Background Emerging difficulty performing cognitively complex everyday tasks, or ‘instrumental activities of daily living’ (IADL) may be an early clinical sign of Alzheimer’s disease (AD). We aimed to investigate how changes over time in everyday functioning relate to cerebral tau burden across the AD clinical spectrum. Methods We included 581 participants (73.9 ± 7.6 years old; 52% female) from the Alzheimer’s Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247). We analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions in mixed-effects models. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). We additionally investigated tau-PET adjusted for, as well as interacting with, amyloid-β. Results Greater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning. These findings remained when adjusting for baseline global cortical amyloid-β; amyloid-β itself was only associated with change over time in FAQ scores when tau was not included in the model. When stratifying by diagnostic group, most associations between tau and everyday functioning, adjusted for amyloid-β, were present only in the symptomatic group. Conclusions The rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid-β, specifically in cognitively symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease.
ImportanceThe ability to separately explore 2 dimensions of self-awareness of memory function—increased and decreased awareness—in cognitively normal older adults provides an important opportunity to understand subtle changes in either direction in relation to risk of Alzheimer disease.ObjectiveTo investigate the association of a novel measure for self-awareness of memory function with future clinical progression in individuals who were cognitively normal at baseline.Design, Setting, and ParticipantsThis cohort study used data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study. Participants were older adults who were cognitively normal (ie, Clinical Dementia Rating [CDR] global score of 0) at baseline and had at least 2 years of follow-up. Data were collected from June 2010 to December 2021 and pulled from the University of Southern California Laboratory of Neuro Imaging database on January 18, 2022. Clinical progression was defined as the first instance of 2 consecutive follow-up CDR scale global scores of 0.5 or greater.Main Outcomes and MeasuresA traditional awareness score was measured by calculating the mean discrepancy between the participant and their study partner’s scores on the Everyday Cognition questionnaire. An unawareness or heightened awareness subscore was generated by capping item-level positive or negative differences at zero before averaging. The main outcome—risk of future clinical progression—was analyzed for each baseline awareness measure using Cox regression analysis. Longitudinal trajectories of each measure were additionally compared using linear mixed-effects models.ResultsThe 436-person sample included 232 (53.2%) female participants, with a mean (SD) age of 74.5 (6.7) years; 25 participants (5.7%) were Black, 14 (3.2%) Hispanic, and 398 (91.3%) White; and 91 participants (20.9%) clinically progressed over their period of observation. Survival analyses showed 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), or equivalently, a 1-point decrease was associated with a 540% increase in progression hazard (95% CI, 183% to 1347%), with no significant results for the heightened awareness or traditional scores.Conclusions and RelevanceIn this cohort study of 436 cognitively normal older adults, unawareness, rather than heightened awareness, of memory decline was strongly associated with future clinical progression, providing further support that discordant self- and informant-reported cognitive decline may provide important information to practitioners.
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