Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

Abstract

BACKGROUND AND OBJECTIVES:

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.

METHODS:

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 (βtime) 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.

RESULTS:

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 (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime 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 (βtime 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.

DISCUSSION:

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.

• Authors: Mark A Dubbelman, Heleen M A Hendriksen, John E Harrison, Everard G B Vijverberg, Niels D Prins, Lior A Kroeze, Lois Ottenhoff, Mardou M S S A Van Leeuwenstijn, Inge M W Verberk, Charlotte E Teunissen, Elsmarieke M van de Giessen, Argonde C Van Harten, Wiesje M Van Der Flier, Sietske A M Sikkes
• Journal: Neurology (Neurology) Vol. 102 Issue 2 Pg. e207978 (Jan 23 2024) ISSN: 1526-632X [Electronic] United States
• PMID: 38165338 (Publication Type: Journal Article)

Chemical References

• Apolipoprotein E4
• Amyloidogenic Proteins
• Biomarkers

Topics

• Female
• Humans
• Male
• Alzheimer Disease (diagnostic imaging)
• Apolipoprotein E4 (genetics)
• Amyloidogenic Proteins
• Biomarkers
• Cognition