Postmortem neurodegenerative markers and trajectories of decline in cognitive systems

Abstract

Objective: To assess whether neurodegenerative pathologies are differentially related to trajectories of change in different cognitive abilities.

Methods: At annual intervals for up to 21 years, 915 older participants in a longitudinal clinical-pathologic cohort study completed a battery of 15 tests from which previously established composite measures of episodic memory, semantic memory, working memory, and perceptual speed were derived. At death, they underwent a neuropathologic examination to quantify Alzheimer disease pathology, Lewy bodies, transactive response DNA-binding protein 43 (TDP-43) pathology, and hippocampal sclerosis plus multiple markers of cerebrovascular disease. Time-varying effect models were used to assess change over time in the relation of neuropathologic markers to cognitive trajectories.

Results: Controlling for pathology, decline in perceptual speed was evident about 15 years before death; modest decline in semantic and working memory occurred later; and there was little change in episodic memory. Each neurodegenerative marker was associated with lower episodic memory function beginning about 10 to 16 years before death. As time before death decreased, Alzheimer disease pathology, Lewy bodies, and hippocampal sclerosis were associated with impairment in other cognitive domains but the association of TDP-43 pathology with cognition continued to be mainly confined to episodic memory.

Conclusions: The results suggest that episodic memory impairment is an early sign of multiple neurodegenerative conditions, which primarily differ in their associations with other cognitive systems.

Figure 1. Residual change in cognitive domains after adjustment for cerebrovascular and neurodegenerative conditions

The time-varying effect model adjusted for age at death, education, sex, AD pathology, gross infarcts, microinfarcts, TDP-43 pathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy, atherosclerosis, and arteriolar sclerosis. The data represent the estimated mean cognition for a woman with average age at death (88.9 years), average years of education (16.4 years), low levels (10th percentile) of AD pathology (0.044), TDP-43 pathology (0), and cerebral amyloid angiopathy (0), and no other neuropathologies, with the black dotted line showing the initial estimated cognitive level and the red dotted line (with blue shading indicating the 95% confidence intervals) showing change in the estimated cognitive level as a function of years before death. AD = Alzheimer disease; TDP-43 = transactive response DNA-binding protein 43.

Figure 2. Neurodegenerative disease and change in cognitive domains (A) AD pathology, (B) Lewy bodies, (C) TDP-43 pathology, and (D) hippocampal sclerosis

The association of markers of neurodegenerative disease with change in different cognitive domains as a function of years before death, from time-varying effect models adjusted for age at death, education, sex, AD pathology, gross infarcts, microinfarcts, TDP-43 pathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy, atherosclerosis, and arteriolar sclerosis. The black dotted lines show the initial cognitive-pathologic association and the red dotted lines (with blue shading indicating the 95% confidence intervals) show change in the cognitive-pathologic associations as a function of years before death. AD = Alzheimer disease; TDP-43 = transactive response DNA-binding protein 43.

Figure 3. Cerebrovascular disease and change in cognitive domains (A) gross infarcts, (B) microinfarcts, (C) cerebral amyloid angiopathy, (D) atherosclerosis, and (E) arteriolar sclerosis

The association of markers of cerebrovascular disease with change in different cognitive domains as a function of years before death, from time-varying effect models adjusted for age at death, education, sex, AD pathology, gross infarcts, microinfarcts, TDP-43 pathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy, atherosclerosis, and arteriolar sclerosis. The black dotted lines show the initial cognitive-pathologic association and the red dotted lines (with blue shading indicating the 95% confidence intervals) show change in the cognitive-pathologic associations as a function of years before death. AD = Alzheimer disease; TDP-43 = transactive response DNA-binding protein 43.

Figure 4. Interaction of AD pathology and hippocampal sclerosis with episodic memory

The association of AD pathology and hippocampal sclerosis with episodic memory as a function of years before death from a time-varying effect model adjusted for age at death, education, sex, gross infarcts, microinfarcts, TDP-43 pathology, Lewy bodies, cerebral amyloid angiopathy, atherosclerosis, and arteriolar sclerosis. The black dotted line shows the initial cognitive-pathologic association and the red dotted line (with blue shading indicating the 95% confidence interval) shows the cognitive-pathologic association as a function of years before death. AD = Alzheimer disease; HS = hippocampal sclerosis; TDP-43 = transactive response DNA-binding protein 43.

Figure 5. Interaction of AD pathology and Lewy bodies with episodic memory

The association of AD pathology and Lewy bodies with episodic memory as a function of years before death from a time-varying effect model adjusted for age at death, education, sex, gross infarcts, microinfarcts, TDP-43 pathology, hippocampal sclerosis, cerebral amyloid angiopathy, atherosclerosis, and arteriolar sclerosis. The black dotted line shows the initial cognitive-pathologic association and the red dotted line (with blue shading indicating the 95% confidence interval) shows the cognitive-pathologic association as a function of years before death. AD = Alzheimer disease; TDP-43 = transactive response DNA-binding protein 43.