Weight, inflammation, and Alzheimer's disease in Down syndrome

PROJECT ABSTRACT/SUMMARY People with Down syndrome (DS) have a 75-90% lifetime risk for developing Alzheimer’s disease (AD).2,3 However, there is marked variability in the timing of AD, with a 30+ year range in the age of onset of clinical dementia8, suggesting that factors beyond trisomy 21 may influence AD in DS. Outside of DS, mid-life obesity or being overweight is an identified risk factor for later life AD, such that efforts to reduce body mass index (BMI) and increase physical activity have been proposed to be promising AD prevention programs. Adults with DS are at risk for being overweight and obese40--42, yet virtually nothing is known about whether mid-life BMI is associated with the timing of AD pathology and symptomology in DS. To date, studies examining BMI and AD in DS have focused on BMI after a clinical AD dementia diagnosis,49,51 used primarily cross-sectional methods,49,50 and/or relied on small sample sizes.51 The proposed F31 will provide training on advanced statistical analytic methods to assess longitudinal data, grow my knowledge on the valid assessment of AD pathology and cognition in DS, and develop professional skills for engaging in multisite research consortiums. The project will leverage already existing data to address three specific aims: 1) evaluate the effect of BMI and weight change on AD biomarkers (PET Aβ and tau PET) across 36 months, 2) examine the effect of BMI and weight change on cognitive performance (episodic memory, executive functioning, motor planning and control, and dementia symptoms) and clinical dementia status (cognitively stable, mild cognitive impairment, and dementia) across 36 months, and 3) explore if inflammatory biomarkers (serum c-reactive protein, IL-6, IL-10, and tumor necrosis factor alpha) are related to BMI and mediate the link between BMI and AD pathology and cognitive decline. This work will help me launch an independent program of research on healthy aging in DS that can inform social policy and intervention for preventing or delaying AD in DS and other at-risk populations.