A population-based meta-analysis of circulating GFAP for cognition and dementia risk

Mitzi M Gonzales^{1

2}, Crystal Wiedner¹, Chen-Pin Wang^{1

3

4}, Qianqian Liu³, Joshua C Bis⁵, Zhiguang Li⁶, Jayandra J Himali^{1

3

7

8

9}, Saptaparni Ghosh^{7

8}, Emy A Thomas¹⁰, Danielle M Parent¹¹, Tiffany F Kautz¹, Matthew P Pase^{7

12

13}, Hugo J Aparicio^{7

8}, Luc Djoussé^{14

15}, Kenneth J Mukamal¹⁶, Bruce M Psaty^{5

17

18

19}, William T Longstreth Jr^{17

20}, Thomas H Mosley Jr²¹, Vilmundur Gudnason^{22

23}, Djass Mbangdadji⁶, Oscar L Lopez²⁴, Kristine Yaffe^{25

26

27

28}, Stephen Sidney²⁹, R Nick Bryan³⁰, Ilya M Nasrallah³⁰, Charles S DeCarli³¹, Alexa S Beiser^{7

8

9}, Lenore J Launer⁶, Myriam Fornage¹⁰, Russell P Tracy¹¹, Sudha Seshadri^{1

2

7

8}, Claudia L Satizabal^{1

3

7}

Affiliations

¹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
² Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
³ Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
⁴ South Texas Veterans Health Care System, Geriatric Research, Education & Clinical Center, San Antonio, Texas, USA.
⁵ Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.
⁶ Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.
⁷ The Framingham Heart Study, Framingham, Massachusetts, USA.
⁸ Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
⁹ Department of Biostatistics, Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁰ Brown Foundation of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹¹ Department of Pathology and Laboratory Medicine, and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.
¹² School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia.
¹³ Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹⁴ Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁵ Boston Veterans Affairs Healthcare System, Boston, Massachusetts, USA.
¹⁶ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹⁷ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁹ Department of Health Systems and Population Health, University of Washington, Seattle, Washington, USA.
²⁰ Department of Neurology, University of Washington, Seattle, Washington, USA.
²¹ The MIND Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.
²² Icelandic Heart Association Research Institute, Kópavogur, Iceland.
²³ Department of Cardiology, University of Iceland, Reykjavik, Iceland.
²⁴ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁵ Department of Psychiatry, University of California, San Francisco, California, USA.
²⁶ Department of Neurology, University of California, San Francisco, California, USA.
²⁷ Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
²⁸ San Francisco VA Medical Center, San Francisco, California, USA.
²⁹ Kaiser Permanente Medical Center Program, Oakland, California, USA.
³⁰ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³¹ Department of Neurology, University of California, Davis, California, USA.

PMID: 36056631
PMCID: PMC9539381
DOI: 10.1002/acn3.51652

Meta-Analysis

A population-based meta-analysis of circulating GFAP for cognition and dementia risk

Mitzi M Gonzales et al. Ann Clin Transl Neurol. 2022 Oct.

. 2022 Oct;9(10):1574-1585.

doi: 10.1002/acn3.51652. Epub 2022 Sep 3.

Authors

Affiliations

¹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
² Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
³ Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
⁴ South Texas Veterans Health Care System, Geriatric Research, Education & Clinical Center, San Antonio, Texas, USA.
⁵ Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.
⁶ Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.
⁷ The Framingham Heart Study, Framingham, Massachusetts, USA.
⁸ Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
⁹ Department of Biostatistics, Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁰ Brown Foundation of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹¹ Department of Pathology and Laboratory Medicine, and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.
¹² School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia.
¹³ Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹⁴ Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁵ Boston Veterans Affairs Healthcare System, Boston, Massachusetts, USA.
¹⁶ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹⁷ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁹ Department of Health Systems and Population Health, University of Washington, Seattle, Washington, USA.
²⁰ Department of Neurology, University of Washington, Seattle, Washington, USA.
²¹ The MIND Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.
²² Icelandic Heart Association Research Institute, Kópavogur, Iceland.
²³ Department of Cardiology, University of Iceland, Reykjavik, Iceland.
²⁴ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁵ Department of Psychiatry, University of California, San Francisco, California, USA.
²⁶ Department of Neurology, University of California, San Francisco, California, USA.
²⁷ Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
²⁸ San Francisco VA Medical Center, San Francisco, California, USA.
²⁹ Kaiser Permanente Medical Center Program, Oakland, California, USA.
³⁰ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³¹ Department of Neurology, University of California, Davis, California, USA.

PMID: 36056631
PMCID: PMC9539381
DOI: 10.1002/acn3.51652

Abstract

Objective: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings.

Methods: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models.

Results: Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = -0.09, [95% confidence interval [CI]: -0.15 to -0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52-4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42-4.53]) over up to 15-years of follow-up.

Interpretation: Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.

PubMed Disclaimer

Conflict of interest statement

Dr Bryan is on the board of directors and owns stock in GalileoCDS, INC. Dr. Gonzales and her husband own stock in Abbvie. Dr Nasrallah has received honoria from Biogen and Eisai. Dr Pase has received honoria from Flordis. Dr Seshadri has received consulting fees from Biogen. Dr Yaffe is a board member of Alector. All other authors report no relevant conflicts of interest.

Figures

**Figure 1**
Pooled associations between circulating GFAP and general cognition. Results are per unit increase in the standardized natural log of GFAP. Linear regression models adjust for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication use, body mass index, apolipoprotein E ε4 status (at least one ε4 allele vs. none), site (if a multi‐site study), and the time interval between the blood draw for GFAP and the outcome variable.

**Figure 2**
Pooled associations between circulating GFAP and neuroimaging outcomes. Results are per unit increase in the standardized natural log of GFAP examining associations with (A) total brain volume and (B) hippocampal volume. Linear regression models adjust for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication use, body mass index, apolipoprotein E ε4 status (at least one ε4 allele vs. none), site (if a multi‐site study), and the time interval between the blood draw for GFAP and the outcome variable.

**Figure 3**
Pooled associations between circulating GFAP and incident dementia. Results are per unit increase in the standardized natural log of GFAP examining associations with (A) incident all cause dementia, (B) incident Alzheimer's disease dementia, (C) incident all cause dementia and Alzheimer's disease dementia (D) with dementia surveillance beginning 2 years after the blood draw for GFAP. Cox proportional hazard models over a maximum of 15‐year follow‐up with age as the time‐scale and adjustment for sex, education, race, diabetes, systolic blood pressure, antihypertensive medication use, body mass index, apolipoprotein ε4 status (at least one ε4 allele vs. none), and site (if a multi‐site study).

See this image and copyright information in PMC

References

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A population-based meta-analysis of circulating GFAP for cognition and dementia risk

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A population-based meta-analysis of circulating GFAP for cognition and dementia risk

Authors

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Conflict of interest statement

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