Clinical and neuropathological associations of plasma Aβ₄₂/Aβ₄₀, p-tau217 and neurofilament light in sporadic frontotemporal dementia spectrum disorders

INTRODUCTION: Plasma amyloid beta₄₂/amyloid beta₄₀ (Aβ₄₂/Aβ₄₀) and phosphorylated tau217 (p-tau217) identify individuals with primary Alzheimer's disease (AD). They may detect AD co-pathology in the setting of other primary neurodegenerative diseases, but this has not been systematically studied. METHODS: We compared the clinical, neuroimaging, and neuropathological associations of plasma Aβ₄₂/Aβ₄₀ (mass spectrometry), p-tau217 (electrochemiluminescence), and neurofilament light ([NfL], single molecule array [Simoa]), as markers of AD co-pathology, in a sporadic frontotemporal dementia (FTD) cohort (n = 620). RESULTS: Aβ₄₂/Aβ₄₀ showed no clinicopathological associations. High p-tau217 was present in amnestic dementia (AmD) presumed to be due to FTD, logopenic primary progressive aphasia (lvPPA), and APOEε4 carriers, and correlated with worse baseline and longitudinal clinical scores, lower hippocampal volumes, and more severe AD co-pathology (Braak Stage). NfL was elevated in all FTD phenotypes, and correlated with clinical scores and frontotemporal brain volumes. DISCUSSION: Plasma p-tau217 has clinical, neuroimaging, and neuropathological correlates in sporadic FTD and may identify FTD cases with AD co-pathology. Highlights: Alzheimer's disease (AD) features could be identified with plasma phosphorylated tau217 (p-tau217) in frontotemporal lobar degeneration (FTLD). Plasma p-tau217 is a better discriminator of AD co-pathology and AD-associated features in FTLD than plasma amyloid beta₄₂/amyloid beta₄₀ (Aβ₄₂/Aβ₄₀) and neurofilament light (NfL). In FTLD, plasma p-tau217, but not Aβ₄₂/Aβ₄₀ or neurofilament light, has phenotypical, neurocognitive, and neuroimaging correlates suggestive of AD co-pathology.