Attributable risk of Alzheimer's dementia attributed to age-related neuropathologies

Abstract

Objective: The degree to which Alzheimer's versus other neuropathologies contribute to the risk of Alzheimer's dementia is unknown. We examined the risk of Alzheimer's dementia attributable to pathologic AD and 8 other neuropathologies.

Methods: Participants (n = 1,161) came from 2 clinical-pathological studies of aging. Multivariable logistic regression models examined associations of 8 neuropathological indices with Alzheimer's dementia and quantified the percentage of cases attributable to each. Furthermore, because some dementia cases are not driven by common neuropathologies, we re-estimated the attributable risks after empirically adjusting for such cases.

Results: Of 1,161 persons, 512 (44.1%) had Alzheimer's dementia at time of death. With the exception of microinfarcts, all neuropathological indices were independently associated with greater odds of Alzheimer's dementia. Two hundred ten (41.0%) Alzheimer's dementia cases were attributable to pathological AD. Separately, 8.9% were attributable to macroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis, 11.7% to transactive response DNA-binding protein 43, 8.1% to cerebral amyloid angiopathy, 6.0% to atherosclerosis, and 5.2% to arteriolosclerosis. A total of 83.3% of cases were attributable to all 8 indices combined. However, after further adjustment for cases driven by other factors, a total of 67.5% of cases were attributable to all 8 neuropathologic indices combined.

Interpretation: Pathological AD accounts for a considerable percentage of Alzheimer's dementia cases, but multiple other neuropathologies also contribute. In total, just over two-thirds of Alzheimer's dementia cases are attributable to common age-related neuropathologies, suggesting that other disease and resilience factors are important. ANN NEUROL 2019;85:114-124.

FIGURE 1:

This figure shows the burden of mixed pathologies in the aging brain. The bar chart in the lower left corner shows the frequencies of individual neuropathological indices investigated in this study. Connected black dots on the x-axis indicate the specific combination of neuropathology represented (top 59 combinations shown). Histograms in the main panel show the frequencies of the neuropathological indices for persons with and without Alzheimer’s dementia proximate to death (present = blue versus absent = black), ordered by their frequency. The height of each bar corresponds to the number of persons with each combination. As illustrated in the figure, neuropathological indices frequently co-occur and the most common are (1) pathological AD only, (2) pathological AD and cerebral amyloid angiopathy, (3) macroscopic infarcts only, (4) pathological AD and Lewy bodies, and (5) pathological AD, cerebral amyloid angiopathy, and TDP-43 pathology. AD = Alzheimer’s disease; CAA = cerebral amyloid angiopathy; Athero = atheroslerosis; LB = lewy body pathology; HS = hippocampal sclerosis; TDP-43 = transactive response DNA-binding protein 43.

FIGURE 2:

This figure compares the areas under the receiver operating characteristic (ROC) curves under different models. The red curve shows the estimated ROC for the model with demographics only; the green curve for the model with demographic and pathological AD; the blue curve for the model with demographic, pathological AD, and other 7 neuropathological indices; and the black curve for the model with demographics, all 8 neuropathologic indices, as well as an empirically derived indicator adjusting for Alzheimer’s dementia not accounted for by these neuropathological indices.

FIGURE 3:

This figure illustrates the empirical approach of identifying individuals whose cognitive decline is not driven by the neuropathological indices studied here. Light gray lines represent model-estimated person-specific residual cognitive decline (ie, change in global cognition not explained by demographics and the 8 common neuropathological indices). The horizontal line represents the median global cognitive score at first AD diagnosis for all incident Alzheimer’s dementia cases (global cognitive score = −1.09). Individuals whose residual decline crossed this threshold were identified as Alzheimer’s dementia cases not accounted for by the 8 neuropathological indices.