Much of late life cognitive decline is not due to common neurodegenerative pathologies

Abstract

Objective: The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline.

Methods: A total of 856 deceased participants from 2 longitudinal clinical-pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7.5 annual evaluations, including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of global Alzheimer pathology, amyloid load, tangle density, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. Random coefficient models were used to examine the linear relation of pathologic indices with global cognitive decline. In subsequent analyses, random change point models were used to examine the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline (ie, nonlinear decline).

Results: Cognition declined a mean of about 0.11 U per year (estimate = -0.109, standard error [SE] = 0.004, p < 0.001), with significant individual differences in rates of decline; the variance estimate for the individual slopes was 0.013 (SE = 0.112, p < 0.001). In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline.

Interpretation: The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.

Figure 1

Spaghetti plot of individual trajectories from a random sample of persons (N=50, Left panel) and mean slope of cognitive decline superimposed on their estimated individual slopes (model derived slopes, Right panel).

Figure 2

Contributions of combinations of the pathologic indices to cognitive decline (model derived slopes).

Figure 3

Variation in cognitive decline explained by the pathologic indices (grey) and the residual, unexplained variation in cognitive decline (white) derived from fully adjusted models.

Figure 4

Contributions of combinations of the pathologic indices to rates of preterminal and terminal cognitive decline, respectively (model derived slopes).

Figure 5

Rate of cognitive decline associated with high (red, 90^th percentile), medium (blue, 50^th percentile) and low (black, 10^th percentiles) levels of presynaptic proteins (model derived).