Levels of plasma neurofilament light and pTau‐181 predict for steeper cognitive decline in Typical AD and Hippocampal‐sparing compared to Limbic‐predominant AD subtype

Abstract

AbstractBackgroundRecent studies suggest plasma neurofilament light (p‐NFL) and phosporylated‐Tau‐181 (p‐pTau181) are valuable biomarkers for detecting faster cognitive decline in patients with Alzheimer’s Disease (AD) dementia. Recently, AD subtyping has been used to subgroup patients into AD phenotypes with possibly different cognitive prognoses. The aim of this study was to investigate the interaction between p‐NFL and p‐pTau‐181 and different AD subtypes to predict decline in episodic memory.MethodIn total, 357 non‐AD (Aß‐) (Cognitive Normal and Mild Cognitive Impairment) and 73 AD subjects (Aß+, according to mainly Amyloid‐PET or ‐CSF) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Subjects had at least one plasma sample and one MRI scan. The latter was used to subtype AD patients (Risacher et al. 2017). AD subjects were subtyped in Limbic‐predominant (18%), typical AD (67%) and Hippocampal‐sparing (15%) subtypes. The ADNI_MEM composite score was used as proxy for cognition. Linear mixed models were tested to predict cognitive decline up to 4.5 years of follow up (27.7±13.1 months) including the interaction between time, AD subtype and p‐NFL and p‐pTau‐181. Age, gender, education, and ApoE4 status were included in the models. Models were selected incrementally through model comparison (AIC, BIC). The final model included both p‐NFL and p‐pTau‐181.ResultThe AD subtypes did not differ in cognition (‐1±0.6 for the whole group) or age (74±8 ys for the whole group), but in gender. Higher p‐NFL levels in patients with Hippocampal‐sparing and Typical AD subtypes showed faster decline in cognition compared to non‐AD patients (p<0.05, both), while Limbic‐predominant did not. For p‐pTau‐181, the interaction with Limbic‐predominant was significant and the model showed stronger separation of cognitive decline across all AD subtypes than p‐NFL. Combining both biomarkers improved the model but only the interactive effects of pTau‐181 for Hippocampal‐sparing and typical AD subtypes were significant (p<0.05, both).ConclusionIn the Limbic‐predominant AD subtype the levels of the two plasma biomarkers p‐NFL and p‐pTau‐181 did not predict for progressive cognitive decline (episodic memory), suggesting that this AD subtype with late disease onset (contrary to the Hippocampal‐sparing subtype), cannot be early detected with plasma p‐NFL and p‐pTau‐181.