Remote Blood Biomarkers of Longitudinal Cognitive Outcomes in a Population Study

Abstract

Objective: The longitudinal association of the blood biomarkers total tau (t-tau), neurofilament light (Nf-L), and glial fibrillary acidic protein (GFAP) with common sporadic Alzheimer disease (AD) and cognitive decline is not established. Methods: Using a single molecule array technology, ultrasensitive immunoassays for serum concentrations of t-tau, Nf-L, and GFAP were measured in a population sample of 1,327 participants (60% African Americans and women) who had a clinical evaluation for AD, had completed in-home cognitive assessments, and had undergone 1.5T structural magnetic resonance imaging. Results: Higher concentrations of serum biomarkers were associated with the development of clinical AD; especially, the time-specific associations were notable: t-tau 8 to 16 years, and Nf-L and GFAP 4 to 8 years prior to clinical AD. Serum biomarkers were associated with faster cognitive decline over 16 years; baseline t-tau > 0.40pg/ml had 30% faster decline, Nf-L > 25.5pg/ml had 110% faster decline, and GFAP > 232pg/ml had 130% faster decline compared to those in the lowest quartile. Participants with baseline GFAP > 232pg/ml showed 160% faster decline in hippocampal volume compared to those with values < 160pg/ml. Additionally, higher baseline t-tau was associated with faster increase in 3rd ventricular volume, and baseline Nf-L and GFAP were associated with faster decline in cortical thickness. Interpretation: Serum t-tau, Nf-L, and GFAP predict the development of sporadic AD and cognitive decline, and changes in structural brain characteristics, suggesting their usefulness not only as screening and predictive biomarkers, but also in capturing the pathogenesis of Alzheimer dementia.

Plasma Glial Fibrillary Acidic Protein Detects Alzheimer Pathology and Predicts Future Conversion to Alzheimer Dementia in Patients With Mild Cognitive Impairment

“…It is possible that GFAP generally increases over time because of its signi cant correlation with age in both Aβ-negative and Aβ-positive groups (Aβ-: r = 0.57; Aβ+: r = 0.46); however, this could also suggest that higher concentrations of plasma GFAP are associated to general worsening in clinical symptoms, as the steepness of the increase in GFAP was higher in the group that evolved to AD dementia. This hypothesis is also reinforced by recent studies on CSF and plasma that show an inverse correlation between concentrations of GFAP and cognition (22,35).…”

“…Glial brillary acidic protein (GFAP) is expressed in the cytoskeleton of astrocytes and has been found signi cantly increased in CSF in AD and other neurodegenerative diseases compared to healthy controls (12)(13)(14)(15). GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD (16)(17)(18)(19)(20)(21)(22)(23)(24). Increase of plasma GFAP in AD patients was associated to amyloid-PET positivity and worse outcomes in global cognition (22,24,25).…”

“…GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD (16)(17)(18)(19)(20)(21)(22)(23)(24). Increase of plasma GFAP in AD patients was associated to amyloid-PET positivity and worse outcomes in global cognition (22,24,25). Even though previous studies suggest that blood GFAP levels are elevated in AD and can identify an amyloid-PET positive status, no studies have been done investigating whether plasma GFAP can predict future conversion to AD dementia in patients with mild cognitive impairment (MCI).…”

Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment

“…Glial fibrillary acidic protein (GFAP) is expressed in the cytoskeleton of astrocytes and has been found significantly increased in CSF in AD and other neurodegenerative diseases compared to healthy controls [12][13][14][15]. GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD [16][17][18][19][20][21][22][23][24]. Different studies have shown that higher concentrations of plasma GFAP were associated to amyloid-PET positivity and worse outcomes in global cognition [22,[24][25][26][27].…”

“…GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD [16][17][18][19][20][21][22][23][24]. Different studies have shown that higher concentrations of plasma GFAP were associated to amyloid-PET positivity and worse outcomes in global cognition [22,[24][25][26][27]. Even though previous studies suggest that blood GFAP levels are elevated in AD and can identify an amyloid-PET positive status, only one study has measured GFAP in cognitively normal subjects followed over time for conversion to dementia (of any kind) [27].…”