Finding subtypes of nonlinear patterns in longitudinal cognition decline

Abstract

AbstractBackgroundTo characterize subtypes of longitudinal cognition decline considering the possible nonlinear patterns.MethodOlder persons without dementia at study enrollment (n = 1,010) had annual cognitive testing for up to 24 years (mean = 9.9 years, SD = 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 and control for neuropathologic burden, we used a novel latent class functional mixed‐effects model which allows individuals to have different nonlinear patterns of cognitive decline under a unified model structure.ResultIn the latent class functional mixed‐effects model, postmortem markers (AD pathology, Lewy bodies, transactive response DNA‐binding protein 43 (TDP‐43) pathology, hippocampal sclerosis, atherosclerosis, gross infarcts) were associated with global cognitive decline. We found four subtypes of longitudinal cognition decline after adjustment for neuropathologic burden. The residual decline after adjustment 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.ConclusionLate‐life cognitive loss involves heterogenous nonlinear patterns. It mainly reflects non‐normative pathologic and mortality‐related processes rather than normative age‐related processes.