Circulating plasminogen activator inhibitor‐1 (PAI‐1) levels in the preclinical stage of Alzheimer’s disease

Abstract

AbstractBackgroundPlasminogen activator inhibitor‐1 (PAI‐1), a secreted glycoprotein and member of the serine protease inhibitor family, has been implicated to have a role in Alzheimer’s disease (AD) pathogenesis by regulating amyloid‐beta (Aβ) accumulation (Neurobiol Aging 32:1079,2011; J Alzheimers Dis. 64:447,2018). A recent study found that plasma PAI‐1 was differentially expressed in subjects with Aβ pathology and neurodegeneration (A+TN+) compared to A‐TN‐ subjects, with decreased plasma PAI‐1 levels in clinical AD compared to cognitively normal controls (Alzheimers Dement 17:1452,2021). However, whether circulating PAI‐1 levels are altered during the preclinical stage of AD, where there is Aβ and tau pathology but no significant cognitive impairment, remains unclear.MethodCognitively normal (Clinical Dementia Rating of 0) volunteers from the Healthy Aging & Senile Dementia and Adult Children Study (Missouri, USA) with body mass index < 30, fasting plasma and cerebrospinal fluid (CSF) samples were included in this cross‐sectional study. Preclinical AD was defined by previously established CSF criteria (preclinical AD: 29 men, 26 women; control: 35 men, 65 women). Plasma PAI‐1 levels were measured by a commercially available immunoassay (MilliporeSigma) and log transformed.ResultIn men, plasma PAI‐1 levels were significantly lower in preclinical AD compared to control subjects (p=0.029) and were associated with CSF Aβ42 and p‐tau181 levels (CSF Aβ42: age‐adjusted beta coefficient 0.38, p=0.007; CSF p‐tau181: age‐adjusted beta coefficient ‐0.32, p=0.026) but not CSF tau levels (p>0.05). In women, there was no significant difference in plasma PAI‐1 levels between preclinical AD and control subjects (p>0.05).ConclusionThese studies raise the possibility that, in men, alterations in peripheral PAI‐1 occur during the earliest stages of AD. Studies in larger cohorts will be needed to confirm these observations and to determine their clinical utility and the underlying mechanisms of any sex differences.