Increased GFAP Concentration First Observed in Presymptomatic Stages of Familial Alzheimer Disease, With Rises Over Time

Nick Fox, MD

According to recently published data, geometric glial fibrillary acidic protein (GFAP) concentration is significantly increased in carriers of familial Alzheimer disease (FAD) relative to noncarriers, with levels beginning to differ at presymptomatic stages, around 16 years before estimated symptom onset.¹

At the conclusion of the analysis, the estimated geometric mean GFAP concentration in symptomatic carriers was 238% (95% CI, 141% to 374%; P <.001) higher than in noncarriers, and was 95% (95% CI, 46% to 159%; P <.001) higher in presymptomatic carriers than in noncarriers, after adjusting for age and sex. Additionally, the age- and sex-adjusted geometric mean GFAP concentration was 73% higher (95% CI, 26% to 138%; P = .001) in symptomatic vs presymptomatic carriers.

Senior investigator Nick Fox, MD, director, Dementia Research Center, University College London, and colleagues concluded that these results "support plasma GFAP being a biomarker of early AD pathology." They also noted that these findings are consistent with other recent studies that showed GFAP increases being associated with subsequent decline in global cognition, amyloid accumulation, and conversion to dementia.

The study included 50 asymptomatic participants, 23 of which were mutation carriers for FAD and 27 noncarrier matched controls. Participants and study clinicians were blinded to FAD mutation status, which was determined using Sanger sequencing. Estimated years to and from symptom onset (EYO) was calculated by subtracting the age at which the participant’s affected parent first developed progressive cognitive symptoms from the participant’s age at blood sampling. GFAP was log-transformed, with estimated coefficients back-transformed and expressed as multiplicative effects and geometric means.

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For noncarriers, the estimated geometric mean plasma GFAP concentration was 54% (95% CI, 2% to 133%; P = .039) higher in females compared with males. There was no meaningful difference between sexes after omitting participants with higher GFAP levels (1 symptomatic mutation carrier, 1 noncarrier). After adjusting for age at visit and sex, geometric mean GFAP concentrations were estimated to be higher in both symptomatic and presymptomatic carriers compared with noncarriers (P <.001 for both comparisons), which remained significant even after removing the 2 outliers. Furthermore, the age- and sex-adjusted geometric mean GFAP concentration in carriers was first significantly higher (P = .04) than in noncarriers at EYO of 16 years.

Regarding the significantly higher plasma GFAP concentrations observed in FAD carriers, the study investigators noted, "these are remarkable differences given this is a blood-based assay." They added, "nonetheless, the overlap between groups, the outliers, and the within-individual variability suggest that plasma GFAP may be most useful in combination with other AD blood biomarkers. This is consistent with recent studies in 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 throughout the entire AD continuum, from preclinical AD to AD dementia. Using a Simoa assay, plasma GFAP levels were found to be significantly higher in individuals with preclinical AD in comparison with cognitive unimpaired amyloid-ß-positive individuals, and were higher among individuals in symptomatic stages of the AD continuum. Furthermore, not only did were plasma GFAP magnitude changes consistently higher than those of cerebrospinal fluid GFAP, but plasma GFAP more accurately discriminated Aß-negative individuals than CSF GFAP (plasma GFAP: area under the curve, 0.69-0.86; CSF GFAP: 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 disease: a longitudinal cohort study. J Neurol Neurosurg Psychiatry. August 10, 2022. 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 across the Alzheimer disease continuum. JAMA Neurol. 2021;78(12):1471-1483. doi:10.1001/jamaneurol.2021.3671.