Lack of awareness, or anosognosia, may be present up to 2 to 3 years before an Alzheimer dementia diagnosis is made.
A cohort study with cognitively normal older adults showed that unawareness, rather than heightened awareness, of memory decline was strongly associated with future clinical progression. This finding supports the idea that discordant self- and informant-reported cognitive decline may provide important information to clinicians.
Loss of memory is a defining symptom of Alzheimer disease, but not all patients are aware of their cognitive decline. This lack of awareness, or anosognosia, may be present up to 2 to 3 years before an Alzheimer dementia diagnosis is made, although is it highly prevalent later in the disease. Its converse, heightened awareness has also been shown to be present in the early stages of Alzheimer disease, with some individuals possessing insight into their early changes in cognition before their friends, family members, and medical practitioners even notice the changes.
This awareness is typically assessed in 1 of 3 ways: an interview with a clinician; comparing the individual’s self-assessment on a memory questionnaire to objective cognition scores; or comparing the individual’s self-assessment to an external assessment by their study partner on the same memory questionnaire.
However, the traditional scoring method has a major disadvantage. When individuals display unawareness in certain domains and heightened awareness in others, those differences are averaged out, making this measure insensitive to subtle changes in either direction. In their new study, investigators developed a new scoring approach that better separates the 2 dimensions of awareness into 2 distinct subscores.
First, the investigators aimed to compare each of the new subscores with each other and with the traditional awareness score, examining their changes over time. The second goal was to examine the association of each of the 3 measures at baseline with future clinical progression from cognitively normal to mild cognitive impairment or Alzheimer disease dementia.
The study included 436 individuals, including 53.2% female participants with a mean age of 74.5 years. The sample included 25 (5.7%) Black participants, 14 (3.2%) Hispanic participants, and 398 (91.3%) White participants. The mean total length of Clinical Dementia Rating (CDR) follow-up time was 5.48 years, and 91 individuals clinically progressed over their period of observation.
Selection criteria required both a participant and study partner response on the memory component of the Everyday Cognition (ECog) questionnaire from the same timepoint, a CDR examination with a global CDR score of 0 occurring within 1 year of their first ECog exam, and at least 2 follow-up CDR time points.
The traditional awareness score was not associated with progression, whereas the unawareness score was associated with progression. A 1-unit increase in the unawareness score was associated with an 84% reduction in progression hazard. Equivalently interpreted, a 1-unit decrease in score was associated with a 540% increase in progression hazard.
The trajectory of each awareness score over time was compared between those who progressed and those who remained stable during the observation period. Each model showed a significant interaction between progression group and time, with patients who progressed showing a steeper decline on every measure of awareness.
To better understand these patterns, the investigators also examined progression within a series of limited time frames, comparing individuals who progressed within 3, 6, or 9 years with those who remained stable for at least 3, 6, or 9 years, respectively. The findings largely agreed with the previous analyses, confirming a greater association between progression and the unawareness scores than with the heightened awareness score. However, the authors noted that these models were each limited in their sample size and confirmatory quantile regression models did not find the same significant difference.
Based on these findings, the investigators concluded that when combined in a single score, the effects of heightened awareness and unawareness in different domains can obscure one another. However, when isolated, researchers and clinicians can more clearly see subtle changes in either dimension, potentially improving early detection of Alzheimer disease and interventions.
Mimmack KJ, Gagliardi GP, Marshall GA, Vannina P. JAMA Netw Open. 2023;6(4):e239964. doi:10.1001/jamanetworkopen.2023.9964