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. 2021 May;27(5):426-438.
doi: 10.1017/S1355617720000934. Epub 2020 Oct 13.

Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease

Roos J Jutten  1 , Sietske A M Sikkes  1   2 , Rebecca E Amariglio  2   3 , Rachel F Buckley  2   3   4   5 , Michael J Properzi  2 , Gad A Marshall  2   3 , Dorene M Rentz  2   3 , Keith A Johnson  2   6 , Charlotte E Teunissen  7 , Bart N M Van Berckel  8 , Wiesje M Van der Flier  1 , Philip Scheltens  1 , Reisa A Sperling  2   3 , Kathryn V Papp  2   3 ; Alzheimer Disease Neuroimaging Initiative; National Alzheimer’s Coordinating Center, the Harvard Aging Brain Study, and the Alzheimer Dementia Cohort
Affiliations

Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease

Roos J Jutten et al. J Int Neuropsychol Soc. 2021 May.

Abstract

Objective: 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.

Method: 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.

Results: 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).

Conclusions: 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.

Keywords: Alzheimer’s disease; Cognitive decline; Disease progression; Outcome measures.

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Figures

Figure 1.
Figure 1.
Comparison between Category Fluency Test (CFT), Word List Delayed Recall, and Mini-Mental State Examination (MMSE), based on LMM adjusting for age, sex and education. Scores were z-transformed using overall group mean and SD, to facilitate comparisons between tests.
Figure 2.
Figure 2.
Annual change for individual tests based on LMM correcting for, age, sex and education, stratified per stage. For each test, scores were z-transformed using baseline overall group mean and SD, to facilitate comparisons between tests.
Figure 2.
Figure 2.
Annual change for individual tests based on LMM correcting for, age, sex and education, stratified per stage. For each test, scores were z-transformed using baseline overall group mean and SD, to facilitate comparisons between tests.
Figure 2.
Figure 2.
Annual change for individual tests based on LMM correcting for, age, sex and education, stratified per stage. For each test, scores were z-transformed using baseline overall group mean and SD, to facilitate comparisons between tests.
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