Associations between cerebrospinal fluid biomarkers in individuals with normal cognitive function, mild cognitive impairment, or Alzheimer's disease by amyloid PET status: a cross-sectional survey

Abstract

BackgroundIt is unclear whether cerebrospinal fluid (CSF) biomarkers play different roles in mild cognitive impairment (MCI) and Alzheimer's disease. We aimed to investigate whether there is a difference in the correlations between CSF tau, P-tau, and Aβ42 in individuals with normal cognitive function, early MCI, late MCI, or Alzheimer's disease. Additionally, we aimed to identify risk factors for the different diagnoses. MethodsIn this cross-sectional study, we included individuals aged 55–90 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with normal cognitive function, early MCI, late MCI, or Alzheimer's disease. From the ADNI, we obtained florbetapir (18F) PET data and concentrations of CSF tau, P-tau, and Aβ42. Partial correlation analysis was performed to assess the correlations between the concentrations of CSF tau, P-tau, and Aβ42 after controlling for age. Multinomial logistic regression was conducted to assess the correlations between demographic and clinical variables in each group. FindingsWe included 558 individuals (140 with normal cognitive function, 233 with early MCI, 125 with late MCI, and 60 with Alzheimer's disease). In the group positive for amyloid plaques on amyloid PET (florbetapir standard uptake value ratio [SUVR] >1·11), a weak correlation existed between CSF Aβ42 and tau in participants with normal cognitive function (r=0·411, p=0·008) or Alzheimer's disease (r=0·298, p=0·027). In the group negative for amyloid plaques on amyloid PET (florbetapir SUVR ≤1·11), a strong positive association existed between CSF Aβ42 and tau in participants with normal cognitive function (r=0·645, p<0·001), early MCI (r=0·560, p<0·001), or late MCI (r=0·486, p=0·003). Aβ42 was significantly correlated with P-tau in individuals with normal cognitive function (r=0·596, p<0·001), early MCI (r=0·543, p<0·001), or late MCI (r=0·395, p=0·019). After adjusting for age, sex, education level, Mini-Mental State Examination (MMSE) score, CSF tau, and CSF P-tau, CSF Aβ42 was significantly associated with early MCI (adjusted odds ratio 0·99, 95% CI 0·99–1·00, p=0·02) and late MCI (0·99, 0·99–1·00, p=0·007) in individuals who were amyloid-PET negative. Among patients who were amyloid-PET positive, factors independently associated with early MCI, late MCI, and Alzheimer's disease were age and MMSE scores. InterpretationIn individuals negative for amyloid plaques on PET, high concentrations of CSF Aβ42 might protect against early and late MCI, although this association needs to be confirmed in future longitudinal studies. The number of patients with Alzheimer's disease with amyloid negativity was too small to allow for multivariate regression analysis. FundingNational Key Research and Development Program (grant number 2016YFC1306505), the National Natural Science Foundation of China (grant numbers 81873778 and 81501097), and the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20152201).