GFAP and NfL: Two Blood Proteins That Predict Dementia Death 5-6 Years in Advance

Early diagnosis of dementia has always been a challenge. Until today, most cases are detected only after symptoms are already clear, which is too late for some treatments. But a study published in Neurology, which analyzed blood samples from approximately 917 participants from the large REGARDS database, shows that a simple blood test of proteins can be associated with an increased risk of death from dementia years in advance. This is a research step that brings us closer to an era of early risk identification.

The Problem: Diagnosis Too Late

Alzheimer's and other dementias are diseases that develop slowly. Brain changes begin many years before symptoms. By the time diagnosis occurs, the damage is already extensive and treatments are limited.

Existing methods for early diagnosis:

• Brain PET scan: Expensive ($3,000-$5,000), radiation exposure
• Spinal fluid test: Invasive, painful, low risk of complications
• Advanced MRI: Expensive, not always available

None of these are suitable for mass screening. Something simpler is needed. A blood test.

The Experiment: A Sub-Sample of Approximately 917 Participants from REGARDS

The team used data from REGARDS (REasons for Geographic and Racial Differences in Stroke), one of the largest medical databases in the US, which has followed 30,239 Black and White individuals across the US since 2003. It is important to clarify: the four proteins were not measured in all 30,239 participants. The biological analysis was based on a random sample of approximately 917 participants (average age at start of follow-up about 67) in whose plasma samples 4 proteins were measured:

• NfL (Neurofilament Light Chain): A protein released from damaged neurons
• Total Tau: Tau protein, linked to Alzheimer's
• GFAP (Glial Fibrillary Acidic Protein): A protein from glial cells (support cells in the brain)
• UCH-L1: A protein from neurons

Participants were then followed for an average period of about 11 years (median about 9.5 years), and all-cause mortality as well as dementia-specific mortality were examined. During follow-up, about half of the participants died.

The Findings: GFAP and NfL Are the Strongest Predictors

Only two proteins showed a significant association with dementia mortality. It is important to understand that the numbers below are Hazard Ratios per one standard deviation increase in protein level, in adjusted models, and not a simple division of "high vs. normal":

GFAP - The Strongest Predictor

• Each one standard deviation increase in blood GFAP level was associated with a 5.66-fold higher risk of death from dementia (95% confidence interval 2.91-11.00)
• The association remained after adjustment for age, sex, race, BMI, diabetes, blood pressure
• GFAP was also associated with an increased risk of death from cardiovascular disease

NfL - Also Strong

• Each one standard deviation increase in NfL level was associated with a 2.72-fold higher risk of death from dementia (95% confidence interval 1.57-4.71)
• Also associated with an increased risk of all-cause mortality
• Rises before an official diagnosis of dementia

Tau and UCH-L1 - Less Strong

Total Tau did not show a significant association with dementia mortality, and UCH-L1 did not show a significant association with dementia mortality. This is interesting because it means not every biomarker is equal. GFAP and NfL are the strong representatives among the four.

As the researchers summarize, the findings indicate that high levels of GFAP and NfL in the blood are associated with a significantly increased risk of death from dementia during the follow-up years. However, this is a statistical association in an observational study, and not a definitive diagnostic tool that determines who will get sick.

Why is GFAP So Strong?

GFAP expresses "astrogliosis" - a response of glial cells to damage. When the brain begins to be damaged (even if not visible on MRI), glial cells activate and begin to "respond." They release GFAP into the blood. This is a very early signal that something is wrong in the brain, even before symptoms appear.

NfL is the opposite - it is released mainly when neurons are physically damaged. Therefore, it is strong as a marker of existing damage, but less strong as an early marker.

Practical Implications

Blood tests for neurological proteins like GFAP and NfL are mainly in research stages and in a few specialized laboratories, and are not yet a routine screening test. They may become more available and affordable in the future, but currently, this is a research tool and not an approved screening test for the general population. Any decision to perform such a test should be made with a doctor.

Who is this particularly relevant for?

1. Family history of Alzheimer's: If a parent or sibling was diagnosed, the risk is increased. It is advisable to consult a doctor about appropriate monitoring
2. Mild symptoms of cognitive decline: Frequent word forgetting or increasing difficulty in daily functioning. In the future, such tests may help distinguish between normal aging and an incipient process, but currently, assessment is clinical
3. People with head injuries (sports impacts, accidents): NfL in particular tracks neuronal damage
4. Adults over 65 interested in risk assessment, with a doctor's guidance

Limitations

It is important to clarify:

• This is not a definitive diagnostic tool. High markers do not mean "you have dementia." They indicate an "increased risk" at the population level
• This is an observational study on a sub-sample: The analysis was based on about 917 people, and a statistical association is not the same as personal prediction
• Other factors can raise the markers: Infections, autoimmune diseases, age
• Need to follow over time: A single test is not enough
• Must be interpreted with a doctor: Do not interpret alone

What to Do to Protect the Brain?

Regardless of a specific test result, the interventions for brain health and prevention of cerebrovascular disease are known and established in other studies (not this one). These are general steps recommended for overall health:

1. Blood pressure control: High blood pressure is linked to accelerated brain damage
2. Diabetes management: Diabetes is linked to a significant increase in dementia risk (general data from the literature, not from this study)
3. Physical activity: About 150 minutes per week is linked to a reduced risk (general data from the literature)
4. Mediterranean/MIND diet: Linked to a lower risk (general data from the literature)
5. Quality sleep: 7-8 hours, without disturbances
6. Maintaining social connections: Loneliness is linked to an increased risk
7. Managing depression/anxiety: Known risk factors

In cases of diagnosed cognitive decline, new drugs (lecanemab, donanemab) are now available that slow the progression of Alzheimer's in its early stages. They are expensive and have side effects, and their use is under the guidance of a specialist.

The Next Step: Where to From Here?

Studies like this strengthen the hope that in the future, blood tests for neurological markers could be integrated into risk assessment. However, more large and validated studies are needed before such a test becomes a routine part of periodic blood tests. Just as cholesterol became a standard over time, neurological markers may take a similar place in the future, but the path there is still long.

The Bottom Line

Early diagnosis of dementia has been a complex idea for decades. This study, which analyzed blood samples from approximately 917 participants from the REGARDS database, found that high levels of GFAP and NfL in the blood are associated with an increased risk of death from dementia during the follow-up years. This is an important finding that hints at a possible direction for early risk identification, but it is still an observational study and not an approved screening test. The direction is promising. The path to broad clinical implementation continues.