Cerebrospinal fluid abnormalities and rate of decline in everyday function across the dementia spectrum: Normal aging, mild cognitive impairment, and Alzheimer disease

Objective: To investigate the effect of cerebrospinal fluid (CSF) abnormalities on the rate of decline in everyday function in normal aging, mild cognitive impairment (MCI), and mild Alzheimer disease (AD). Design: Immunoassays of total tau (t-tau), tau phosphorylated at threonine 181 (p-tau₁₈₁), and β-amyloid 1-42 (Aβ₄₂) concentrations were performed in CSF obtained from participants in the Alzheimer's Disease Neuroimaging Initiative. Random effects regressions were used to examine the relationship among CSF abnormalities, cognitive impairment (assessed with the Alzheimer Disease Assessment Scale-cognitive subscale [ADAS-Cog]), and functional decline (assessed with the Pfeffer Functional Activities Questionnaire) and to determine whether the impact of CSF abnormalities on functional decline is mediated by cognitive impairment. Setting: Fifty-eight sites in the United States andCanada. Participants: One hundred fourteen cognitively intact adults, 195 patients with MCI, and 100 patients with mild AD. Main Outcome Measure: Decline in the Pfeffer Functional Activities Questionnaire score. Results: Abnormalities in all CSF analytes were associated with functional decline in MCI, and all but the t-tau: Aβ₄₂ ratio were associated with functional decline in controls. No abnormal CSF analyte was associated with functional decline in AD. Among controls, p-tau₁₈₁ concentration was the most sensitive to functional decline, whereas in MCI it was Aβ₄₂ concentration. Cerebrospinal fluid biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog score among controls and variably so in MCI, whereas the ADAS-Cog score was unequivocally more sensitive than CSF biomarkers in AD. The impact of CSF abnormalities on functional decline in MCI was partially mediated by their effect on cognitive status. Across all diagnostic groups, persons with both tau and Aβ₄₂ abnormalities exhibited the steepest rate of functional decline. Conclusions: Abnormalities in CSF are associated with functional decline and thus with future development of AD in controls and patients with MCI. However, they do not predict further functional degradation in patients with AD. Persons with comorbid tau and Aβ₄₂ abnormalities are at greatest risk of functional loss.