Alzheimer’s disease detected in blood a decade before clinical symptoms

Blood levels of glial fibrillary acidic protein (GFAP), a marker for astrogliosis, were highest around 10 years before the onset of symptoms in an inherited form of Alzheimer’s disease.

Three plasma biomarkers – phosphorylated tau (p-tau181), neurofilament light chain (NfL) and GFAP – were higher in mutation carriers than non-carriers in a Swedish cohort of autosomal dominant Alzheimer’s disease (ADAD), reported Caroline Graff, MD, PhD, of Karolinska Institutet in Stockholm, and her colleagues at Brain.

The trajectories showed that plasma GFAP concentrations began to change about 10 years before the expected onset of Alzheimer’s symptoms, followed by p-tau181 about 6 years before onset and NfL about 2 years before onset. .

“In total, plasma p-tau181, GFAP, and NfL appear to be feasible biomarkers for detecting different AD-related pathologies already in presymptomatic individuals,” Graff and colleagues wrote.

“Our results suggest that plasma GFAP may reflect Alzheimer’s disease pathology upstream of tangle accumulation and neurodegeneration,” they added. “The implications of these results require further validation, particularly given the limited sample size.”

The conclusions echo those announced in december by researchers for Mainly hereditary Alzheimer network, which showed elevations in plasma GFAP in hereditary Alzheimer’s disease a decade before the expected onset of symptoms. Other studies have shown Elevated plasma GFAP in older people at risk for Alzheimer’s disease.

“The exact origin of GFAP measured in plasma is not known,” Graff said. MedPage today. “This area of ​​research is currently of great interest because it may be an indication of some sort of inflammatory process in the brain..”

“The value of having a marker so many years before expected symptoms is that it gives a very large window of opportunity for intervention or monitoring,” Graff pointed out. “That is, it may be possible to delay the development of symptoms if the trigger for the increase in GFAP levels can be stopped or impeded. GFAP measurement would also be a possible marker to measure the effectiveness of the intervention.”

emerging blood biomarkers of Alzheimer’s disease can help trace pathology, but it’s unclear what disease processes can be detected in blood or whether blood biomarkers work well in clinical and preclinical stages of disease, Graff and colleagues noted.

The researchers evaluated 164 plasma samples from 33 carriers of the ADAD mutation and 42 non-carriers obtained from 1994 to 2018. ADAD is caused by mutations in the amyloid precursor protein. (APP), presenilin1 (DOG1), or presenilin2 (PSEN2) Genoa; it accounts for less than 1% of all Alzheimer’s cases. People with a relative whose Alzheimer’s disease was caused by a mutation have a 50% risk of developing the disease themselves.

Study participants came from two APPLICATION families (APPswe and Application Park) and an DOG1 family. In ADAD, the average age of onset of symptoms in a family can be used to estimate the expected age of onset for those at risk. The mean age at onset was 54 APPswe carriers of mutations, 56 Application Parkand 52 in the DOG1 family.

The characteristics of the carrier and non-carrier groups did not show statistical differences in the initial age, the year of expected onset, the proportion with a APOE4 allele and sex. Mixed-effects models showed that plasma concentrations of NfL, GFAP, and p-tau181, but not total tau, were increased in carriers compared to non-carriers. Plasma p-tau181 showed correlations with levels of total tau and p-tau181 in cerebrospinal fluid.

“We want to replicate the study using a larger sample set,” Graff said. “We will include more sampling time in the same individuals, as well as increasing the number of individuals from families with ADAD.”

The results also “strongly suggest that studies of sporadic Alzheimer’s disease should be conducted since the underlying pathology of hereditary and sporadic Alzheimer’s disease is the same,” she noted.