Plasma tau biomarkers are distinctly associated with tau tangles and decreased with Lewy body pathology.

INTRODUCTION: Plasma-to-autopsy studies are essential to understand how tau blood biomarkers change in relation to Alzheimer's disease (AD) brain pathology and how they are influenced by brain co-pathologies and comorbidities. METHODS: Plasma samples from 102 brain donors of the Vallecas Alzheimer Reina Sofia cohort were analyzed using a mass spectrometry method to measure the levels of six phosphorylated and two non-phosphorylated tau biomarkers. RESULTS: In cases with high pathological burden of AD, phosphorylated tau (p-tau)217 showed associations with neurofibrillary tangle counts across all regions, while p-tau205 was primarily linked to the frontal cortex, and the non-phosphorylated tau peptides were linked to the temporal cortex. Plasma tau levels decreased as Lewy body pathology progressed, even among individuals at the same tau Braak stage. All plasma biomarkers correlated with creatinine levels, as a marker of renal dysfunction, but this effect was mitigated when using the ratios phospho/non-phospho. DISCUSSION: Understanding how plasma tau biomarkers are influenced by co-pathologies and comorbidities is crucial for their accurate implementation. HIGHLIGHTS: The plasma phosphorylated tau (p-tau)217 ratio, followed by the p-tau205 ratio and p-tau217, were the best-performing biomarkers for detecting neuropathologically confirmed Alzheimer's disease (AD). In high AD cases, p-tau217 showed associations with neurofibrillary tangle (NFT) counts across all regions, while p-tau205 was primarily linked to the frontal cortex, and non-phosphorylated tau peptides were linked to the temporal cortex. We observed a decline in plasma tau levels as Lewy body pathology progressed, even among individuals at the same tau Braak stage. All plasma biomarkers correlated with creatinine levels, as a marker of renal dysfunction, but this effect was mitigated when using the ratios. Plasma p-tau199 displayed a distinct behavior compared to other p-tau species, showing no association with NFT counts in any brain region, but demonstrating significant correlations with brain volume and an effect on survival time.