Body mass index and blood volume influence plasma biomarkers and positron emission tomography classification in preclinical Alzheimer's disease

Abstract INTRODUCTION Blood‐based biomarkers (BBMs) are promising tools for Alzheimer's disease (AD) diagnosis, but their accuracy may be affected by body mass index (BMI) and blood volume (BV) through dilution. We investigated how BMI and BV influence BBM concentrations and PET prediction. METHODS Data from 241 cognitively unimpaired participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were examined to evaluate the influence of BMI/BV on BBMs (Aβ 42/40 , p‐Tau 181 , p‐Tau 217 , glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and BBM‐based PET predictions. RESULTS Elevated BMI/BV associated with lower BBM concentrations, especially for p‐Tau 217 and NfL, independent of brain amyloid burden. BMI‐stratified thresholds improved amyloid PET prediction, with higher BBM thresholds and area under the curve (AUC) values seen in normal weight compared to overweight or obese participants. Drastic BMI/BV declines due to weight loss increased BBM variability and systematic PET misclassification. DISCUSSION Adjusting for BMI/BV in BBM‐based diagnostics appears to improve accuracy and reliable detection of AD pathology, especially in preclinical stages. Highlights Body mass index (BMI) and blood volume (BV) significantly influenced plasma BBM concentrations in cognitively unimpaired (CU) individuals. Blood‐based biomarkers (BBMs) associated more strongly with BV than with BMI. Dilution effects were independent of brain amyloid burden. BMI‐stratified BBM thresholds improved amyloid positron emission tomography (PET) classification accuracy. Declines in BMI/BV resulted in PET prediction bias and systematic errors.