CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease

ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A42/A40 and A42/A38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A42 alone. MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of A42, A40, and A38 were assessed. CSF As were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid (F-18-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients. ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A42/A40 and A42/A38 ratios were significantly better predictors of abnormal amyloid PET than CSF A42. Lower A42, A42/A40, and A42/A38 ratios, but not A40 and A38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A38, A40, and A42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A42/A40 and A42/A38 ratios showed increased accuracy compared to A42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all As (including A42) were decreased. InterpretationThe CSF A42/A40 and A42/A38 ratios are significantly better than CSF A42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF A42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A42 should be used in the clinical work-up of AD.