•Data were obtained from ADNI.

•Observational cohort of 1,266 participants.

•Subjects included in this study included cognitively unimpaired, mild cognitive impairment, and Alzheimer’s dementia,

•Subjects were further categorized by baseline HbA1c as non-diabetic (<5.7%), pre-diabetic (5.7-6.4%), or diabetic (≥6.5%).

•Outcomes included plasma amyloid-β (Aβ42, Aβ40, and Aβ42/40 ratio) and phosphorylated tau biomarkers (p-tau) across multiple assay platforms, amyloid and tau PET measures, cerebral white matter and meta-temporal volumetric measures, and WMH volume.

•Associations were evaluated using multivariable linear regression adjusted for follow-up time and demographic and clinical covariates.

Baseline demographic and clinical characteristics stratified by HbA1c category are shown in Table 1. Baseline plasma amyloid-β measures (Aβ42, Aβ40, and the Aβ42/40 ratio) and p-tau levels generally did not differ significantly across HbA1c categories (Table 2). Differences were observed in select volumetric and PET measures (Table 3), specifically composite reference SUVR, eroded subcortical white matter SUVR, and cerebral white matter volume, which remained significant after multiple-comparison correction. Tau meta-temporal volume was different across groups but was not sustained after correction. No significant associations were observed with meta-temporal tau PET burden, total brain volume, or WMH volume.

Baseline HbA1c levels are generally not associated with AD biomarkers, nor with cerebrovascular disease as measured by WMH. Most amyloid PET, tau PET, and volumetric measures did not maintain significant differences across groups. Generally, plasma Aβ42/40 ratio did not show overwhelming differences across groups. Our results indicate a minimal association between T2DM pathophysiology and in vivo neuropathological markers of AD, suggesting a different mediating mechanism.