Cerebrospinal Fluid Tau Protein and Periventricular White Matter Lesions in Patients with Mild Cognitive Impairment: Implications for 2 Major Pathways

Background: Mild cognitive impairment (MCI) may be a heterogeneous condition rather than a uniform disease entity. Objective: To develop reliable tools that aid in identifying patients at risk of developing Alzheimer disease (AD) among heterogeneous populations with MCI to maximize the benefits of emerging therapies for AD. Design: A 2-year prospective study. Setting: Clinical follow-up in an outpatient memory clinic. Patients: Seventy-two consecutive older patients with memory complaints. Main Outcome Measures: Cerebrospinal fluid tau levels, severity of periventricular and deep white matter lesions, silent brain infarction on magnetic resonance imaging, plasma homocysteine levels, apolipoprotein E genotype, and other vascular risk factors were assessed at baseline. Results: Fifty-seven patients were diagnosed as having amnestic MCI. Forty-one patients with (AD-converted MCI group) or without (progressive MCI group) conversion to dementia and AD progressed over time, whereas the other 16 patients remained cognitively stable (stable MCI group). The stable MCI group was characterized by normal cerebrospinal fluid tau levels and a high grade of periventricular white matter lesions (PWMLs). The progressive MCI and AD-converted MCI groups had increased cerebrospinal fluid tau levels and low grades of PWMLs. A logistic regression model showed that age was significantly associated with developing PWMLs (P=.03; odds ratio, 1.15; 95% confidence interval, 1.0-1.3). Conclusions: Tau-related AD pathologic conditions and possibly ischemic PWMLs represent 2 major etiologies in the development of MCI, reflecting heterogeneity in the clinical progression. Because the progressive type of MCI may be a primary target of clinical trials that aim at secondary prevention of dementia, these patients should be identified by appropriate biomarkers and neuroimaging techniques.