A recent 17-year German cohort study investigated the link between dementia-related blood biomarker levels and non-modifiable risk factors. Researchers found that age, APOE ε4 status, and particularly female sex significantly influence the levels of blood biomarkers related to Alzheimer’s disease. This finding provides new insight into how these risk factors impact the course of the disease.
Blood tests are becoming more significant in identifying individuals at risk for dementia, potentially leading to earlier detection and treatment.
In a recent study, researchers claimed to have discovered significant hints on the potential contributions of age, sex, hormonal changes, and heredity to the expression of specific dementia biomarkers in the blood. The study investigates how blood tests that track these biomarkers can assist researchers in better understanding and eventually diagnosing illnesses such as Alzheimer’s.
The journal Neurology published the study [1].
Three Key Biomarkers
The research centered on three critical biomarkers:
- Neurofilament Light Chain Proteins (NfL): These proteins are a component of nerve cells’ internal structure. When neurons experience damage, neurofilament proteins can seep into the bloodstream, indicating neuronal injury.
- Glial Fibrillary Acidic Proteins (GFAP): Astrocytes are a type of glial cell in the central nervous system that produce a protein known as GFAP. These proteins are released when cells work to repair injury. Elevated blood levels may suggest brain injury or inflammation.
- Phosphorylated Tau 181 (p-tau181): Phosphorylated Tau 181 or p-tau181 is a tau protein variant with phosphate groups. It is linked to the development of neurofibrillary tangles, a hallmark of Alzheimer’s disease.
P-tau181 is a well-known biomarker for Alzheimer’s disease that predicts tau and amyloid β abnormalities. Compared to other indicators, blood levels of neurofilament light (NfL) chains may suggest non-disease-specific neurodegeneration and could be used to track disease progression.
The expression of glial fibrillary acidic protein (GFAP) can help determine the level of astrocyte activation, which may assist with the early detection of Alzheimer’s.
Few studies have looked into the possible usage of detecting NfL and GFAP levels to aid in Alzheimer’s diagnosis and monitoring. Furthermore, it is yet unknown how the presence of non-modifiable factors such as menopause, age, sex, and apolipoprotein e4 (APOEe4) levels may impact these biomarker levels.
Non-Modifiable Factors and Biomarker Variability
Non-modifiable factors, such as age, sex, and APOE ε4 status, significantly influence the biomolecular profile in Alzheimer’s. Since misinterpreting biomarker levels might result in incorrect diagnostic findings, medical professionals must recognize these influences.
Healthcare practitioners can create age- and sex-adjusted thresholds by incorporating these innate traits into diagnostic criteria. Assessing a patient’s APOE ε4 status also improves the accuracy of tracking the course of the disease and refines risk assessment.
About the Study
The recent study examined possible connections between dementia-related blood biomarkers of P-tau181, NfL, and GFAP and non-modifiable risk variables such as age, sex, and APOE ε4 status. The cohort study’s participants were community-dwelling adults aged 50 to 75 with no history of dementia.
The German ESTHER project involved monitoring all participants for 17 years. The researchers compared 513 participants who experienced dementia during the study with 513 participants who did not. At the beginning of the trial, the average age of the participants was 64. They also studied the effects of menopause on biomarker levels.
Researchers collected blood samples from participants at three intervals during the study to assess levels of three biomarkers: NfL, GFAP, and p-tau181.
Next, the researchers evaluated the biomarker levels in individuals with and without dementia in the following ways: before and after menopause in female participants; in male and female participants; in individuals with and without a gene associated with Alzheimer’s disease; and throughout time as individuals aged.
The Study Findings
Biomarker Levels Increase with Age
When researchers controlled for sex, age, and APOEe4, a genetic biomarker that suggests a high risk of Alzheimer’s disease, they discovered that greater levels of all three markers were associated with older ages.
For instance, NfL levels increased from an average of 10 pg/mL at age 50 to 25 pg/mL at age 75. Over the same age range, GFAP concentrations rose from 45 pg/mL to 140 pg/mL. At age 75, phosphorylated tau 181 levels increased more modestly, from 0.5–1.5 pg/mL at age 50 to 2-3 pg/mL.
Genetic Variation and Sex Affect Biomarker Profiles
The researchers also discovered sex-based disparities in biomarker levels. Glial fibrillary acidic proteins were more abundant in women, but neurofilament light chain proteins were more abundant in men.
Furthermore, APOEe4 gene carriers showed higher amounts of tau and glial fibrillary acidic proteins than non-carriers, highlighting the gene’s significance in regulating biological responses to dementia-related modifications.
Menopause may Influence Neuroinflammatory Responses
Females who had not yet gone through menopause exhibited higher levels of glial fibrillary acidic protein (GFAP) than those who had. This discrepancy might be due to changes in sex hormone levels during menopause, which may have an impact on the brain’s neuroinflammatory pathways.
Conclusion and Limitations of the Study
Compared to the male research participants, women, especially those who were premenopausal, had considerably higher baseline levels of GFAP and saw a faster increase in GFAP levels over time. Sex-dependent astrocytic responses to hormones and greater neuroinflammation in women could be the cause of these sex differences. Nonetheless, more research is needed to understand the mechanisms that underpin the link between GFAP levels and female sex.
APOEe4 status might potentially play a role in astrocytic responses. However, more research is required to elucidate how this genotype contributes to the maintenance of GFAP and NfL levels.
The study’s conclusions support the necessity for age- and sex-specific reference values for P-tau181, NfL, and GFAP blood levels.
Although these strategies can make it easier to employ biomarkers for dementia diagnosis, more research is needed to determine whether sex-specific variations in the brain influence biomarker levels in the blood.
According to study author Hannah Stocker, PhD, MPH, of Heidelberg University in Germany, an in-depth understanding of these biomarkers would enhance their capacity to use straightforward blood tests to screen for dementia in the future. She said that their findings highlight the necessity of investigating these biomarkers further, including during menopause, in the development of dementia.
The study only included people of European descent. Consequently, the results might not be readily applicable to other demographic groups.
Alzheimer’s Research Association is a non-profit organization dedicated to helping caregivers of Alzheimer’s disease and dementia. We provide the latest information and news about the illness and helpful tips to help caregivers cope with their daily caregiving challenges. We realize the most important thing that a caregiver needs is financial assistance. Therefore, we provide grants to caregivers to ease their financial burden. Caregivers can apply for grants here: Alzheimer’s Grant Application.
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References
- Stocker, H., Beyer, L., Trares, K., Stevenson-Hoare, J., Rujescu, D., Holleczek, B., Beyreuther, K., Schoettker, B., Gerwert, K. and Brenner, H., 2025. Association of Nonmodifiable Risk Factors With Alzheimer Disease Blood Biomarkers in Community-Dwelling Adults in the ESTHER Study. Neurology, 104(9), p.e213500.
- Bose, P. Age and sex shape Alzheimer’s blood biomarkers, study finds. News Medical. https://www.news-medical.net/news/20250422/Age-and-sex-shape-Alzheimere28099s-blood-biomarkers-study-finds.aspx. Published Online: 22nd April, 2025. Accessed: 12th May, 2025.
- Age, Sex and Genetics Affect Blood Biomarkers for Dementia. Technology Networks: Proteomics and Metabolomics. https://www.technologynetworks.com/proteomics/news/age-sex-and-genetics-affect-blood-biomarkers-for-dementia-398699. Published Online: 17th April, 2025. Accessed: 12th May, 2025.
- Teller, S. Study Links Age, Sex, Genetics to Dementia Biomarkers. Legal Reader. https://www.legalreader.com/study-links-age-sex-genetics-to-dementia-biomarkers/. Published Online: 16th April, 2025. Accessed: 12th May, 2025.
- How do age, sex, hormones and genetics affect dementia biomarkers in the blood? Science Daily. https://www.sciencedaily.com/releases/2025/04/250416164524.htm. Published Online: 16th April, 2025. Accessed: 12th May, 2025.
- Age and Sex: Influences on Alzheimer’s Blood Biomarkers. Reach MD. https://reachmd.com/news/age-and-sex-influences-on-alzheimers-blood-biomarkers/2474296/. Published Online: 23rd April, 2025. Accessed: 12th May, 2025.
- Sex and age play key roles in dementia biomarker levels. News Medical. https://www.news-medical.net/news/20250416/Sex-and-age-play-key-roles-in-dementia-biomarker-levels.aspx. Published Online: 16th April, 2025. Accessed: 12th May, 2025.
