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. 2019;48(3-4):131-142.
doi: 10.1159/000504341. Epub 2020 Jan 3.

Neurodegenerative Patterns of Cognitive Clusters of Early-Onset Alzheimer's Disease Subjects: Evidence for Disease Heterogeneity

Meredith L Phillips  1 , Eddie C Stage Jr  2   3 , Kathleen A Lane  3   4 , Sujuan Gao  3   4 , Shannon L Risacher  3   5 , Naira Goukasian  6 , Andrew J Saykin  3   5   7   8 , Maria C Carrillo  9 , Bradford C Dickerson  10 , Gil D Rabinovici  11 , Liana G Apostolova  2   3   5   7   8 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Neurodegenerative Patterns of Cognitive Clusters of Early-Onset Alzheimer's Disease Subjects: Evidence for Disease Heterogeneity

Meredith L Phillips et al. Dement Geriatr Cogn Disord. 2019.

Abstract

Background/aims: Alzheimer's disease (AD) with onset before 65 (early-onset AD [EOAD]) occurs in approximately 6% of cases and can affect nonmemory domains. Here, we analyze patterns of impairment in amnestic EOAD individuals using data-driven statistical analyses.

Methods: Cognitive data of 146 EOAD subjects were Z-normalized to 395 cognitively normal (CN) individuals. Domain-averaged Z-scores were adjusted for age, sex, and education followed by Wald cluster analysis of residuals. Magnetic resonance imaging and positron emission tomography comparisons of EOAD clusters to age-matched CN were done using Statistic Parametric Mapping 8. Cluster-level-family-wise error (p < 0.05) correction was applied. Mixed-effect models were used to compute longitudinal change across clusters.

Results: Scree plot using the pseudo-T-squared suggested a 4-cluster solution. Cluster 1 (memory-predominant impairment) showed atrophy/hypometabolism in medial/lateral temporal, lateral parietal, and posterior cingulate regions. Cluster 2 (memory/visuospatial-predominant) showed atrophy/hypometabolism of medial temporal, temporoparietal, and frontal cortices. Cluster 3 (memory, language, and executive function) and Cluster 4 (globally impaired) manifested atrophy and hypometabolism throughout the brain. Longitudinally between-cluster differences in the visuospatial and language/executive domains were significant, suggesting phenotypic variation.

Conclusion: We observed significant heterogeneity in cognitive presentation among amnestic EOAD subjects and patterns of atrophy/hypometabolism in each cluster in agreement with the observed cognitive phenotype.

Keywords: Cognition; Cognitive patterns; Early-onset Alzheimer’s disease; Heterogeneity; Magnetic resonance imaging; Positron emission tomography.

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Conflict of interest statement

Disclosure Statement: The authors have no conflicts of interest to declare

Figures

Figure 1.
Figure 1.
MRI significance and β Coefficient maps showing the comparison of each cluster to cognitively normal participants. The significance maps show p<0.05 thresholded FWE cluster-level corrected results.
Figure 2.
Figure 2.
[18F]FDG PET significance and β Coefficient maps showing the comparison of each cluster to cognitively normal participants. The significance maps show p<0.05 thresholded FWE cluster-level corrected results.
Figure 3.
Figure 3.
Amyloid PET Significance and β Coefficient maps showing the comparison of each cluster to cognitively normal participants. The significance maps show p<0.05 thresholded FWE cluster-level corrected results.
Figure 4.
Figure 4.
Longitudinal Cognitive Decline with 95% confidence interval by domain. Each figure shows the predicted change in standard deviation over 60 months of each cluster.
See this image and copyright information in PMC

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