Awareness of memory impairment typically begins to decline several years before dementia onset, according to research published online ahead of print August 26 in Neurology. The decline in awareness is associated with postmortem evidence of TDP-43 pathology, tangles, and gross cerebral infarcts.
An unexpected finding of the study, according to the investigators, is that decline in awareness of memory impairment in dementia begins earlier in younger people, compared with older people. “The reason for this is uncertain, but it likely reflects a general awareness that memory loss is more normative at older ages rather than an age-related difference in awareness of one’s own memory loss,” said Robert S. Wilson, PhD, Professor of Neurological Sciences and Psychology at Rush University Medical Center in Chicago.
Participants Were Cognitively Healthy at Enrollment
It is unclear how common unawareness about one’s memory loss is, as well as when such unawareness develops. Some studies have shown an association between unawareness and dementia severity, but other research has found no such association. Longitudinal studies have not settled the question of whether unawareness changes over time. These studies mainly have focused on patients with prevalent dementia.
Dr. Wilson and colleagues analyzed data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study, three longitudinal clinical–pathologic studies of older persons without cognitive impairment at enrollment. All participants were age 50 or older at baseline. At the time of the analyses, 3,298 people had completed the baseline evaluation and agreed to brain autopsy at death. After the investigators excluded ineligible participants, 2,115 people were eligible for follow-up. Follow-up data were available for 2,092 people.
To track change in memory awareness in dementia, the researchers examined a subset of 239 persons who completed at least four annual evaluations and developed incident dementia before their last evaluation. This population had a mean baseline age of 79.2 and a mean follow-up of 10.8 years.
To investigate the pathologic basis of unawareness of memory impairment, the investigators analyzed a second subset of people who underwent neuropathologic examinations. A total of 662 participants underwent a brain autopsy and neuropathologic examination, and results were available for the first consecutive 627 persons. Dr. Wilson and colleagues analyzed the association of memory awareness with TDP-43 pathology in 585 of these patients. This population died at a mean age of 89.1 with a mean of 9.2 years of follow-up.
All participants had an annual clinical assessment that included a medical history, neurologic examination, and tests of memory and cognition. Participants were asked two questions about their memory that the researchers combined to obtain a subjective memory measure. In addition, participants underwent 19 cognitive tests annually, including tests of episodic, semantic, and working memory. After each evaluation, a clinician blinded to previously collected data diagnosed dementia.
Brain removal occurred at a mean of 8.2 hours after death. The neuropathologic examination included quantification of β-amyloid-immunoreactive plaques and tau-immunoreactive tangles. Researchers also assessed TDP-43 in six brain regions.
Memory Awareness Declined Before Dementia Onset
At baseline, subjective memory rating and episodic memory performance had normal distributions in the full study population. Patients did not tend to overestimate or underestimate their memory ability. Objective memory performance and subjective memory rating declined over time. Higher subjective memory at baseline predicted less episodic memory decline.
In the subset of 239 people, loss of memory awareness occurred in nearly all persons who developed dementia. Time of unawareness onset and rate of progression varied, however. Starting at a mean of 2.6 years before dementia onset, episodic memory awareness began to decline sharply at a mean rate of 0.260 units per year, which is nearly half of the baseline standard deviation. Memory awareness began to decline two to three years earlier in younger persons, compared with older persons. Neither sex nor education was related to change in memory awareness.
In the subset of 385 people with postmortem data, the measure of episodic memory awareness declined a mean of 0.035 units per year. In this group, TDP-43 pathology, tangle density, and gross cerebral infarcts were associated with more rapid decline in episodic memory awareness. When the researchers accounted for these associations, they found no change in episodic memory awareness. Dr. Wilson’s group also analyzed the entire study population who died with and without dementia and found that TDP-43 pathology, tangle density, and gross infarcts were each associated with declining awareness of episodic memory impairment in each subgroup, although the associations were stronger in the subgroup with dementia.
Findings Must Be Replicated