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Alzheimer’s disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer’s Association (NIA-AA) research framework.
Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models.
1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p < .001). Word List Delayed Recall (β = −.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p < .001) and 4 (β = −2.23, p < .001).
We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.
Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aβ) burden.
In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63–90 years (mean 73.7±6) with 6–20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aβ burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aβ burden and SCC. A post-hoc mediation model was implemented to further understand the relationship between Aβ burden and SCC via their relationship with education.
Age (β = −0.84, p = 0.36) and sex (β = −0.55, p = 0.22) did not modify the relationship between SCC and Aβ burden. Fewer years of education was correlated with greater SCC (r = −0.12, p = 0.05), but the relationship between Aβ burden and SCC was stronger in those with more education (β = 1.16, p < 0.05). A partial mediation effect was found of Aβ burden on SCC via education (b = −0.12, 95% CI [−0.31, −0.02]).
These findings suggest that the association between SCC and Aβ burden becomes stronger with greater educational attainment. Thus, SCC may be of particular importance in highly educated CN individuals harboring amyloid pathology.
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