Temporal Course and Pathologic Basis of Unawareness of Memory Loss in Dementia

Objective: To characterize the natural history and neuropathologic basis of unawareness of memory loss in late-life dementia.

Methods: Analyses are based on 2,092 older persons from 3 longitudinal clinical-pathologic cohort studies who had no memory or cognitive impairment at baseline. Annual evaluations included clinical classification of dementia plus self-rating and performance testing of memory. At death, there was a uniform neuropathologic examination to quantify 7 dementia-related pathologies.

Results: In the full group, memory ratings were modestly correlated with memory performance (intercepts r = 0.26, p < 0.001; slopes r = 0.23, p < 001) and so we regressed each person's memory performance on their memory ratings, and the residuals provided longitudinal indicators of memory awareness. In a subset of 239 persons who developed dementia, episodic memory awareness was stable until a mean of 2.6 years before dementia onset (95% credible interval -2.7, -1.6); thereafter, memory awareness declined rapidly (mean annual change -0.32, 95% credible interval -0.37, -0.28). Older age at baseline was associated with later onset of memory unawareness. In a subset of 385 persons who died and underwent neuropathologic examination, transactive response DNA-binding protein 43 (TDP-43) pathology, tau tangles, and gross cerebral infarcts were related to decline in memory awareness. In the absence of these pathologies, no decline in memory awareness was evident. Results were similar in subgroups with and without dementia.

Conclusions: Awareness of memory impairment typically begins to decline about 2-3 years before dementia onset and is associated with postmortem evidence of TDP-43 pathology, tangles, and gross cerebral infarcts.