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

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.