Elevated protease-activated receptor 4 (PAR4) gene expression in Alzheimer’s disease predicts cognitive decline

• Published in: Neurobiology of aging 2024-08, Vol.140, p.93-101
• Main Authors: Winfree, Rebecca L., Erreger, Kevin, Phillips, Jared, Seto, Mabel, Wang, Yanling, Schneider, Julie A., Bennett, David A., Schrag, Matthew S., Hohman, Timothy J., Hamm, Heidi E.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Brain - metabolism; Cerebrovascular disease; Cognition; Cognitive Dysfunction - etiology; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cytokines; Female; Fibrinogen - genetics; Fibrinogen - metabolism; Gene Expression - genetics; Humans; Inflammation; Inflammation - genetics; Inflammation Mediators - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Male; NF-kappa B - genetics; NF-kappa B - metabolism; PAR4; Receptors, Thrombin - genetics; Receptors, Thrombin - metabolism; RNA, Messenger - metabolism; Thrombin; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2024.04.007

Platelet activation of protease-activated receptor 4 (PAR4) and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption, and inflammation. We evaluated mRNA expression of the PAR4 gene F2RL3 in human brain and global cognitive performance in participants with and without cognitive impairment or dementia. Data were acquired from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). F2RL3 mRNA was elevated in AD cases and was associated with worse retrospective longitudinal cognitive performance. Moreover, F2RL3 expression interacted with clinical AD diagnosis on longitudinal cognition whereas this relationship was attenuated in individuals without cognitive impairment. Additionally, when adjusting for the effects of AD neuropathology, F2RL3 expression remained a significant predictor of cognitive decline. F2RL3 expression correlated positively with transcript levels of proinflammatory markers including TNFα, IL-1β, NFκB, and fibrinogen α/β/γ. Together, these results reveal that F2RL3 mRNA expression is associated with multiple AD-relevant outcomes and its encoded product, PAR4, may play a role in disease pathogenesis. •F2RL3 mRNA was elevated in AD and associated with worse cognitive performance.•F2RL3 mRNA interacted with clinical AD diagnosis on longitudinal cognition.•F2RL3 mRNA correlated with β-amyloid, tau, and severity of CAA.•F2RL3 mRNA correlated with transcript levels of proinflammatory markers.