APOE ɛ4/ɛ4 Is Associated with Aberrant Motor Behavior Through Both Lewy Body and Cerebral Amyloid Angiopathy Pathology in High Alzheimer’s Disease Pathological Load

Article type: Research Article

Authors: Garcia-Segura, Monica Emili^a | Fischer, Corinne E.^{a; b; c} | Schweizer, Tom A.^{a; b; d; e; f} | Munoz, David G.^{a; g; h; *}

Affiliations: [a] Keenan Research Centre for Biomedical Research, The Li Ka Shing Knowledge Institute, St. Michaels Hospital, Toronto, ON, Canada | [b] Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada | [c] Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada | [d] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada | [e] Department of Surgery, Division of Neurosurgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada | [f] Division of Neurosurgery, St. Michaels Hospital, Toronto, ON, Canada | [g] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada | [h] Division of Pathology, St. Michaels Hospital, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Dr. David G. Munoz, Department of Laboratory Medicine, Room 2-0097 CC Wing, St. Michaels Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada. Tel.: +1 416 864 5858; Fax: +1 416 864 5648; E-mail: [email protected].

Abstract: Background:Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer’s disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. Objective:To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. Methods:Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ4 & ɛ4 and ɛ4/ɛ4 groups depending on ɛ4 copy number within APOE. Presence of AMB was assessed using NPI-Q. Results and Conclusion:AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOE ɛ4 alleles as compared to No ɛ4 & ɛ4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes.

Keywords: Aberrant motor behavior, Alzheimer’s disease, APOE gene, cerebral amyloid angiopathy, Lewy bodies, neuropathology, neuropsychiatric symptoms

DOI: 10.3233/JAD-190643

Journal: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1077-1087, 2019