TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia

Abstract

Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP ) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer's disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer's-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer's-type dementia. Data came from 946 older adults with ( n = 398) and without dementia ( n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer's disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer's-type dementia formerly labelled 'pure pathologic diagnosis of Alzheimer's disease' was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer's-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer's disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer's disease and TDP-43 pathologies were associated with higher odds of clinical Alzheimer's-type dementia (odds ratio = 6.73, 95% confidence interval = 4.18, 10.85) than pathologic Alzheimer's disease alone (odds ratio = 4.62, 95% confidence interval = 2.84, 7.52). In models examining TDP-43 stage, a dose-response relationship with clinical Alzheimer's-type dementia was observed, and a significant association was observed starting at stage 2, extension beyond the amygdala. In this large sample from almost 1000 community participants, we observed that TDP-43 proteinopathy was very common, frequently mixed with pathological Alzheimer's disease, and associated with a higher likelihood of the clinical expression of clinical Alzheimer's-type dementia but only when extended beyond the amygdala.

Keywords: Alzheimer’s disease; TDP-43; dementia; epidemiology; neuropathology.

TDP-43 proteinopathy may lower the threshold for clinical expression of Alzheimer-type dementia. James et al. investigate the relationship between TDP-43 and Alzheimer’s dementia in a large cohort of community-dwelling older adults. Mixed Alzheimer/TDP-43 pathology is associated with increased likelihood of clinical Alzheimer-type dementia proximate to death, independent of other pathologies.

Figure 1

Mixed Alzheimer’s disease and TDP-43 pathologies by clinical Alzheimer’s-type dementia status proximate to death. Red = presence of pathologic diagnosis of Alzheimer’s disease (AD) without TDP-43. Blue = presence of pathologic transactive response DNA-binding protein 43 (TDP-43) without AD. Purple = presence of both AD and TDP-43. White = absence of AD and TDP-43.

Figure 2

Odds ratios for clinical Alzheimer’s-type dementia. Odds ratios provided for pathologic diagnosis of Alzheimer’s disease (AD) mixed with TDP-43 pathology, for pathologic diagnosis of AD without TDP-43 pathology, and for TDP-43 pathology without pathologic AD compared to not having pathologic diagnosis of AD or TDP-43 pathology, from a model adjusted for age, sex, education, cerebral infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis.