The Aβ1-42/Aβ1-40 ratio in CSF is more strongly associated to tau markers and clinical progression than Aβ1-42 alone

Background: Cerebrospinal fluid (CSF) A beta 1-42 levels and the A beta 1-42/A beta 1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional pathophysiological processes. Aims: To compare A beta 1-42 and the A beta 1-42/A beta 1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression. Methods: We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF A beta 1-42 and A beta 1-42/A beta 1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as"positive" or"negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models. Results: In the 1791 participants, the agreement between A beta 1-42 and A beta 1-42/A beta 1-40 was 78.3%. The A beta 1-42/A beta 1-40 ratio showed a stronger correlation with tTau and pTau181 than A beta 1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low A beta 1-42/A beta 1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for A beta 1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs. Conclusion: Although A beta 1-42 and A beta 1-42/A beta 1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the A beta 1-42/A beta 1-40 ratio in clinical laboratories in the context of AD.