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

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

Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

INTRODUCTION: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aß) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty-nine percent had neither Aß nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aß only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non-demented persons Aß was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. HIGHLIGHTS: Amyloid beta (Aß; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aß should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.

Changes in self- and study partner-perceived cognitive functioning in relation to amyloid status and future clinical progression: Findings from the SCIENCe project.

INTRODUCTION: We investigated changes in self- and study partner-reported self-perceived cognitive decline in relation to amyloid pathology and clinical progression, in a sample of cognitively normal individuals. METHODS: A total of 404 participants (63 ± 9 years, 44% female) and their study partners completed the Cognitive Change Index (CCI) yearly (0.7-6.8 follow-up years; n visits = 1436). Baseline and longitudinal associations between (change in) CCI scores, amyloid, and clinical progression were modeled in linear mixed models and Cox regressions. RESULTS: CCI-study partner scores of amyloid-positive individuals increased over time (B = 1.79, 95% confidence interval [CI] = [0.51, 3.06]), while CCI-self scores remained stable (B = -0.45, 95% CI = [-1.77, 0.87]). Ten-point higher baseline CCI-study partner (hazard ratio [HR] = 1.75, 95% CI = [1.30, 2.36]) and CCI-self scores (HR = 1.90, 95% CI = [1.40, 2.58]) were associated with an approximately 2-fold increased risk of progression to mild cognitive impairment or dementia. DISCUSSION: Study partner-reported but not self-perceived complaints increase over time in amyloid-positive individuals, supporting the value of longitudinal study partner report, even in initially cognitively normal individuals.

Longitudinal change in ATN biomarkers in cognitively normal individuals.

BACKGROUND: Biomarkers for amyloid, tau, and neurodegeneration (ATN) have predictive value for clinical progression, but it is not clear how individuals move through these stages. We examined changes in ATN profiles over time, and investigated determinants of change in A status, in a sample of cognitively normal individuals presenting with subjective cognitive decline (SCD). METHODS: We included 92 individuals with SCD from the SCIENCe project with [18F]florbetapir PET (A) available at two time points (65 ± 8y, 42% female, MMSE 29 ± 1, follow-up 2.5 ± 0.7y). We additionally used [18F]flortaucipir PET for T and medial temporal atrophy score on MRI for N. Thirty-nine individuals had complete biomarker data at baseline and follow-up, enabling the construction of ATN profiles at two time points. All underwent extensive neuropsychological assessments (follow-up time 4.9 ± 2.8y, median number of visits n = 4). We investigated changes in biomarker status and ATN profiles over time. We assessed which factors predisposed for a change from A- to A+ using logistic regression. We additionally used linear mixed models to assess change from A- to A+, compared to the group that remained A- at follow-up, as predictor for cognitive decline. RESULTS: At baseline, 62% had normal AD biomarkers (A-T-N- n = 24), 5% had non-AD pathologic change (A-T-N+ n = 2,) and 33% fell within the Alzheimer's continuum (A+T-N- n = 9, A+T+N- n = 3, A+T+N+ n = 1). Seventeen subjects (44%) changed to another ATN profile over time. Only 6/17 followed the Alzheimer's disease sequence of A → T → N, while 11/17 followed a different order (e.g., reverted back to negative biomarker status). APOE ε4 carriership inferred an increased risk of changing from A- to A+ (OR 5.2 (95% CI 1.2-22.8)). Individuals who changed from A- to A+, showed subtly steeper decline on Stroop I (ß - 0.03 (SE 0.01)) and Stroop III (- 0.03 (0.01)), compared to individuals who remained A-. CONCLUSION: We observed considerable variability in the order of ATN biomarkers becoming abnormal. Individuals who became A+ at follow-up showed subtle decline on tests for attention and executive functioning, confirming clinical relevance of amyloid positivity.