Differential Cognitive Decline in Alzheimer’s Disease Is Predicted by Changes in Ventricular Size but Moderated by Apolipoprotein E and Pulse Pressure

Article type: Research Article

Authors: Sapkota, Shraddha^{a; *} | McFall, G. Peggy^{b; c} | Masellis, Mario^{a; d} | Dixon, Roger A.^{b; c; 1} | Black, Sandra E.^{a; d; 1}

Affiliations: [a] Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada | [b] Department of Psychology, University of Alberta, Edmonton, AB, Canada | [c] Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada | [d] Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Shraddha Sapkota, Department of Neurology, University of California, Davis, 1590 Drew Avenue, Unit #100, Davis, CA 95618, USA. Tel.: 530-754-0809; E-mail: sapkota@ucdavis.edu.

Note: [1] These authors contributed equally to this work as co-senior authors.

Abstract: Background:Differential cognitive trajectories in Alzheimer’s disease (AD) may be predicted by biomarkers from multiple domains. Objective:In a longitudinal sample of AD and AD-related dementias patients (n = 312), we tested whether 1) change in brain morphometry (ventricular enlargement) predicts differential cognitive trajectories, 2) further risk is contributed by genetic (Apolipoprotein E [APOE] ɛ4+) and vascular (pulse pressure [PP]) factors separately, and 3) the genetic + vascular risk moderates this pattern. Methods:We applied a dynamic computational approach (parallel process models) to test both concurrent and change-related associations between predictor (ventricular size) and cognition (executive function [EF]/attention). We then tested these associations as stratified by APOE (ɛ4–/ɛ4+), PP (low/high), and APOE+ PP (low/intermediate/high) risk. Results:First, concurrently, higher ventricular size predicted lower EF/attention performance and, longitudinally, increasing ventricular size predicted steeper EF/attention decline. Second, concurrently, higher ventricular size predicted lower EF/attention performance selectively in APOE ɛ4+ carriers, and longitudinally, increasing ventricular size predicted steeper EF/attention decline selectively in the low PP group. Third, ventricular size and EF/attention associations were absent in the high APOE+ PP risk group both concurrently and longitudinally. Conclusion:As AD progresses, a threshold effect may be present in which ventricular enlargement in the context of exacerbated APOE+ PP risk does not produce further cognitive decline.

Keywords: Alzheimer’s disease, Apolipoprotein E, attention, brain imaging, executive control, pulse pressure

Keywords: ClinicalTrials.gov, NCT01800214. Registered on 27 February 2013.

DOI: 10.3233/JAD-215068

Journal: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 545-560, 2022