Integrated amyloid, neurodegeneration, and vascular biomarkers estimate the risk of dementia progression in mild cognitive impairment

Background Progression from mild cognitive impairment (MCI) to dementia arises from heterogeneous mechanisms involving Alzheimer's disease (AD) pathology and vascular factors. Objective This study aimed to develop a multimodal biomarker model to estimate the risk of dementia progression and to examine whether carotid atherosclerosis provides independent prognostic value, particularly in amyloid-β (Aβ)-negative MCI. Methods We retrospectively analyzed 300 individuals with MCI who underwent baseline [ 18 F]florbetapir PET, structural MRI, carotid Doppler ultrasound, cognitive assessments, and APOE genotyping (2018–2021). Participants were followed for a total of 37 months to dementia based on longitudinal cognitive and functional decline, independent of follow-up amyloid PET findings. Aβ positivity was defined using Brain Amyloid Plaque Load criteria. Multivariable logistic regression and receiver operating characteristic analyses were performed. Results Among 189 Aβ-positive individuals, 30.7% (n = 58) progressed to Aβ-positive AD dementia, while 9.0% (n = 10) of 111 Aβ-negative individuals developed non-AD dementia. Independent factors estimating Aβ-positive AD dementia included higher Aβ burden (OR 2.34, p < 0.001), smaller hippocampal volume (OR 0.71, p < 0.001), greater carotid plaque count (OR 1.45, p = 0.001), lower Mini-Mental State Examination (OR 1.11, p = 0.002), and APOE ε4 carriage (OR 1.82, p = 0.021). The integrated model showed excellent performance (AUC 0.903; 95% CI: 0.814–0.968). In Aβ-negative MCI, carotid plaque burden was the primary estimator of non-AD dementia progression. Conclusions The prominent prognostic role of carotid plaques in Aβ-negative MCI underscores the vascular contributions to non-amyloid cognitive decline and highlights the importance of evaluating both AD-related and vascular mechanisms in prodromal dementia.