Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease...

It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups.

Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (β_time) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years.

We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (β_time range -0.30 to -0.71), followed by delayed word list recognition (β_time range -0.18 to -0.50). Functional decline (β_time range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (β_time range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction.

In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.