Evolution of anosognosia in alzheimer's disease and its relationship to amyloid

Abstract

Objective: Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer's disease (AD) that adversely affects a patient's safety and decision-making. However, there is a lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta-amyloid (Aβ) burden in a large cohort (N = 1,070) of individuals across the disease spectrum.

Methods: Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aβ deposition was measured at baseline using [18F]florbetapir positron emission tomographic imaging.

Results: Aβ predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aβ burden. Aβ and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (-0.08 discrepant-points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (-0.23 discrepant-points/yr), reaching anosognosia 3.2 years before dementia onset.

Interpretation: Aβ burden is associated with a progressive decrease in self-awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2020;87:267-280.

FIGURE 1:

Awareness of memory deficits decreases over time in high-amyloid participants. Left: Longitudinal changes in awareness (discrepant-points between participants and partners) in low (top row) and high (bottom row) amyloid participants. Middle: Longitudinal changes in participants’ self-complaints about memory deficits over time. Higher values are indicative of more severe memory difficulty reports. Right: Longitudinal changes in partners’ complaints about memory deficits over time. Higher values are indicative of more severe memory difficulty reports. In high-amyloid cognitively normal (CN), mild cognitive impairment (MCI), and dementia participants, self-complaints do not increase over time as much as partners’ complaints increase, resulting in a progressive decrease in memory awareness. [Correction added on December 11, 2019, after first online publication: In the preceding sentence, “Alzheimer disease” has been changed to “dementia.”] Shading represents 95% confidence intervals. All plots are adjusted for age and sex.

FIGURE 2:

Significant anosognosia is observed 3 years before progression to dementia. Longitudinal changes in participants’ self-complaints and partners’ complaints in cognitively normal (CN; n = 68) and mild cognitive impairment (MCI; n = 135) participants who clinically progressed during the study. Slopes were obtained from a linear mixed effect model with random intercept and slope predicting complaints over time, adjusting for age and sex. Dotted lines are located at −1.6 years and + 3.2 years.

FIGURE 3:

Anosognosia in cognitively normal (CN) and mild cognitive impairment (MCI) participants predicts future clinical progression. Top row: Kernel density plots of awareness for the CN (left) and MCI (right) participants who clinically progressed or remained stable. The left and right dotted lines are the awareness thresholds for significant anosognosia (−0.26) and heightened awareness (+0.20), respectively. Bottom row: Survival curves indicating the probability of remaining stable within a diagnostic group for CN and MCI participants with low awareness/anosognosia versus those with normal or heightened awareness at baseline.