Cognitive Heterogeneity and Risk of Progression in Data-Driven Subtle Cognitive Decline Phenotypes

Abstract

Background: There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer's disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults.

Objective: We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of ≤129 across subgroups.

Methods: Hierarchical cluster analysis was conducted on individual baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer's Disease Research Center longitudinal cohort. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score ≤129, by cluster group.

Results: Cluster analysis identified 5 groups: All-Average (n = 139), Low-Visuospatial (n = 46), Low-Executive (n = 51), Low-Memory/Language (n = 83), and Low-All Domains (n = 46). Subgroups had unique demographic and clinical characteristics. Rates of progression to MCI/dementia or to DRS ≤129 were faster for all subgroups (Low-All Domains progressed the fastest > Low Memory/Language≥Low-Visuospatial and Low-Executive) relative to the All-Average subgroup.

Conclusion: Faster progression in the Low-Visuospatial, Low-Executive, and Low-Memory/Language groups compared to the All-Average group suggests that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. Use of comprehensive neuropsychological test batteries that assess several domains may be a key first step toward an individualized approach to early detection and fewer missed opportunities for early intervention.

Keywords: Alzheimer’s disease; cognitive phenotypes; heterogeneity; subtle cognitive decline.

Fig. 1

Baseline neuropsychological scores across the cluster-derived groups of cognitively unimpaired participants. Mean neuropsychological domain scores, rather than individual scores, are used for the figure only: Memory (CVLT Learning and Delay, Logical Memory Delay), Language (BNT/MINT, Category Fluency, Letter Fluency), Processing Speed (Trails A), Executive Functioning (Trails B, WCST Categories), Visuospatial (Block Design, CDT Command).

Fig. 2

Kaplan Meier curves for time to (A) progression to consensus MCI/dementia diagnosis and (B) progression to a Dementia Rating Scale score ≤129 since baseline visit.