Beyond the Triad: Incorporating Alzheimer's Disease and α-Synuclein Testing in the Evaluation of Idiopathic Normal Pressure Hydrocephalus

Abstract

Idiopathic normal pressure hydrocephalus (iNPH), characterized by ventriculomegaly and Hakim's triad of gait disturbance, cognitive impairment, and urinary dysfunction, is common in older adults. iNPH also remains one of the few potentially reversible neurological conditions, typically treated with cerebrospinal fluid (CSF) shunting. Although many patients improve, shunt responsiveness varies widely (≈60–90%), and a subset of patients show only transient benefit. A major contributor to this variability is the high prevalence of comorbid neurodegenerative disease with symptom overlap, particularly Alzheimer's disease (AD) and α-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The impact of these concomitant conditions on shunt outcomes, however, remains uncertain. We describe the incorporation of AD CSF biomarkers and α-synuclein skin biopsy into the iNPH evaluation to identify coexisting pathology. When integrated into routine workflow, approximately 32% of patients demonstrated AD-consistent CSF profiles and 31% had biopsy-confirmed α-synuclein pathology. We propose adopting concomitant neurological testing, especially in patients with atypical features to help inform patient selection and guide expectations. As the awareness and potential prevalence of iNPH rises and shunt procedures carry meaningful complication risks, delineating how comorbid disease modifies outcomes will be essential to improving the long-term success of shunting in iNPH.