Plasma Amyloid-β Homeostasis Is Associated with Body Mass Index and Weight Loss in People with Overweight and Obesity

Article type: Research Article

Authors: Brook, Emily S.^{a; b} | D’Alonzo, Zachary J.^{a; b} | Lam, Virginie^{a; c} | Chan, Dick C.^d | Dhaliwal, Satvinder S.^{a; f; g; h} | Watts, Geraldb F.^{d; e} | Mamo, John C.L.^{a; c; i} | Takechi, Ryusuke^{a; c; *}

Affiliations: [a] Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, Australia | [b] Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, Australia | [c] School of Population Health, Faculty of Health Sciences, Curtin University, Bentley, Australia | [d] Medical School, University of Western Australia, Perth, Australia | [e] Cardiometabolic Service, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Australia | [f] Duke-NUS Medical School, National University of Singapore, Singapore | [g] Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia | [h] Singapore University of Social Sciences, Singapore | [i] Perron Institute of Neurological and Translational Sciences, Nedlands, Australia

Correspondence: [*] Correspondence to: Ryusuke Takechi, PhD, Curtin University Faculty of Health Sciences, Perth, WA, Australia. Tel.: +0430 227 755; E-mail: R.Takechi@curtin.edu.au.

Abstract: Background:Obesity is linked to a higher incidence of Alzheimer’s disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied. Objective:We hypothesized that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalize plasma concentrations of Aβ. Methods:Plasma concentrations of Aβ40, Aβ42, and Aβ42/40 ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations. Results:Plasma Aβ42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p < 0.0001), and 11.76% lower compared to participants with an overweight BMI (p < 0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p = 0.0005) and was associated with a 6.5% decrease in plasma Aβ40 (p = 0.0425). However, weight loss showed negligible correlations with plasma Aβ40, Aβ42, and Aβ42/40 ratio. Conclusion:Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.

Keywords: Alzheimer’s disease, amyloid-β, body mass index, obesity, weight loss

DOI: 10.3233/JAD-220529

Journal: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 653-664, 2023