IMPACT OF TDP-43 AND HIPPOCAMPAL SCLEROSIS ON LATE-LIFE COGNITIVE DECLINE

Abstract

There is increasing recognition of the role of TAR-DNA binding protein 43kDa (TDP-43) and hippocampal sclerosis (HS) pathology in AD and dementia. We studied TDP-43/HS pathology and the rate of decline in global cognition and 5 specific cognitive domains, and determined the impact of AD mixed with TDP-43 pathology on late-life cognitive decline Data came from 1,374 community-based older persons from the Religious Orders Study and the Rush Memory and Aging Project who completed detailed annual cognitive testing and systematic neuropathological examination to identify AD, TDP-43, HS, and other age-related pathologies. To assess distinct rates of cognitive decline in single and mixed pathology profiles, persons were categorized into 4 groups; (1) a group without TDP, HS, or AD pathology (n=378), (2) TDP with or without HS, and no AD (TDP/HS) (n=91), (3) AD without TDP/HS (n=535), and (4) AD with TDP/HS (AD/TDP or AD/TDP/HS) (n=352). Rates of cognitive decline by pathologic groupings were examined using mixed-effect models adjusted for age, sex, education, and other pathologies, followed by post-hoc comparisons. Compared to those without TDP, HS, or AD, those with TDP/HS and no AD had a faster decline in global cognition (p=0.007) and episodic memory (p<0.001); however compared to persons with isolated AD, the TDP/HS without AD group had slower decline in global cognition (p=0.02) and episodic memory (p=0.01). The mixed AD with TDP/HS group had faster decline in global cognition and all 5 cognitive domains, compared to the AD alone and TDP/HS groups. In subsequent analyses, persons with mixed AD/TDP/HS had significantly faster decline in global cognition (p=0.02) and individual cognitive domains, specifically episodic (p=0.01) and semantic memory (p=0.006), than those with mixed AD/TDP. These data show that TDP/HS without AD pathology contributes to late-life memory decline but this decline is slower than that seen in those with AD only. Mixed AD and TDP pathologies show an additive effect on decline, with mixed AD/TDP/HS showing faster decline in memory and language. These findings have important implications for the development of biomarkers and for prognosis of late-life cognitive decline.