Alzheimer’s Disease Detected in Blood a Decade Before Clinical Symptoms

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Blood concentrations of glial fibrillary acidic protein (GFAP), a marker of astrogliosis, were higher about 10 years before symptom onset 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 the Karolinska Institutet in Stockholm, and colleagues in Brain.

Trajectories showed plasma GFAP concentrations started to change approximately 10 years before expected onset of Alzheimer’s symptoms, followed by p-tau181 at approximately 6 years before onset, and NfL approximately 2 years before onset.

“Altogether, plasma p-tau181, GFAP, and NfL seem to be feasible biomarkers to detect different Alzheimer’s disease-related pathologies already in presymptomatic individuals,” Graff and colleagues wrote.

“Our results suggest that plasma GFAP might reflect Alzheimer’s disease pathology upstream to accumulation of tangles and neurodegeneration,” they added. “The implications of these findings need additional validation, in particular because of the limited sample size.”

The findings echoed those reported in December by researchers for the Dominantly Inherited Alzheimer Network, which showed plasma GFAP elevations in hereditary Alzheimer’s a decade before expected symptom onset. Other studies have shown elevated plasma GFAP in older adults at risk of Alzheimer’s disease.

“The exact origin of GFAP measured in plasma is not known,” Graff told MedPage Today. “This area of research is currently of great interest since it may be an indication of some kind 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 of the increased GFAP levels can be stopped or hindered. Measurement of GFAP would also be a possible marker to measure the effectiveness of the intervention.”

Emerging blood-based biomarkers of Alzheimer’s can help trace pathology but it’s not clear which disease processes can be detected in blood or whether blood biomarkers work well in both clinical and preclinical disease stages, Graff and colleagues noted.

The researchers evaluated 164 plasma samples from 33 ADAD mutation carriers and 42 non-carriers obtained from 1994 to 2018. ADAD is caused by mutations in the amyloid precursor protein (APP), presenilin1 (PSEN1), or presenilin2 (PSEN2) genes; it accounts for less than 1% of all Alzheimer’s cases. People with a parent whose Alzheimer’s disease was caused by a mutation have a 50% risk of developing the disease themselves.

Study participants came from two APP families (APPswe and APParc) and one PSEN1 family. In ADAD, the mean age at symptom onset in a family can be used to estimate the expected onset age for at-risk individuals. The mean age at onset was 54 in APPswe mutation carriers, 56 in APParc, and 52 in the PSEN1 family.

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

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

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

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

The study was supported by grants from several entities including the Swedish Brain Foundation, the Swedish Alzheimer’s Foundation, and the ALF project.

Graff disclosed no relationships with industry. Co-authors disclosed multiple relationships with industry.

Primary Source

Brain

Source Reference: Johansson C, et al “Plasma biomarker profiles in autosomal dominant Alzheimer’s disease” Brain 2023; DOI: 10.1093/brain/awac399.

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