Increase in GFAP concentration first observed in presymptomatic stages of familial Alzheimer’s disease, with increases over time


According to recently published data, the geometric concentration of glial fibrillary acidic protein (GFAP) is significantly increased in carriers of familial Alzheimer’s disease (FAD) compared to non-carriers, with levels beginning to differ in presymptomatic stages, approximately 16 years before the estimated onset of symptoms.1

At the end of the analysis, the estimated geometric mean concentration of GFAP in symptomatic carriers was 238% (95% CI, 141% to 374%; P P <.001 higher in presymptomatic carriers than non-carriers after adjusting for age and sex. addition the geometric mean of gfap concentration adjusted gender was ci to>P = 0.001) in symptomatic vs presymptomatic carriers.

Lead researcher Nick Fox, MD, director of the Dementia Research Center, University College London, and colleagues concluded that these results “confirm that plasma GFAP is a biomarker of early pathology in Alzheimer’s disease.” They also noted that these findings are consistent with other recent studies that have shown increases in GFAP to be associated with later decline in global cognition, amyloid accumulation, and conversion to dementia.

The study included 50 asymptomatic participants, of whom 23 carried mutations for FAD and 27 matched non-carrier controls. Study participants and clinicians were not informed of the FAD mutation status, which was determined using Sanger sequencing. The estimated number of years before and since symptom onset (EYO) was calculated by subtracting the age at which the participant’s affected relative first developed progressive cognitive symptoms from the participant’s age at the time of onset. blood sample. GFAP was log-transformed, with estimated coefficients back-transformed and expressed as multiplicative effects and geometric means.

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For non-carriers, the estimated geometric mean plasma GFAP concentration was 54% (95% CI, 2% to 133%; P = 0.039) higher in women than in men. There was no significant gender difference after omitting participants with higher GFAP levels (1 symptomatic mutation carrier, 1 non-carrier). After adjusting for age at visit and gender, geometric mean GFAP concentrations were estimated to be higher in symptomatic and presymptomatic carriers than in non-carriers (P <.001 for both comparisons which remained significant even after removing the outliers. in addition geometric mean of age- and sex-adjusted gfap concentration carriers was initially significantly higher>P = 0.04) than in non-carriers at 16-year-old EYO.

Regarding the significantly higher plasma GFAP concentrations seen in FAD carriers, the study investigators noted, “these are remarkable differences considering this is a blood test.” They added, “Nevertheless, the overlap between groups, outliers and intra-individual variability suggest that plasma GFAP may be more useful in combination with other AD blood biomarkers. This is consistent with recent studies on sporadic AD showing higher diagnostic yield for detecting underlying amyloid/AD pathology when GFAP was used in combination with other plasma markers.”

In 2021, notable findings published in JAMA Neurology highlighted the value of plasma GFAP as a sensitive biomarker across the AD continuum, from preclinical AD to AD dementia. Using a Simoa test, plasma GFAP levels were found to be significantly higher in people with preclinical AD compared to amyloid-ß-positive people without cognitive impairment, and were higher in people with symptomatic stages of the AD continuum. Moreover, not only were changes in the amplitude of plasma GFAP consistently higher than those of GFAP in cerebrospinal fluid, but plasma GFAP more accurately discriminated Aβ-negative individuals than GFAP in cerebrospinal fluid. CSF (plasma GFAP: area under the curve, 0.69-0.86; GFAP in CSF: AUC, 0.59-0.76).2

REFERENCES
1. O’Connor A, Abel E, Benedet A, et al. Plasma GFAP in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. J Neurol Neurosurg Psychiatry. 2022 Aug 10. doi:10.1136/jnnp-2022-329663.
2. Benedet AL, Mila-Aloma M, Vrillon A, et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels in the Alzheimer’s disease continuum. JAMA Neurol. 2021;78(12):1471-1483. doi:10.1001/jamaneurol.2021.3671.
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