Sexually Dimorphic Association of Circulating Plasminogen Activator Inhibitor-1 Levels and Body Mass Index with Cerebrospinal Fluid Biomarkers of Alzheimer’s Pathology in Preclinical Alzheimer’s Disease

Article type: Research Article

Authors: Eruysal, Emily^{a; 1} | Ravdin, Lisa^b | Zhang, Cenai^b | Kamel, Hooman^{a; b} | Iadecola, Costantino^{a; b} | Ishii, Makoto^{a; b; *}

Affiliations: [a] Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA | [b] Department of Neurology, Weill Cornell Medicine, New York, NY, USA

Correspondence: [*] Correspondence to: Makoto Ishii, MD, PhD, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 E. 61st Street, 3rd Floor, New York, NY 10065, USA. Tel.: +1 646 962 8256; Fax: 646 962 0535; E-mail: [email protected].

Note: [1] Present address: Department of Anesthesia, New York Presbyterian Hospital – Weill Cornell Medicine, New York, NY, USA.

Abstract: Background:Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis that is associated with adiposity, has been implicated in Alzheimer’s disease (AD) pathogenesis. However, whether circulating PAI-1 levels are altered during preclinical AD remains unclear. Objective:To measure plasma PAI-1 levels in cognitively normal cerebrospinal fluid (CSF) AD biomarker positive and biomarker negative participants and to examine the association of plasma PAI-1 levels with CSF AD biomarkers and Mini-Mental State Examination (MMSE) scores. Methods:In this cross-sectional study, plasma PAI-1 levels were measured in 155 cognitively normal (Clinical Dementia Rating, CDR 0) non-obese older adults. 29 men and 26 women were classified as preclinical AD by previously established CSF tau/Aβ42 criteria. All analyses were sex stratified due to reported sex differences in PAI-1 expression. Results:Plasma PAI-1 levels were associated with body mass index (BMI) but not age in men and women. In men, plasma PAI-1 levels and BMI were lower in preclinical AD compared to control. Plasma PAI-1 levels were positively associated with CSF amyloid-β42 (Aβ42) and CSF Aβ42/Aβ40 and negatively associated with CSF tau/Aβ42, while BMI was positively associated with CSF Aβ42 and negatively associated with CSF p-tau181 and CSF tau/Aβ42. In women, plasma PAI-1 levels and BMI were similar between preclinical AD and control and were not associated with CSF AD biomarkers. For men and women, plasma PAI-1 levels and BMI were not associated with MMSE scores. Conclusion:These findings suggest that there are significant sex differences in the systemic metabolic changes seen in the preclinical stage of AD.

Keywords: Adipokines, Alzheimer’s disease, amyloid beta-peptides, body weight, body mass index, biomarker, immunoassay, PAI-1, sexual dimorphism, tau proteins

DOI: 10.3233/JAD-220686

Journal: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1073-1083, 2023