APP and Cognitive impairment: PAI-1 is also the main physiological inhibitor of tissue plasminogen activator (tPA) and our prior work has shown that young adult, and middle-aged tPA−/− mice exhibit significant cognitive impairment, neuroinflammation, white matter injury, blood brain barrier leakage, glymphatic dysfunction, and increased deposition of thrombin, amyloid precursor protein, amyloid beta, and fibrin in the brain (Yu et al., 2019b).