An inherited form of Alzheimer’s disease (AD) could potentially be diagnosed at very early stages through levels of a protein called “glial fibrillary acidic protein” (GFAP) in an individual’s blood plasma, claims a study published in the journal Brain “Plasma biomarker profiles in autosomal dominant Alzheimer’s disease”. The study also corroborates earlier findings on changes in phosphorylated tau181 (P-tau181) and neurofilament light chain (NfL) levels in the plasma, however, changes in plasma GFAP concentrations precede changes in P-tau181 and NfL, the study found.

Early diagnosis of any disease offers the opportunity for early treatment and better outcomes. This is particularly true for progressive neurodegenerative diseases such as AD where pathological processes begin to take root in the brain decades before clinical manifestations of dementia become apparent.

Researchers at the Karolinska Institute in Sweden together with collaborators at the Landspitali University Hospital in Iceland, Gothenburg University, and the University College London in the U.K., conducted a longitudinal study to explore the diagnostic power of plasma biomarkers by comparing 33 individuals with autosomal dominant mutations known to cause AD and 42 individuals who did not carry such mutations.

“Our results suggest that GFAP, a presumed biomarker for activated immune cells in the brain, reflects changes in the brain due to Alzheimer’s disease that occur before the accumulation of tau protein and measurable neuronal damage,” said Charlotte Johansson, the lead author of the study, who is a doctoral student at the department of neurobiology, care sciences and society, at the Karolinska Institute. “In the future, it could be used as a noninvasive biomarker for the early activation of immune cells such as astrocytes in the central nervous system, which can be valuable to the development of new drugs and to the diagnostics of cognitive diseases.”

Autopsy studies over the years have established that progressive neurodegeneration and inflammatory glial activation in AD are associated with the accumulation of beta-amyloid plaques and tau tangles in the parenchyma of the brain. These abnormalities ultimately manifest as cognitive deficits in memory and speech.

Despite the increase in AD in recent years, affecting nearly 70% of all individuals with dementia, detecting the disease at early stages has remained a challenge. It is unclear whether changes detected in the peripheral circulation during early (pre-symptomatic) and later (clinical) stages, truly reflect the pathological progression of the disease in the brain. These unanswered questions necessitated investigations into the timing and performance of plasma biomarkers in AD.

Individuals with a parent with AD caused by a genetic lesion have a 50% chance of developing the disease themselves. These rare and inherited forms of AD account for less than 1% of all patients with AD.

In the current study on 164 blood plasma samples collected between 1994 and 2018, the results show changes in several blood protein concentrations in the mutation carriers. The samples included 33 plasma samples from individuals with mutations in the genes amyloid precursor protein (APP), presenilin1 (PSEN1), or presenilin 2 (PSEN2), known to cause Autosomal dominant Alzheimer’s Disease (ADAD).

“The first change we observed was an increase in GFAP approximately ten years before the first disease symptoms,” said Caroline Graff, PhD, professor of neurobiology, care sciences and society, who is the senior author of the study. “This was followed by increased concentrations of P-tau181 and, later, NfL (neurofilament light protein), which we already know is directly associated with the extent of neuronal damage in the Alzheimer brain. This finding about GFAP improves the chances of early diagnosis.”

Potentially diagnostic peripheral perturbations in GFAP must be validated in further studies to translate these findings into a clinical diagnostic tool.

The study was sponsored by the Swedish Brain Foundation, the Swedish Alzheimer’s Foundation, and with ALF project grants.

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