Soluble and plaque amyloid associations with peripheral glucose dysregulation modulated by tau pathology in Alzheimer’s disease

Background Glucose metabolic dysfunction in Alzheimer’s disease (AD) has been reported to be associated with soluble amyloid-β oligomers (OAβ) and plaque amyloid. However, the potential modulatory role of tau pathology in these associations remains to be fully elucidated. Objectives To investigate whether tau pathology modifies the relationship between plasma OAβ burden, plaque amyloid, and systemic glucose metabolism in individuals across the AD spectrum. Design Cross-sectional observational study. Setting Memory clinic-based cohort from a single tertiary academic medical center in Republic of Korea. Participants A total of 113 older adults, including cognitively normal individuals, patients with mild cognitive impairment, and Aβ-PET–positive dementia patients. Measurements Plasma oligomeric Aβ (OAβ) levels were measured in blood samples using the Multimer Detection System, which quantifies oligomeric forms of Aβ in plasma. Aβ plaque deposition was assessed using [¹⁸F]-flutemetamol PET, and tau pathology was assessed using [¹⁸F]-flortaucipir PET, from which Braak staging was determined. Glucose metabolism was evaluated using fasting plasma glucose and hemoglobin A1c (HbA1c). Generalized linear models were used to examine the associations and potential interactions between plasma OAβ burden and plaque Aβ with tau pathology, adjusting for clinical covariates. Results A significant interaction was identified between plasma OAβ levels and Braak stage III/IV, but not Braak I or V/VI, when referenced to Braak 0. Only at Braak 0, higher plasma OAβ levels were associated with higher HbA1c compared with Braak stage III/IV (β = −4.191, 95 % CI −7.714 to −0.669, p = 0.020). No significant interactions were observed for fasting glucose or for Aβ-PET SUVR. Sensitivity analyses adjusting for diabetes diagnosis and excluding dementia participants confirmed the robustness of these findings. Conclusion Soluble Aβ oligomers, rather than plaque amyloid, are selectively associated with systemic glucose dysregulation in the absence of overt tau pathology. Tau staging may be crucial for identifying AD subgroups vulnerable to metabolic dysfunction potentially associated with early Aβ toxicity.