Preclinical Alzheimer's and vascular biomarkers alter brain aging in cognitively normal adults: a MRI-based study

Introduction: The aging global population underscores the need to understand brain aging and its links to neurodegenerative diseases. While most brain aging studies use cognitive impairment as exclusion criteria, preclinical biomarkers may influence results, potentially masking early pathological effects. This study evaluates how preclinical AD and vascular biomarkers impact brain aging models in cognitively normal subjects. Methods: Using baseline data from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS), we analyzed 1,380 cognitively unimpaired participants (50+ years) stratified into five groups based on cerebrospinal fluid biomarkers (Aβ42, t-tau, p-tau) and vascular pathology (Fazekas scale, microbleeds). Structural MRI volumes of cortical/subcortical regions were normalized and compared using Nadaraya-Watson kernel regression. Bootstrapping and Bonferroni-corrected statistical tests assessed differences in the relationship between age and brain volume between groups. Results: Significant differences emerged in the relationship between age and brain volume in biomarker-negative and biomarker-positive groups, particularly in the entorhinal cortex, amygdalas, and basal forebrain (p < 0.01). The AD and mixed AD/vascular groups showed the largest deviations. Gender-specific analyses revealed stronger effects in males. Vascular pathology alone affected distinct regions (e.g., left entorhinal cortex) without amygdala involvement, suggesting disease-specific atrophy patterns. Discussion: Preclinical AD and vascular biomarkers significantly alter brain aging in cognitively normal individuals. These findings highlight the importance of biomarker stratification in brain age studies to avoid biased estimates. Entorhinal cortex and amygdala volumes may serve as sensitive early indicators of neurodegeneration, supporting their use in targeted interventions and personalized monitoring.