Early and late change on the preclinical Alzheimer's cognitive composite in clinically normal older individuals with elevated amyloid β

Abstract

Introduction: Sensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials.

Methods: We examined amyloid β (Aβ)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort.

Results: Aβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression.

Discussion: This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the prevention trial design.

Keywords: Amyloid PET; Cognitive composite; Longitudinal cognitive decline; Preclinical Alzheimer's disease; Secondary prevention.

Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Longitudinal change by Aβ status for the PACC and individual tests in the HABS. Aβ-related decline in present for the PACC4-96 (A) and all individual components (B–F). Z-scores are shown on the y-axis for all tests. Abbreviations: HABS, Harvard Aging Brain Study; PACC, preclinical Alzheimer cognitive composite.

Fig. 2

Effect sizes reflecting the group difference between Aβ+ and Aβ− groups after 3 and 5 years of follow-up across PACC iterations from the HABS. Effect sizes reflect the β estimate of the group difference between Aβ+ and Aβ− groups, divided by the standard error of that estimate. Blue is used to highlight PACC iterations that have excluded the FCSRT-Free, green is used to highlight the PACC iteration that excludes LMDR, and orange is used to highlight the PACC iteration that excludes the MMSE. Red is used to highlight the PACC-96. Removal of the FCSRT-Free results in smaller effect sizes at Year 3 and 5 (blue). Removal of LMDR results in a smaller effect size at Year 3 but not at Year 5 (green). Removal of the MMSE results in a larger effect size at Year 3 but not at Year 5 (orange). All other iterations are shown in gray. PACC iterations are as follows: (A) five components (FCSRT-Free, FCSRT-Total, LMDR, DS, and MMSE); (B) FCSRT-Free and FCSRT-Total combined (FCSRT-96, LMDR, DS, and MMSE); (C) no FCSRT-Total (FCSRT-Free, LMDR, DS, and MMSE); (D) no FCSRT-Free (FCSRT-Total, LMDR, DS, and MMSE); (E) no MMSE (FCSRT-Free, FCSRT-Total, LMDR, and DS); (F) no LMDR (FCSRT-Free, FCSRT-Total, DS, and MMSE); (G) no DS (FCSRT-Free, FCSRT-Total, LMDR, and MMSE); and (H) neither FCSRT measures (LMDR, DS, and MMSE). Abbreviations: FCSRT, Free and Cued Selective Reminding Test; HABS, Harvard Aging Brain Study; MMRM, mixed model of repeated measure; MMSE, Mini-Mental State Examination; PACC, preclinical Alzheimer cognitive composite.

Fig. 3

PACC decline by CDR progressor status in the HABS. A consistent pattern is present for the PACC4-96 (A) and individual components (B–F), such that decline is strongest in Aβ+ participants that also progress on the CDR 0.5. FCSRT-Free Recall is the only measure to show significant decline in the Aβ+ stable group (D). Z-scores are shown on the y-axis for all tests. Abbreviations: CDR, Clinical Dementia Rating; FCSRT, Free and Cued Selective Reminding Test; HABS, Harvard Aging Brain Study; PACC, preclinical Alzheimer cognitive composite.

Fig. 4

Effect sizes reflecting the group difference between the subset of Aβ+ CDR progressors and the Aβ− group after 3 and 5 years of follow-up across PACC iterations from the HABS. Effect sizes reflect the β estimate of the group difference between Aβ+ and Aβ− groups, divided by the standard error of that estimate. Blue is used to highlight PACC iterations that have excluded the FCSRT-Free, green is used to highlight the PACC iteration that excludes LMDR. Orange is used to highlight the PACC iteration that excludes the MMSE. Red is used to highlight the PACC-96. Removal of LMDR results in a smaller effect size at Year 3 but not at Year 5 (green). Removal of both FCSRT measures results in a smaller effect sizes at Year 5 (H). All other iterations are shown in gray. PACC iterations are as follows: (A) five components (FCSRT-Free, FCSRT-Total, LMDR, DS, and MMSE); (B) FCSRT-Free and FCSRT-Total combined (FCSRT-96, LMDR, DS, and MMSE); (C) no FCSRT-Total (FCSRT-Free, LMDR, DS, and MMSE); (D) no FCSRT-Free (FCSRT-Total, LMDR, DS, and MMSE); (E) no MMSE (FCSRT-Free, FCSRT-Total, LMDR, and DS); (F) no LMDR (FCSRT-Free, FCSRT-Total, DS, and MMSE); (G) no DS (FCSRT-Free, FCSRT-Total, LMDR, and MMSE); (H) neither FCSRT measures (LMDR, DS, and MMSE). Abbreviations: FCSRT, Free and Cued Selective Reminding Test; HABS, Harvard Aging Brain Study; MMRM, mixed model of repeated measure; MMSE, Mini-Mental State Examination; PACC, preclinical Alzheimer cognitive composite.