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Multicenter Study
. 2018;65(3):1029-1039.
doi: 10.3233/JAD-171088.

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression

Nienke M E Scheltens  1 , Betty M Tijms  1 , Martijn W Heymans  2 , Gil D Rabinovici  3 , Brendan I Cohn-Sheehy  3 , Bruce L Miller  3 , Joel H Kramer  3 , Steffen Wolfsgruber  4 , Michael Wagner  4 , Johannes Kornhuber  5 , Oliver Peters  6 , Philip Scheltens  1 , Wiesje M van der Flier  1   1 ; Amsterdam Dementia Cohort, Alzheimer’s Disease Neuroimaging Initiative, German Dementia Competence Network, University of San Francisco Memory and Aging Center
Affiliations
Multicenter Study

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression

Nienke M E Scheltens et al. J Alzheimers Dis. 2018.

Abstract

Background: Alzheimer's disease (AD) is a heterogeneous disorder.

Objective: To investigate whether cognitive AD subtypes are associated with different rates of disease progression.

Methods: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses.

Results: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05).

Conclusions: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

Keywords: Alzheimer’s disease; clustering; cognition; dementia; disease progression; mortality; phenotypes; subtypes.

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Figures

Fig. 1.
Fig. 1.
Estimated changes over time inADphenotypes based on repeatedMMSE(left) andCDRsob (right) measures. The blue lines represent the memory phenotype; the red lines represent the non-memory phenotype. Linear mixed models showed that non-memory patients were characterized by faster yearly decline on MMSE than memory patients (2.81 ± 0.16 versus 1.92 ± 0.14, pinteraction < 0.001). In addition, non-memory patients showed faster yearly increase in CDR sob (1.79 ± 0.13 versus 1.32 ± 0.12, pinteraction < 0.001).
Fig. 2.
Fig. 2.
Kaplan-Meier curves visualizing mortality in AD phenotypes. Numbers of entering the intervals 4, 6, and 8 years are depicted below the figure. Cox proportional hazard models showed that compared with the memory subtype, patients with a non-memory subtype had an increased risk of mortality (uncorrected model 1: HR 1.36, CI = 1.00–1.85, p = 0.05; corrected model 2 [age, sex, APOE genotype]: HR 1.66, CI 1.18–2.32, p <0.01; corrected model 3 [age, sex, APOE genotype, and baseline MMSE]: HR 1.58, CI 1.12–2.21, p <0.01).
See this image and copyright information in PMC

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