Orthostatic hypotension ups dementia risk in T2DM

Having an orthostatic hypotension (OH) appears to promote the development of dementia in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI), suggests a study.

“In T2DM with MCI patients, Alzheimer’s disease (AD) biomarkers and complement proteins mediate the effects of OH on cognitive impairment, and OH may be a risk factor of progression from MCI to dementia in T2DM,” said lead author Dr Qiao Xiong, Department of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China.

Xiong and colleagues obtained blood samples and general healthy information from 249 T2DM patients with MCI (mean age 67.040 years) and isolated complement proteins of astrocyte-derived exosomes. They also quantified AD biomarkers of neuronal cell-derived exosomes isolated using enzyme-linked immunosorbent assay and conducted cognitive assessments at patient enrolment and follow-up.

In mediation analysis, AD biomarkers and complement proteins partially mediated the association between OH and cognitive impairment in T2DM patients: baseline Aβ42 (21.97 percent of total effect), T-tau (21.97 percent of total effect), P-T181-tau (29.67 percent of total effect), C3b (47.60 percent of total effect), and C5b-9 (52.50 percent of total effect). [J Clin Endoc Metab 2024;109:1454-1463]

On the other hand, “CD55 could not modulate the relationship between OH and cognition,” the researchers said.

In Cox proportional hazards regression, T2DM patients with OH showed a higher risk of developing dementia than their counterparts without OH.

“[W]e demonstrate that in patients with T2DM and MCI, OH is associated with cognitive impairment, and mediated by baseline Aβ42, T-tau, P-T181-tau, C3b, and C5b-9,” Xiong said. “OH can be used as a risk factor of dementia in T2DM with MCI.”

Mechanism

In an earlier study, OH correlated with cognitive decline longitudinally. However, the mechanisms behind the relationship between OH and cognition remained uncertain. [Eur J Neurol 2020;27:160‐167]

“One possibility is that OH leads to cerebral hypoperfusion, with subsequent consequences on Aβ and tau protein levels,” Xiong said.

Previous studies found that cerebral hypoperfusion could stimulate HIF-1 expression, which binds to the promoter of β-secretase and increases its expression. Cerebral hypoperfusion could also increase β-/γ-secretase activity, thus increasing the brain’s production of Aβ. [J Biol Chem 2007;282:10873‐10880; Mol Neurobiol 2012;47:425‐434; Am J Pathol 2010;177:300‐310]

Additionally, hypoperfusion has an impact on peptidases that degrade Aβ peptides, which then results in reduced Aβ clearance. [Front Aging Neurosci 2014;6:238; Brain Res 2019;1723:146379]

Cognitive decline

Some population-based studies of middle-aged and older people showed the association of OH with a higher risk of dementia and cognitive decline longitudinally. [Neurology 2018;91:e759‐ee68; Eur Heart J 2018;39:3135‐3143]

“Our previous study demonstrated that the T2DM patients with OH had transient, posture-mediated cognitive deficits compared with individuals with diabetes without OH,” Xiong said. [Ann Neurol 2019;86:754‐761]

“As the prevalence of OH is high in patients with T2DM, early identification and treatment of OH may greatly reduce the risk of dementia in T2DM patients with MCI,” the researchers said.