mean of 10.1 years prior to death. On neuropathologic examination, we collected semiquantitative measures of TDP-43 pathology, density of neuronal neurofibrillary tangles, area occupied by amyloid-beta plaques, and the presence of alpha-synuclein Lewy bodies from multiple brain regions. Gross and microscopic cerebral infarcts and hippocampal sclerosis were also identified. MAIN OUTCOMES AND MEASURES Annual rate of change in a previously established composite measure of global cognition during a mean of 10.1 years of annual observation before death. RESULTS Transactive response DNA-binding protein 43 pathology, ranging from sparse to severe, was identified in 46% of participants and was associated with amyloid plaques, tangles, and hippocampal sclerosis but not neocortical Lewy bodies or cerebral infarcts. After controlling for amyloid plaques, tangles, and hippocampal sclerosis, TDP-43 pathology was associated with more rapid cognitive decline and accounted for nearly as much of the variability in rates of global cognitive decline as did tangles. Transactive response DNA-binding protein 43 pathology had a distinct cognitive profile that differed from other neuropathologic processes (related to decline in episodic and working memory but not in other cognitive domains), and it was elevated in those who developed dementia but not in those with mild cognitive impairment. CONCLUSION AND RELEVANCE The results suggest that TDP-43 is an important brain pathology underlying cognitive decline and dementia in old age.