Change of Amyloid-β 1-42 Toxic Conformer Ratio After Cerebrospinal Fluid Diversion Predicts Long-Term Cognitive Outcome in Patients with Idiopathic Normal Pressure Hydrocephalus

Background: Alzheimer's disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-beta 1-42 (A beta(42)) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity. Objective: This observational study points to A beta(42) toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH. Methods: The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in A beta(42) toxic conformer ratio (%) [A beta 42 toxic conformer/A beta 42 x 100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, A beta(42), and A beta(42) toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively. Results: In the first cohort, A beta(42) toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement. Conclusion: Change in A beta(42) toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group.