Glial Fibrillary Acidic Protein High in Preclinical Alzheimer Disease

Individuals with preclinical AD may be characterized via the use of neuroinflammatory biomarkers, which could inform participant selection in disease-modifying clinical trials.

The use of neuroinflammatory plasma biomarkers to characterize individuals with preclinical Alzheimer disease (AD) is important for the selection of participants in clinical trials of new disease-modifying agents, according to study findings published study journal Alzheimer’s Research & Therapy.

For the study, researchers explored plasma biomarkers related to the neuroinflammation that is associated with AD in a group of individuals with preclinical AD. Further, they sought to compare these individuals with healthy older individuals, realizing that the use of a preclinical population will add valuable evidence to the body of literature on the onset of AD. An exploratory, cross-sectional substudy of a previously performed study that was registered in an international trial register was conducted.

Although the behavior of inflammatory biomarkers in patients with AD compared with healthy older individuals is well known, determining the behavior of these biomarkers in participants with preclinical AD is not well understood and can help supplement clinical information associated with the onset of AD. If these neuroinflammatory biomarkers are found to differ among those with preclinical AD, they may be used to select individuals with preclinical AD who are most likely to develop AD, who can then be chosen to participate in clinical trials of new disease-modifying agents.

A total of 50 healthy older individuals (mean age, 71.9 years; mean Mini-Mental State Examination [MMSE] score, >24) and 50 participants with preclinical AD (mean age, 73.4 years; mean MMSE, >24) were enrolled in the study. Those with preclinical AD were defined by cerebrospinal fluid (CSF) beta-amyloid 1-42 (Aβ1-42) levels of <1000 pg/mL.

Measuring GFAP and YKL-40 in plasma of subjects with preclinical AD could be of added value to further differentiate subjects with lowered CSF Aβ42 from otherwise healthy elderly to better define the preclinical AD status.

Four neuroinflammatory biomarkers were determined in plasma:

  • Glial fibrillary acidic protein (GFAP)
  • Glycoprotein YKL-40 (also known as chitinase-3-like protein-1 [CHI3L1])
  • Monocyte chemoattractant protein-1 (MCP-1)
  • Eotaxin-1

Overall, 62 of the participants were male and 38 were female. The mean age of all participants was 72.6±4.6 years. Mean overall MMSE score was 28.7±0.49. In total,
32 participants were carriers of the apolipoprotein E (APOE) ε4 allele — which is known to be a clear risk factor for the development of AD. All of the participants had a Clinical Dementia Rating score of 0.

The researchers found that the number of participants in the different APOE ε4 status categories differed significantly between those in the Aβ+ and Aβ– groups (P =.003). Further, plasma GFAP concentration was significantly higher in the Aβ+ group compared with the Aβ– group (P <.001).

In line with the results of prior studies, GFAP was significantly higher among participants with preclinical AD compared with healthy older individuals. When preclinical AD was defined according to phosphorylated tau 181 (Ptau181)/Aβ1-42 ratio, YKL-40 also differed significantly between the groups. This might be indicative of the fact that GFAP and YKL-40 are more sensitive markers of the inflammatory process in response to the Aβ misfolding and aggregation that is occurring. This is observed with the lower Aβ1-42 levels in CSF.

Limitations of the current study warrant mention. The correlation reported between CSF Aβ42 and the CSF Ptau/Aβ42 ratio was based inherently on the use of CSF Aβ42 in the latter ratio. Further, since GFAP correlated significantly with the CSF Ptau/Aβ42 ratio but not with CSF Aβ42, this might be due to differences in sample size. Additionally, the individuals included in this analysis were not referred to a memory clinic; rather, they voluntarily participated in the study.

“Measuring GFAP and YKL-40 in plasma of subjects with preclinical AD could be of added value to further differentiate subjects with lowered CSF Aβ42 from otherwise healthy elderly to better define the preclinical AD status,” the researchers noted.

However, their study was exploratory and warrants further research.

They concluded that “If further research shows that these inflammatory plasma biomarkers are specific for (preclinical) AD, measuring these can be an important step forward in characterizing otherwise healthy elderly with preclinical AD in a less invasive manner,” the researchers concluded.


Prins S, de Kam ML, Teunissen CE, Groeneveld GJ. Inflammatory plasma biomarkers in subjects with preclinical Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):106. doi:10.1186/s13195-022-01051-2