Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers

Jacob Labonte¹, Michael A Sugarman^{1

2}, Erika Pettway¹, Henrik Zetterberg^{3

4

5

6

7

8}, Kaj Blennow^{5

6

9

10}, Nicholas J Ashton^{6

7

11

12

13}, Thomas K Karikari^{5

6

14}, Hugo J Aparicio^{1

15}, Brandon Frank^{1

16}, Yorghos Tripodis^{1

17}, Brett Martin^{1

18}, Joseph N Palmisano^{1

18}, Eric G Steinberg¹, Irene Simkin¹⁹, Lindsay A Farrer^{1

15

17

19

20

21

22}, Gyungah R Jun¹⁹, Katherine W Turk^{1

15

16}, Andrew E Budson^{1

15

16}, Maureen K O'Connor^{1

23}, Rhoda Au^{1

15

20

21

24}, Lee E Goldstein^{1

18

22

25}, Robert A Stern^{1

15

24

26}, Thor D Stein^{1

16

27

28}, Ann C McKee^{1

15

16

27

28}, Wei Qiao Qiu^{1

29

30}, Jesse Mez^{1

15}, Sarah J Banks³¹, Michael L Alosco^{1

15}

Affiliations

¹ Boston University Alzheimer's Disease Research Center and BU CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
² Department of Neurology, Medical University of South Carolina, Charleston, SC, USA.
³ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁴ UK Dementia Research Institute at UCL, UCL Institute of Neurology, University College London, London, UK.
⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁷ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁹ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹⁰ Division of Life Sciences and Medicine, and Department of Neurology, Neurodegenerative Disorder Research Center, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
¹¹ Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹² NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹³ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹⁴ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁵ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
¹⁶ US Department of Veteran Affairs, VA Boston Healthcare System, Jamaica Plain, MA, USA.
¹⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁸ Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
¹⁹ Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁰ The Framingham Heart Study, Framingham, MA, USA.
²¹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²² Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²³ Department of Neuropsychology, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
²⁴ Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁵ Department of Biomedical, Electrical, and Computer Engineering, Boston University College of Engineering, Boston, MA, USA.
²⁶ Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁷ Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁸ US Department of Veteran Affairs, VA Bedford Healthcare System, Bedford, MA, USA.
²⁹ Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³⁰ Department of Pharmacology and Experimental Therapeutics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³¹ Departments of Neuroscience and Psychiatry, University of California, San Diego, CA, USA.

PMID: 40151917
PMCID: PMC12450407
DOI: 10.1177/13872877251329468

Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers

Jacob Labonte et al. J Alzheimers Dis. 2025 May.

. 2025 May;105(2):443-452.

doi: 10.1177/13872877251329468. Epub 2025 Mar 28.

Authors

Affiliations

¹ Boston University Alzheimer's Disease Research Center and BU CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
² Department of Neurology, Medical University of South Carolina, Charleston, SC, USA.
³ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁴ UK Dementia Research Institute at UCL, UCL Institute of Neurology, University College London, London, UK.
⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁷ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁹ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹⁰ Division of Life Sciences and Medicine, and Department of Neurology, Neurodegenerative Disorder Research Center, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
¹¹ Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹² NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹³ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹⁴ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁵ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
¹⁶ US Department of Veteran Affairs, VA Boston Healthcare System, Jamaica Plain, MA, USA.
¹⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁸ Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
¹⁹ Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁰ The Framingham Heart Study, Framingham, MA, USA.
²¹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²² Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²³ Department of Neuropsychology, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
²⁴ Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁵ Department of Biomedical, Electrical, and Computer Engineering, Boston University College of Engineering, Boston, MA, USA.
²⁶ Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁷ Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁸ US Department of Veteran Affairs, VA Bedford Healthcare System, Bedford, MA, USA.
²⁹ Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³⁰ Department of Pharmacology and Experimental Therapeutics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³¹ Departments of Neuroscience and Psychiatry, University of California, San Diego, CA, USA.

PMID: 40151917
PMCID: PMC12450407
DOI: 10.1177/13872877251329468

Abstract

BackgroundSex differences have consistently been identified on autopsy, neuroimaging, and cerebrospinal fluid outcomes related to Alzheimer's disease (AD), but the exact mechanisms for these associations are unclear. Blood-based biomarkers are practical alternatives for the investigation of mechanisms of AD, in addition to accurate disease detection and monitoring.ObjectiveThe objective of this study was to examine sex differences across a panel of blood-based plasma biomarkers in participants with and without cognitive impairment due to AD.MethodsPlasma samples were collected from 567 participants from across the AD diagnostic continuum (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia) and analyzed for glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau at threonine 181 (p-tau₁₈₁), and total tau (t-tau). Baseline and longitudinal analyses evaluated for any significant associations between sex and AD-related plasma biomarkers.ResultsFemales were found to have higher plasma GFAP compared to males at baseline regardless of cognitive diagnosis. Among those with AD dementia, females were also found to have higher NfL levels compared to males. Longitudinal analyses found that higher plasma NfL at baseline was associated with an increased risk of worsening AD dementia status only in females. No significant findings were observed for p-tau₁₈₁ or t-tau.ConclusionsThis study found significant sex differences in plasma biomarkers of GFAP and NfL. Further research is needed to better understand the underlying mechanisms mediating these differences.

Keywords: Alzheimer's disease; blood-based plasma biomarkers; female; glial fibrillary acidic protein; neurofilament light; p-tau181; sex; t-tau.

PubMed Disclaimer

Conflict of interest statement

Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MLA receives research support from Life Molecular Imaging Inc and Rainwater Charitable Foundation Inc. He has also received a single time honorarium from the Michael J Fox Foundation for services unrelated to this study. He received royalties from Oxford University Press Inc. AEB receives research support from Bristol-Myers Squibb and Vox Neuro. He receives consulting monies from Eli Lilly and AbbVie. He receives royalties from Elsevier and Oxford University Press. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. KT receives industry funding from Vox Neuro. RA serves as a scientific advisor to Signant Health and NovoNordisk and as a consultant to the Davos Alzheimer's Collaborative. None of this research, consulting, or royalties are related to this study. Henrik Zetterberg, Rhoda Au, and Michael L Alosco are Editorial Board Members of this journal but were not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

Figures

**Figure 1.**
Plasma GFAP values across the entire sample and three diagnostic groups, separated by sex. Values are the estimated marginal means for log-transformed and standardized plasma GFAP levels, accounting for age, race, education and *APOE ε4* carrier status as covariates. Differences between groups were significant (p < .05) for all four comparisons.

**Figure 2.**
Relationship between plasma neurofilament light (NfL) and risk for longitudinal change on the Clinical Dementia Rating scale (CDR) over a mean follow-up interval of 4.6 years, separated by sex. The sample was split into tertiles of NfL based on their baseline visit. The figure displays the percentage of participants with a CDR score of zero at baseline and at their final study visit; lower values reflect a greater proportion of participants with impairment. Solid lines show females and dotted lines show males. As shown, the relationship between baseline NfL and longitudinal decline was greater for female compared to male participants, especially for females in the highest NfL tertile.

See this image and copyright information in PMC

References

1. Riedel BC, Thompson PM, Brinton RD. Age, APOE and sex: Triad of risk of Alzheimer’s disease. J Steroid Biochem Mol Biol 2016; 160: 134–147. - PMC - PubMed
1. Lin KA, Choudhury KR, Rathakrishnan BG, et al. Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement Transl Res Clin Interv 2015; 1: 103–110. - PMC - PubMed
1. Payami H, Zareparsi S, Montee KR, et al. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 1996; 58: 803–811. - PMC - PubMed
1. Oveisgharan S, Arvanitakis Z, Yu L, et al. Sex differences in Alzheimer’s disease and common neuropathologies of aging. Acta Neuropathol (Berl) 2018; 136: 887–900. - PMC - PubMed
1. Rowe AA, Reyes S, Velasquez MJ, et al. Title: Female sex hormones exacerbate retinal neurodegeneration. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Atypon
- PubMed Central
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers

Affiliations

Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous