Objective: To assess the contribution of Apolipoprotein E4 (APOE4) in Parkinson’s Disease (PD)-related cognitive impairment by analyzing its impact on Gray Matter Volume (GMV).

Background: Cognitive impairment is a prevalent non-motor symptom of PD. Yet, how it arises in PD remains unclear, demonstrating a need for further research to better detect those at-risk for it and identify early treatments to slow progression. APOE4 has been associated with PD cognitive decline, however, results are inconsistent and further clarification is required [1]. Reduced GMV has been observed in PD patients with cognitive impairment and in APOE4 carriers with cognitive deficits [2,3]. However, no study has investigated APOE4 status, GMV changes in cognitive brain regions, and cognitive function in a cohort of PD patients.

Method: Data for 52 PD APOE4 carriers and 123 PD APOE4 non-carriers was used from the Parkinson’s Progression Marker’s Initiative (PPMI). T1-weighted MRI images for each subject was extracted and underwent the CAT12 toolbox processing pipeline within SPM12 in MATLAB for Voxel-Based Morphometry (VBM) analysis [4]. A two-sample unpaired t-test including age and total intercranial volume (TIV) as co-variates compared GMV differences between carriers and non-carriers. Analyses were restricted to regions of interests (ROIs) previously reported to be associated with cognition and/or are adversely affected in PD APOE4 carriers. This includes the anterior and posterior cingulate, middle temporal gyrus, hippocampus, caudate nucleus, precuneus, and insula [5-12]. Linear regression models using R studio analyzed associations between GMV of ROIs and cognitive function (measured by Montreal Cognitive Assessment (MoCA) scores) based on APOE4 status [13]. Significant associations were examined for the impact of APOE4 status.

Results: PD APOE4 carriers and non-carriers did not significantly differ in MoCA scores. Preliminary analysis for investigated ROIs did not reveal significant differences in GMV using VBM between the two groups. Overall, no preliminary associations were present between GMV of ROIs and MoCA scores based on APOE4 status.

Conclusion: Preliminary observations suggest that VBM analysis for certain ROIs may not be able to detect changes in GMV in PD with APOE4, however further analyses with structural MRI are necessary to finalize this controversial aspect.

References: [1] Collins LM, Williams-Gray CH. The Genetic Basis of Cognitive Impairment and Dementia in Parkinson’s Disease. Front Psychiatry. 2016;7:89. doi:10.3389/fpsyt.2016.00089
[2] Xu Y, Yang J, Hu X, Shang H. Voxel-based meta-analysis of gray matter volume reductions associated with cognitive impairment in Parkinson’s disease. J Neurol. 2016;263(6):1178-1187. doi:10.1007/s00415-016-8122-3
[3] Spampinato MV, Rumboldt Z, Hosker RJ, Mintzer JE. Apolipoprotein E and Gray Matter Volume Loss in Patients with Mild Cognitive Impairment and Alzheimer Disease. Radiology. 2011;258(3):843-852. doi:10.1148/radiol.10100307
[4] Christian Gaser, Robert Dahnke, Paul M Thompson, Florian Kurth, Eileen Luders, Alzheimer’s Disease Neuroimaging Initiative. CAT – A Computational Anatomy Toolbox for the Analysis of Structural MRI Data. bioRxiv. Published online January 1, 2022:2022.06.11.495736. doi:10.1101/2022.06.11.495736
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[10] Rubin RD, Watson PD, Duff MC, Cohen NJ. The role of the hippocampus in flexible cognition and social behavior. Front Hum Neurosci. 2014;8:742. doi:10.3389/fnhum.2014.00742
[11] Shang S, Chen YC, Zhang H, et al. Mapping the Interactive Effects of ApoE Gene Polymorphism on Caudate Functional Connectivity in Mild Cognitive Impairment Associated With Parkinson’s Disease. Front Neurosci. 2020;14:857. doi:10.3389/fnins.2020.00857
[12] Leech R, Sharp DJ. The role of the posterior cingulate cortex in cognition and disease. Brain. 2014;137(1):12-32. doi:10.1093/brain/awt162
[13] R Core Team (2023). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. .

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