Using a genetic risk score to estimate the earliest age of Alzheimer’s disease-related physiologic change in Body Mass Index

Objectives Weight loss is common in the years before an Alzheimer’s disease (AD) diagnosis, likely due to changes in appetite and diet. The age at which this change in body mass index (BMI) emerges is unclear but may point to the earliest manifestations of AD, timing that may be important for identifying windows of intervention or risk reduction. We examined the association between AD genetic risk and cross-sectional BMI across adults in mid-to late-life as an innovative approach to determine the age at which BMI changes and may indicate preclinical AD. Design Observational study Setting UK Biobank Participants 407,386 UK Biobank non-demented participants aged 39-70 with Caucasian genetic ancestry enrolled 2007-2010. Main Outcome Measures BMI (kg/m2) was constructed from height and weight measured during the initial visit. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 genetic variants previously confirmed to be genome-wide significant predictors of AD (Z-scored). We evaluated whether the association of AD-GRS with BMI differed by age using linear regression with adjustment for sex and genetic ancestry, stratified by age grouping (40-60, 61+). We calculated the earliest age at which high AD-GRS predicted divergence in BMI compared to normal age-related BMI trends with linear and quadratic terms for age and interactions with AD-GRS. Results In 39-49 year olds, AD-GRS was not significantly associated with lower BMI (0.00 kg/m2 per SD in AD-GRS; 95%CI: -0.03,0.03). In 50-59 year olds AD-GRS was associated with lower BMI (-0.03 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.06,-0.01) and this association was stronger in 60-70 year olds (-0.09 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.12,-0.07). Model-based BMI age-curves for people with high versus low AD-GRS scores began to diverge after age 47. Interpretation Genetic factors that increase AD risk begin to predict lower BMI in adults by age 50, with greater effect later in older ages. Weight loss may manifest as an early pathophysiologic change associated with AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by NIA grants T32-AG-049663 (WDB), K24-AG031155 (KY), RF1AG052132 (RAW and MMG), and R01AG059872 (MMG) and Community of Madrid Grant 2018-T1/BMD-11226 (SW). None of the authors’ funding organizations contributed to the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. All authors are independent from the funders. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Researchers can apply to UK Biobank (www.ukbiobank.ac.uk) to access the data used in this study. No additional data is available.