Varied effects of age-related neuropathologies on the trajectory of late life cognitive decline

Abstract

The objective of this study was to examine whether the effects of age-related neuropathologies on cognition change over time. Participants were 1096 deceased persons from two clinical-pathologic studies. All were without dementia at baseline, completed a detailed battery of cognitive tests annually over up to 21 years, died, and underwent detailed neuropathologic examinations to identify Alzheimer's disease pathology, vascular pathologies (i.e. macro- and microscopic infarcts, atherosclerosis, arteriolar sclerosis, and cerebral amyloid angiopathy), Lewy bodies, transactive response DNA-binding protein 43 (TDP-43) pathology, and hippocampal sclerosis. A time-varying effects model was used to flexibly characterize the trajectory of global cognition and assess whether the effects of demographics and each neuropathologic index on cognition changed over time. Results indicated that the mean trajectory of global cognition was characterized by gradual cognitive decline beginning ∼15 years before death and accelerated decline in the last few years. With the exception of microinfarcts and arteriolar sclerosis, all neuropathologies were associated with the cognitive trajectory. However, the nature of their associations varied. Alzheimer's disease pathology, macroscopic infarcts, Lewy bodies, TDP-43 pathology, and hippocampal sclerosis were associated with progressive cognitive decline, with their deleterious effects increasing over time. By contrast, atherosclerosis and cerebral amyloid angiopathy pathology were associated with a lower level of cognition but their effects were relatively stable over time. These results suggest that age-related neuropathologies are differentially related to late life cognitive trajectories. Whereas some contribute to progressive cognitive deterioration, others lower the level of cognition but exert relatively stable effects over time.

Keywords: Alzheimer’s; TDP-43; cognitive ageing; neuropathology; small vessel disease.

Figure 1

The estimated mean trajectory of global cognitive function (dotted red line) and the corresponding 95% confidence band (shaded area) derived from the fully-adjusted TVEM model. Dark blue indicates the area of the trajectory with the most dense cognitive data, and light blue indicates tails where cognitive data are more sparse.

Figure 2

The estimated effects of age (A, dotted red line), education (B, dotted red line), and male sex (C, dotted red line) on the trajectory of global cognition and the corresponding 95% confidence bands (shaded areas) derived from the fully-adjusted TVEM model. Dark blue indicates the area of the trajectory with the most dense cognitive data, and light blue indicates tails where cognitive data are more sparse.

Figure 3

The estimated effects of Alzheimer’s disease pathology (A, dotted red line), hippocampal sclerosis (B, dotted red line), and macroscopic infarcts (C, dotted red line) on the trajectory of global cognition and the corresponding 95% confidence bands (shaded areas) derived from the fully-adjusted TVEM model. Dark blue indicates the area of the trajectory with the most dense cognitive data, and light blue indicates tails where cognitive data are more sparse.

Figure 4

The estimated effects of Lewy body pathology (A, dotted red line) and TDP-43 pathology (B, dotted red line) on the trajectory of global cognition and the corresponding 95% confidence bands (shaded areas) derived from the fully-adjusted TVEM model. Dark blue indicates the area of the trajectory with the most dense cognitive data, and light blue indicates tails where cognitive data are more sparse.

Figure 5

The estimated effects of atherosclerosis (A, dotted red line) and cerebral amyloid angiopathy pathology (B, dotted red line) on the trajectory of global cognition and the corresponding 95% confidence bands (shaded areas) derived from the fully-adjusted TVEM model. Dark blue indicates the area of the trajectory with the most dense cognitive data, and light blue indicates tails where cognitive data are more sparse.