Unawareness of memory decline—as opposed to greater awareness—is associated strongly with future clinical progression of Alzheimer’s disease in older adults, according to new findings.¹

These findings were the result of a cohort study examining 2 specific elements of self-awareness of memory function in cognitively normal older adults: increased and decreased awareness.

Ideally, the research would lead to greater general knowledge about changes in either direction of these 2 dimensions, in relation to Alzheimer’s disease risk. It was authored by Kayden J. Mimmack, MS, from the Department of Neurology at Massachusetts General Hospital, Harvard Medical School.

“Based on previous findings, we hypothesized that greater baseline unawareness would be associated with impending clinical progression, and we expected this association to be weaker for heightened awareness,” Mimmack and colleagues wrote.²

Background and Findings

The investigators conducted a cohort study using data from the Alzheimer's Disease Neuroimaging Initiative, a multicenter study. The study’s 436 total participants were older adults who had normal cognitive function at the beginning of the study and were followed up for a minimum of 2 years.

Of the 436 participants in total included in the study, the research team noted that the group was 53.2% female and had a mean age of 74.5 years. Of the sample, 5.7% were reported as Black, 3.2% were Hispanic, and 91.3% were White.

The team collected data in the period between June of 2010 to December of 2021, and extracted information from the University of Southern California Laboratory of Neuro Imaging database in January of 2022. They defined clinical progression as being the first occurrence of 2 consecutive follow-up CDR scale global scores of 0.5 or more.

The traditional awareness score was calculated by the investigators by averaging the differences between the participant and their study partner's scores on the Everyday Cognition questionnaire. To generate an unawareness or heightened awareness subscore, positive or negative differences were capped by the research team at zero before averaging at the item-level.

The primary outcome, which was the risk of future clinical progression of the disease, was analyzed for each baseline awareness measure using Cox regression analysis. Linear mixed-effects models were also used to compare the longitudinal trajectories of each measure.

The investigators reported overall that in the observation period, 20.9% of participants ended up clinically progressing. The team also noted that a 1-point improvement on the unawareness subscore was associated with an 84% reduction in progression hazard (hazard ratio, 0.16 [95% CI, 0.07-0.35]; P < .001).

Conversely, the investigators found that a 1-point decrease was associated with a 540% increase in progression hazard (95% CI, 183% - 1347%). Additionally, they found that no substantial results were reported for the heightened awareness or traditional scores of the study.

They concluded that when these effects are combined, heightened awareness and unawareness may end up obscuring one another. Despite this fact, when isolated, the team noted that both researchers and physicians may be better able to identify subtle movement in either dimension.

“These new subscores hold potential for the early detection of AD and intervention in clinic, as well as greater specificity and sensitivity in research into the relationship between awareness and AD,” they wrote.

References

1. ^{Mimmack KJ, Gagliardi GP, Marshall GA, Vannini P, Alzheimer’s Disease Neuroimaging Initiative. Measurement of Dimensions of Self-awareness of Memory Function and Their Association With Clinical Progression in Cognitively Normal Older Adults. JAMA Netw Open. 2023;6(4):e239964. doi:10.1001/jamanetworkopen.2023.9964}
2. ^{Hanseeuw BJ, Scott MR, Sikkes SAM, et al; Alzheimer’s Disease Neuroimaging Initiative. Evolution of anosognosia in Alzheimer’s disease and its relationship to amyloid. Ann Neurol. 2020;87(2):267-280. doi:10.1002/ana.25649.}