Age, Sex and Genetics Affect Blood Biomarkers for Dementia
A study identifies age, sex, genetics and menopause as key factors influencing blood biomarkers linked to dementia risk.
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A long-term study has identified factors that influence the levels of blood-based biomarkers associated with dementia, offering insights into how these indicators vary by age, sex, genetics and menopausal status. The findings were published April 16, 2025, in Neurology, the journal of the American Academy of Neurology.
Study explores shifts in dementia biomarkers over time
The study analyzed blood samples from 1,026 participants, drawn from a broader 17-year research project. Half of the participants developed dementia during the study period, while the other half did not. All individuals were approximately 64 years old at the outset.
Researchers tracked three key biomarkers associated with neurodegenerative changes: neurofilament light chain proteins, glial fibrillary acidic proteins and phosphorylated tau 181. Each of these markers reflects distinct processes in the brain. Neurofilament light chain proteins signal damage to nerve cells. Glial fibrillary acidic proteins are linked to astrocyte activation, a response to injury. Phosphorylated tau 181 is associated with the pathological accumulation of tau protein, a hallmark of Alzheimer’s disease.
Neurofilament light chain proteins
These proteins are part of the internal structure of nerve cells. When neurons are damaged, neurofilament proteins can leak into the blood, serving as a marker of neuronal injury.Glial fibrillary acidic proteins (GFAP)
GFAP is a protein produced by astrocytes, a type of glial cell in the central nervous system. Increased levels in the blood can indicate inflammation or damage in the brain.Phosphorylated tau 181
This is a form of the tau protein modified by the addition of phosphate groups. It is associated with the formation of neurofibrillary tangles, which are characteristic of Alzheimer’s disease.Biomarker levels rise with age
Blood samples were collected at three intervals during the study to monitor changes over time. After controlling for age, sex and presence of the APOEe4 allele – a genetic variant strongly tied to Alzheimer’s disease – researchers observed that older participants had consistently higher levels of all three biomarkers.
APOEe4
A genetic variant of the apolipoprotein E gene, APOEe4 is a well-established risk factor for late-onset Alzheimer’s disease and influences the metabolism of lipids and brain proteins.For example, neurofilament light chain protein levels rose from an average of 10 pg/mL at age 50 to 25 pg/mL at age 75. Glial fibrillary acidic protein concentrations increased from 45 pg/mL to 140 pg/mL across the same age span. Phosphorylated tau 181 levels showed a more modest rise, from 0.5–1.5 pg/mL at age 50 to 2–3 pg/mL at age 75.
“Gaining a better understanding of these biomarkers will help improve our ability to test for dementia in the future with simple blood tests."
Dr. Hannah Stocker.
Sex and genetic variation influence biomarker profiles
The study also identified sex-based differences in biomarker levels. Women showed higher concentrations of glial fibrillary acidic proteins, while men had greater levels of neurofilament light chain proteins.
Additionally, individuals with the APOEe4 gene exhibited elevated levels of both tau and glial fibrillary acidic proteins compared to non-carriers, underscoring the gene’s role in modulating biological responses to dementia-related changes.
Menopause may shape neuroinflammatory responses
Among female participants, those who had not yet undergone menopause had higher levels of glial fibrillary acidic proteins than those who had. This difference is thought to be linked to fluctuating levels of sex hormones during menopause, which may influence neuroinflammatory pathways in the brain.
“Our research underscores the need to further explore these biomarkers, including during menopause, in the development of dementia.”
Dr. Hannah Stocker
Study limitations
The study cohort was limited to individuals of European descent. As a result, the findings may not be directly applicable to other population groups.
Reference: Stocker H, Beyer L, Trares K, et al. Association of nonmodifiable risk factors with Alzheimer disease blood biomarkers in community-dwelling adults in the Esther study. Neurology. 2025;104(9):e213500. doi: 10.1212/WNL.0000000000213500
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