Altered Amyloid-β and Tau Proteins in Neural-Derived Plasma Exosomes of Type 2 Diabetes Patients with Orthostatic Hypotension

Background: Emerging evidence suggests a role for orthostatic hypotension (OH) in contributing to the progression of Alzheimer’s disease (AD). The exosomes in the blood can reflect the pathological changes in the brain. Objective: To investigate whether neural-derived plasma exosomes pathogenic proteins of AD levels are associated with OH in diabetes mellitus (DM) patients. Methods: There were 274 subjects without dementia included in the study: 81 control participants (controls), 101 normotensive patients with DM without OH, and 92 patients with DM and neurogenic OH (DMOH). Neural-derived exosomal proteins were measured by ELISA kits for amyloid-β (Aβ) and tau. Results: The neural-derived exosome levels of Aβ42, total tau (T-tau), and tau phosphorylated at threonine 181 (P-T181-tau) in the DM with OH group were higher than those in the DM and control groups. Multivariable linear regression analysis showed that the presence of OH in patients with DM was associated with elevated exosomal Aβ42 (β= 0.172, p = 0.018), T-tau (β= 0.159, p = 0.030), and P-T181-tau (β= 0.220, p = 0.003) levels after adjustment for age, sex, APOE ɛ4, duration of type 2 diabetes, HbA1c, and cardiovascular risk factors. Furthermore, the levels of Aβ42, T-tau, and P-T181-tau in neural-derived exosomes were correlated with HIF-1α levels and the drop in mean cerebral blood flow velocity from the supine to upright position. Conclusion: The presence of OH in DM patients was independently associated with elevated the Aβ42, T-tau, and P-T181-tau levels in neural-derived plasma exosomes. Cerebral hypoperfusion from DM with OH are likely candidate mechanisms.