Scientists say they have found important clues about the roles that age, sex, hormonal changes and genetics might play in how certain biomarkers for dementia are expressed in the blood.
“Blood tests that detect biomarkers for Alzheimer’s disease and other dementias are emerging and as these tests are further developed, they are becoming important tools for understanding and diagnosing these conditions,” said author Hannah Stocker, PhD, MPH, of Heidelberg University in Germany.
“Our findings provide valuable insights into how age, sex, genetics and hormonal changes during menopause are linked to three biomarkers believed to influence the risk of dementia.”
The authors of the study published in Neurology, the medical journal of the American Academy of Neurology, analysed data from a larger 17-year study, comparing 513 people who developed dementia during the study with 513 people who remained free of dementia during that time. The participants had an average age of 64 at the start of the study.
Researchers took blood samples from participants three times during the study to measure levels of three biomarkers: neurofilament light chain proteins, glial acidic proteins and phosphorylated tau 181.
Neurofilament light chain proteins are found in the blood when nerve cells are injured or die. Glial acidic proteins are released when cells work to repair injury.
Phosphorylated tau 181 is linked to the build-up of amyloid proteins in the body, which occurs in Alzheimer’s.
The teams then compared levels of the biomarkers in people with and without dementia in the following ways: over time as people aged; in male and female participants; in people with and without a gene linked to Alzheimer’s; and in female participants before and after menopause.
After adjusting for age, sex, and APOEe4, a genetic biomarker that indicates a strong risk of Alzheimer’s disease, they found that an older age was tied to higher levels of all three markers.
For neurofilament light chain proteins, people of 75 had an average of 25 picograms per millilitre (pg/ml) compared with people aged 50 with an average of 10 pg/ml. For glial acidic proteins, people aged 75 had an average of 140 pg/ml compared with people aged 50 with an average of 45 pg/ml. For phosphorylated tau 181, people of 75 had an average of two to three pg/ml compared to people aged 50 with an average of 0.5 to 1.5 pg/ml.
Researchers also found that females had higher levels of glial acidic proteins, while male participants had higher levels of neurofilament light chain proteins.
In addition, they found people who had the APOEe4 gene had higher levels of tau and glial acidic proteins.
Finally, the study found that female participants who had not yet gone through menopause had higher levels of glial acidic proteins, which Stocker noted may be due to having higher levels of sex hormones. Stocker said previous studies have found a link between sex hormones and neuro-inflammation.
“Gaining a better understanding of these biomarkers will help improve our ability to test for dementia in the future with simple blood tests,” she said. “Our research underscores the need to further explore these biomarkers, including during menopause, in the development of dementia.”
A limitation of the study was that participants were of European descent, so the results may not be the same for other populations.
Study details
Association of non-modifiable risk factors with Alzheimer’s disease blood biomarkers in community-dwelling adults in the ESTHER Study.
Hannah Stocker, Léon Beyer, Kira Trares, Joshua Stevenson-Hoare, Dan Rujescu, Bernd Holleczek, Konrad Beyreuther, Ben Schoettker, Klaus Gerwert, Hermann Brenner.
Published in Neurology on 13 May 2025.
Abstract
Background and Objectives
Dementia-related blood biomarkers are the future of large-scale dementia risk stratification; however, the extent to which phosphorylated tau (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are associated with non-modifiable risk factors has yet to be confirmed in the community, and the role of menopause has yet to be investigated. Therefore, the aim of this study was to examine the association of age, sex, APOEe4 status, and menopause, with dementia-related blood biomarker levels (P-tau181, NfL, and GFAP) and rate of change over 11 years in longitudinal biomarker measurements in community-dwelling adults.
Methods
Within this German population-based Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung cohort study (n = 9,940), a nested case-control study of 1,026 participants (1:1, without dementia during follow-up: incident dementia during follow-up) aged 50–75 years at baseline followed over 17 years was conducted. Blood biomarker measurements (P-tau181, NfL, and GFAP) were completed in blood from baseline, 8-year, and 11-year follow-ups, and cross-sectional and longitudinal regression analyses were used to assess the association with age, sex, APOEe4, and menopause.
Results
The mean age of participants was 64, and women accounted for slightly more than half (54%) of the sample. Age was cross-sectionally and longitudinally significantly associated with all dementia-related biomarkers (p < 0.001). NfL and GFAP levels more strongly correlated (Spearman R = 0.55 and 0.49) with age at baseline than P-tau181 levels (Spearman R = 0.21). Women experienced significantly higher levels and rates of increase in GFAP (p < 0.001) while men experienced higher levels of NfL after adjusting for age and APOEe4 (p < 0.01). APOEe4 status was significantly associated with baseline and longitudinal levels of P-tau181 (baseline β = 0.30, p < 0.05) and GFAP (baseline β = 15.84, p < 0.001). Of interest, premenopausal status was significantly associated with higher GFAP levels after adjusting for age, sex, and APOEe4 (β = 19.09, p < 0.05).
Discussion
This population-based study on dementia biomarkers found that P-tau181 was dependent on age and APOEe4; NfL on age and sex; and GFAP on age, sex, APOEe4, and menopause status. GFAP levels and rate of increase were higher in women, especially in premenopausal participants. Future research should confirm these findings and further explore the role of menopause in dementia pathogenesis among women.
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