CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios improve the diagnostic accuracy for Alzheimer’s disease

New biomarkers of algorithms may improve the diagnostic accuracy of cerebrospinal fluid (CSF) for Alzheimer’s disease (AD. The present study aimed to determine whether Aβ42/Aβ40 and Aβ42/Aβ38 ratios improve the diagnostic accuracy of AD during predementia and dementia stages in comparison to CSF Aβ42 alone. The study included three different cohorts comprising a total of 1182 subjects in whom CSF levels of Aβ42, Aβ40 and Aβ38 were assessed. CSF Aβs were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As standard of truth we used either amyloid (18F-flutemetamol) PET imaging or clinical diagnosis of well-characterized patients. Cohort 1 included 215 patients with mild cognitive symptoms, who underwent 18F-flutemetamol PET imaging. Cohort 2 comprised 339 subjects including controls, and patients with stable mild cognitive impairment, prodromal AD, AD dementia, Lewy body disease with dementia, subcortical vascular dementia and frontotemporal dementia. Cohort 3 comprised 628 participants including control, AD and Lewy body dementia groups. In cohort 1, the CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios were significantly better predictors of abnormal amyloid PET than CSF Aβ42 when using the Euroimmun immunoassay (Aβ42/Aβ40 ratio, AUC=0.95; Aβ42/Aβ38 ratio, AUC=0.94; Aβ42, AUC=0.89). Very similar results were obtained with the Meso Scale Discovery and Quanterix assays. Further, lower Aβ42, Aβ42/Aβ40 and Aβ42/Aβ38 ratios, but not Aβ40 and Aβ38, correlated with smaller hippocampal volumes. However, lower Aβ38, Aβ40 and Aβ42, but not the ratios, correlated with non-AD-specific subcortical changes, i.e. larger lateral ventricles and white matter lesions. In cohorts 2-3, the Aβ42/Aβ40 and Aβ42/Aβ38 ratios showed increased accuracy compared to Aβ42 when distinguishing AD from non-AD dementias, especially from Lewy body disease with dementia and subcortical vascular dementia, where all Aβs (including Aβ42) were decreased. Finally, the in vitro stability Aβ42, Aβ42/Aβ40 and Aβ42/Aβ38 were assessed in CSF samples after storage in polypropylene tubes. The ratios were less affected by storage of CSF in polypropylene tubes than Aβ42 alone. In conclusion, the present study shows that the CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are significantly better than CSF Aβ42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios better reflect AD-type pathology, whereas CSF Aβ42 also decline in response to non-AD subcortical pathologies. Finally, the ratios are more stable during CSF storage. These findings strongly suggest that CSF Aβ42/Aβ40 and Aβ42/Aβ38 measurements rather than CSF Aβ42 should be used in the clinical work-up of AD.