Diabetes mellitus accelerates preclinical Alzheimer's disease progression by amplifying the amyloid-to-tau pathway and attenuating brain-cognition resilience

Background Diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD), but its stage-dependent effects on the ATN framework remain unclear. Objective To determine whether DM differentially affects clinical progression from cognitively normal (CN) to mild cognitive impairment (MCI) versus MCI to AD, how DM modulates the ATN cascade, and the optimal follow-up for detecting structural-cognitive changes. Methods We analyzed longitudinal data from 1638 ADNI participants (765 CN, 71 with DM; 873 MCI, 91 with DM). Clinical progression was assessed by Cox regression. Annualized slopes of ATN biomarkers and cognition were estimated. Moderation analyses tested DM × predictor interactions on A→T (amyloid→tau) and N→C (neurodegeneration→cognition) pathways with FDR correction. Piecewise linear mixed models identified the optimal knot for structural-cognitive coupling. Results DM increased CN-to-MCI risk (adjusted HR = 1.73, p = 0.028) but not MCI-to-AD progression (adjusted HR = 1.10, p = 0.574). In CN, DM amplified amyloid-driven tau accumulation in entorhinal cortex (A→T interaction β = 0.77, FDR p = 0.043) and attenuated the protective effect of hippocampal volume on cognition (e.g., hippocampal volume slope × DM on MMSE slope: β = −0.19, FDR p = 0.031). These effects were absent in MCI (all FDR p > 0.05). A 36-month follow-up was the optimal window for detecting robust structural-cognitive coupling in the CN cohort, independent of DM status. Conclusions Diabetes accelerates preclinical AD by amplifying A→T and eroding structural-cognitive resilience, but does not hasten progression from established MCI to AD. A minimum 36-month observation period is recommended for early-phase prevention trials.