Normative Cognitive Decline in Old Age

Objective To characterize trajectories of normative cognitive aging. Methods Older persons without dementia at study enrollment (n = 1,010) had annual cognitive testing for up to 24 years (mean = 9.9 years, standard deviation = 5.0), died, and underwent a neuropathologic examination to quantify 9 postmortem markers of common neurodegenerative and cerebrovascular conditions. To accommodate the heterogeneity in cognitive trajectories, we used functional mixed effects models, which allow individuals to have different patterns of cognitive decline under a unified model structure. Results In a functional mixed effects model, postmortem markers (Alzheimer disease pathology, Lewy bodies, transactive response DNA-binding protein 43 pathology, hippocampal sclerosis, atherosclerosis, gross infarcts) were associated with global cognitive decline. Residual global cognitive decline after adjustment for neuropathologic burden was weakly related to age at death; it occurred in only about one-third of participants, mostly proximate to death. Results were comparable after eliminating the initial cognitive assessments to minimize retest learning or controlling for frailty proximate to death. Analyses were also conducted with composite measures of episodic memory and perceptual speed. Residual decline not attributable to neuropathologic burden was confined to a subset for each outcome and was most evident proximate to death. Age at death was unrelated to residual decline in episodic memory but was related to residual decline in perceptual speed. Interpretation Late life cognitive loss mainly reflects non-normative pathologic and mortality-related processes rather than normative age-related processes. ANN NEUROL 2020;87:816-829