Plasma glial fibrillary acidic protein, neurofilament light, phosphorylated‐tau‐181 and amyloid β_42/40 as prognostic biomarkers for clinical progression to dementia in individuals with subjective cognitive decline and mild cognitive impairment

Abstract

BackgroundBlood‐based biomarkers can provide a non‐invasive and accessible way to identify neurodegenerative diseases before the clinical onset of dementia. Our study aimed to examine whether levels of phosphorylated‐tau‐181 (pTau181), amyloid beta1‐42/1‐40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are associated with risk of developing dementia in a memory clinic population of individuals with either subjective cognitive decline (SCD) or mild cognitive impairment (MCI).MethodFrom the Amsterdam Dementia Cohort we included 311 individuals with SCD (age 61±9 years, n=128 (41%) female, MMSE 29±1) and 252 with MCI (age 65±7 years, n=89 (35%) female, MMSE 27±2), who had annual follow‐up visits for re‐evaluation of diagnosis (average follow‐up duration: 2.7±1.7 years.) Baseline plasma biomarkers were measured using Simoa and the associations of the Z‐transformed biomarker concentrations with incident dementia were evaluated using Cox regression models adjusted for age, sex, baseline diagnosis and the interaction between baseline diagnosis (SCD/MCI) and the biomarker concentration. The markers were first evaluated individually and then simultaneously in a combined model. We stratified results for baseline diagnosis when the biomarker*diagnosis interaction was significant.ResultDuring follow‐up, 94 individuals developed dementia (14 with SCD, 80 with MCI at baseline, 86 Alzheimer’s Disease, 8 other forms of dementia; average time to progression: 2.8±1.8 years). We found an interaction between baseline diagnosis and NfL for incident dementia (p=0.03). No other interactions were found. In the total set, both high baseline pTau181 (hazard ratio (HR)=3.4 (95%CI: 1.3–9.0); figure 1A), and high baseline GFAP (HR=5.5 (95%CI: 1.6–18.6); figure 1B) were associated with increased risk of dementia, but the association with Aβ42/40 was not significant (HR=0.4 (95%CI: 0.2–1.1)). NfL had no significant association with increased dementia incident risk in both SCD subset (HR=1.8, (95%CI: 0.9‐3.6)) and the MCI subset (HR= 1.3, (95%CI: 1.0–1.6)). When we simultaneously entered all biomarkers, pTau181 and GFAP remained significantly associated with incident dementia (table 1.)ConclusionOur results suggest that plasma GFAP and pTau181 have prognostic value to predict dementia in individuals presenting at a memory clinic.

Risk of cognitive decline progression is associated to increased blood‐brain‐barrier permeability: A longitudinal study in a memory unit clinical cohort

“…Multiple studies have analyzed possible predictors that identify subjects at higher risk of clinical worsening, most of them in the AD continuum assessing AD pathology‐related fluid biomarkers as well as imaging biomarkers such as the dementia conversion‐related pattern (ADCRP) on [18F] Fluorodeoxyglucose Positron Emission Tomography (FDG PET) 43–47 . Our results show factors already described as strongly associated with progression of cognitive decline such as b‐AD (abnormal Aβ42/p‐Tau181 ratio), APOE‐ε4 carrier status, and female sex 48 .…”