Abstract
BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of abnormal proteins, such as β-amyloid and tau, in the brain, which precedes cognitive impairment. Although diabetes mellitus (DM) is a well-established risk factor for AD, few studies have investigated how the presence of DM affects the sequential pathogenesis of AD, specifically within the amyloid-tau-neurodegeneration (ATN) and cognition framework. OBJECTIVES: This study aims to investigate the trajectories of ATN biomarkers in relation to the presence of DM in the preclinical and prodromal stages of AD. DESIGN: Participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline were included. Subjects were followed for 12-192 months, with neuroimaging and cognitive assessments conducted at every 12 or 24 months. SETTING: This study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. PARTICIPANTS: A total of 603 participants aged 55-90 years were included, comprising 284 CN (25 with DM, 259 without DM) and 319 MCI (39 with DM, 280 without DM) individuals. MEASUREMENTS: ATN biomarkers were identified using florbetapir positron emission tomography (PET), flortaucipir PET, and magnetic resonance imaging (MRI), respectively. Cognition was assessed using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE). Moderation analysis was conducted to investigate the effect of DM on the association between ATN biomarkers of AD. RESULTS: Elevated amyloid standardized uptake value ratios (SUVRs) were associated with increased tau levels in the hippocampus, and this association was significantly enhanced by the presence of DM in MCI participants (p = 0.021). DM also strengthened the association between increased tau SUVR levels and neurodegeneration (indicated by decreased entorhinal cortical volumes; p = 0.005) in those with MCI. Furthermore, DM enhanced the association of decreased entorhinal (p = 0.012) and middle temporal cortex (p = 0.031) volumes with increased (worsened) CDR-SB scores in MCI participants. However, DM did not predict significant longitudinal changes in ATN pathology or cognitive decline in CN participants. CONCLUSIONS: Our study suggests that DM may increase the risk of AD by accelerating each step of the A-T-N cascade in the prodromal stage of AD, underscoring the importance of DM management in preventing the MCI conversion to AD.