Objectives:This observational study aimed to explore the pathophysiology of idiopathic normal-pressure hydrocephalus (iNPH) and to evaluate the diagnostic and prognostic value of CSF biomarkers.Methods:Lumbar CSF of patients with iNPH and healthy elderly individuals (HI) and ventricular CSF (VCSF) from the patients with iNPH pre and 6 months postsurgery were analyzed by ELISA. We analyzed neurofilament light protein (NFL), myelin basic protein (MBP), a panel of β-amyloid isoforms (Aβ38, Aβ40, and Aβ42), soluble amyloid precursor protein (sAPP) isoforms sAPPα and sAPPβ, total and phosphorylated tau protein (t- and p-tau), and inflammatory markers interleukin 8, interleukin 10, and monocyte chemoattractant protein 1.Results:NFL was elevated and amyloid precursor protein (APP)–derived proteins and tau proteins were lower in patients with iNPH than in HI. Postsurgery, there was an increase of NFL, APP-derived proteins, p-tau, and albumin in VCSF, whereas levels of MBP and t-tau had decreased. Improved patients showed a greater increase of APP-derived proteins in VCSF following shunting than did those who did not improve.Conclusions:We interpret our data as iNPH pathophysiology to be characterized by a reduced periventricular metabolism and axonal degeneration but no major cortical damage.