. 2020 Jan 21;94(3):e254-e266.

doi: 10.1212/WNL.0000000000008682. Epub 2019 Dec 9.

Association of CD14 with incident dementia and markers of brain aging and injury

Matthew P Pase¹, Jayandra J Himali¹, Alexa S Beiser¹, Charles DeCarli¹, Emer R McGrath¹, Claudia L Satizabal¹, Hugo J Aparicio¹, Hieab H H Adams¹, Alexander P Reiner¹, W T Longstreth Jr¹, Myriam Fornage¹, Russell P Tracy¹, Oscar Lopez¹, Bruce M Psaty¹, Daniel Levy¹, Sudha Seshadri², Joshua C Bis¹

Affiliations

¹ From the Harvard T.H. Chan School of Public Health (M.P.P.), Boston; Department of Neurology (J.J.H., A.S.B., C.L.S., H.J.A., S.S.), Boston University School of Medicine; Framingham Heart Study (M.P.P., J.J.H., A.S.B., C.D., E.R.M., C.L.S., H.J.A., D.L., S.S.), MA; Centre for Human Psychopharmacology (M.P.P.), Swinburne University of Technology; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health & The University of Melbourne, Australia; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, MA; Department of Neurology (C.D.), School of Medicine & Imaging of Dementia and Aging Laboratory, Center for Neuroscience, University of California Davis, Sacramento; Departments of Epidemiology (H.H.H.A.) and Radiology and Nuclear Medicine (H.H.H.A.), Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology (A.P.R., W.T.L., B.M.P.), Fred Hutchinson Cancer Research Center (A.P.R.), Department of Neurology (W.T.L.), Cardiovascular Health Research Unit, Department of Medicine (B.M.P., J.C.B.), and Department of Health Services (B.M.P.), University of Washington, Seattle; Human Genetics Center, Department of Epidemiology (M.F.), Human Genetics & Environmental Sciences, School of Public Health (M.F.), and The Brown Foundation Institute of Molecular Medicine, Research Center for Human Genetics (M.F.), University of Texas Health Science Center, Houston; Departments of Pathology and Laboratory Medicine (R.P.T.) and Biochemistry (R.P.T.), Larner College of Medicine, University of Vermont, Burlington; Department of Neurology (O.L.), School of Medicine, University of Pittsburgh, PA; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; The Population Sciences Branch of the National Heart, Lung and Blood Institute (D.L.), NIH, Bethesda, MD; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S.), University of Texas Health Sciences Center, San Antonio; Department of Neurology (E.R.M.), Brigham & Women's Hospital; and Harvard Medical School (E.R.M.), Boston, MA.
² From the Harvard T.H. Chan School of Public Health (M.P.P.), Boston; Department of Neurology (J.J.H., A.S.B., C.L.S., H.J.A., S.S.), Boston University School of Medicine; Framingham Heart Study (M.P.P., J.J.H., A.S.B., C.D., E.R.M., C.L.S., H.J.A., D.L., S.S.), MA; Centre for Human Psychopharmacology (M.P.P.), Swinburne University of Technology; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health & The University of Melbourne, Australia; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, MA; Department of Neurology (C.D.), School of Medicine & Imaging of Dementia and Aging Laboratory, Center for Neuroscience, University of California Davis, Sacramento; Departments of Epidemiology (H.H.H.A.) and Radiology and Nuclear Medicine (H.H.H.A.), Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology (A.P.R., W.T.L., B.M.P.), Fred Hutchinson Cancer Research Center (A.P.R.), Department of Neurology (W.T.L.), Cardiovascular Health Research Unit, Department of Medicine (B.M.P., J.C.B.), and Department of Health Services (B.M.P.), University of Washington, Seattle; Human Genetics Center, Department of Epidemiology (M.F.), Human Genetics & Environmental Sciences, School of Public Health (M.F.), and The Brown Foundation Institute of Molecular Medicine, Research Center for Human Genetics (M.F.), University of Texas Health Science Center, Houston; Departments of Pathology and Laboratory Medicine (R.P.T.) and Biochemistry (R.P.T.), Larner College of Medicine, University of Vermont, Burlington; Department of Neurology (O.L.), School of Medicine, University of Pittsburgh, PA; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; The Population Sciences Branch of the National Heart, Lung and Blood Institute (D.L.), NIH, Bethesda, MD; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S.), University of Texas Health Sciences Center, San Antonio; Department of Neurology (E.R.M.), Brigham & Women's Hospital; and Harvard Medical School (E.R.M.), Boston, MA. suseshad@bu.edu.

PMID: 31818907
PMCID: PMC7108812
DOI: 10.1212/WNL.0000000000008682

Association of CD14 with incident dementia and markers of brain aging and injury

Matthew P Pase et al. Neurology. 2020.

. 2020 Jan 21;94(3):e254-e266.

doi: 10.1212/WNL.0000000000008682. Epub 2019 Dec 9.

Authors

Affiliations

¹ From the Harvard T.H. Chan School of Public Health (M.P.P.), Boston; Department of Neurology (J.J.H., A.S.B., C.L.S., H.J.A., S.S.), Boston University School of Medicine; Framingham Heart Study (M.P.P., J.J.H., A.S.B., C.D., E.R.M., C.L.S., H.J.A., D.L., S.S.), MA; Centre for Human Psychopharmacology (M.P.P.), Swinburne University of Technology; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health & The University of Melbourne, Australia; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, MA; Department of Neurology (C.D.), School of Medicine & Imaging of Dementia and Aging Laboratory, Center for Neuroscience, University of California Davis, Sacramento; Departments of Epidemiology (H.H.H.A.) and Radiology and Nuclear Medicine (H.H.H.A.), Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology (A.P.R., W.T.L., B.M.P.), Fred Hutchinson Cancer Research Center (A.P.R.), Department of Neurology (W.T.L.), Cardiovascular Health Research Unit, Department of Medicine (B.M.P., J.C.B.), and Department of Health Services (B.M.P.), University of Washington, Seattle; Human Genetics Center, Department of Epidemiology (M.F.), Human Genetics & Environmental Sciences, School of Public Health (M.F.), and The Brown Foundation Institute of Molecular Medicine, Research Center for Human Genetics (M.F.), University of Texas Health Science Center, Houston; Departments of Pathology and Laboratory Medicine (R.P.T.) and Biochemistry (R.P.T.), Larner College of Medicine, University of Vermont, Burlington; Department of Neurology (O.L.), School of Medicine, University of Pittsburgh, PA; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; The Population Sciences Branch of the National Heart, Lung and Blood Institute (D.L.), NIH, Bethesda, MD; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S.), University of Texas Health Sciences Center, San Antonio; Department of Neurology (E.R.M.), Brigham & Women's Hospital; and Harvard Medical School (E.R.M.), Boston, MA.
² From the Harvard T.H. Chan School of Public Health (M.P.P.), Boston; Department of Neurology (J.J.H., A.S.B., C.L.S., H.J.A., S.S.), Boston University School of Medicine; Framingham Heart Study (M.P.P., J.J.H., A.S.B., C.D., E.R.M., C.L.S., H.J.A., D.L., S.S.), MA; Centre for Human Psychopharmacology (M.P.P.), Swinburne University of Technology; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health & The University of Melbourne, Australia; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, MA; Department of Neurology (C.D.), School of Medicine & Imaging of Dementia and Aging Laboratory, Center for Neuroscience, University of California Davis, Sacramento; Departments of Epidemiology (H.H.H.A.) and Radiology and Nuclear Medicine (H.H.H.A.), Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology (A.P.R., W.T.L., B.M.P.), Fred Hutchinson Cancer Research Center (A.P.R.), Department of Neurology (W.T.L.), Cardiovascular Health Research Unit, Department of Medicine (B.M.P., J.C.B.), and Department of Health Services (B.M.P.), University of Washington, Seattle; Human Genetics Center, Department of Epidemiology (M.F.), Human Genetics & Environmental Sciences, School of Public Health (M.F.), and The Brown Foundation Institute of Molecular Medicine, Research Center for Human Genetics (M.F.), University of Texas Health Science Center, Houston; Departments of Pathology and Laboratory Medicine (R.P.T.) and Biochemistry (R.P.T.), Larner College of Medicine, University of Vermont, Burlington; Department of Neurology (O.L.), School of Medicine, University of Pittsburgh, PA; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; The Population Sciences Branch of the National Heart, Lung and Blood Institute (D.L.), NIH, Bethesda, MD; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S.), University of Texas Health Sciences Center, San Antonio; Department of Neurology (E.R.M.), Brigham & Women's Hospital; and Harvard Medical School (E.R.M.), Boston, MA. suseshad@bu.edu.

PMID: 31818907
PMCID: PMC7108812
DOI: 10.1212/WNL.0000000000008682

Abstract

Objective: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.

Methods: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.

Results: We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; p = 0.01) following adjustments for age, sex, APOE ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.

Conclusion: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

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Figures

**Figure 1. Overview of the study design**
Framingham Heart Study cohort: soluble cluster of differentiation 14 (sCD14) was measured at examination 7. Baseline brain MRI and cognitive testing were performed within a mean of 0.8 (SD 0.8) years after the blood draw for sCD14. A second round of brain MRI and cognitive testing was performed again after 7 years. Cardiovascular Health Study cohort: sCD14 was measured at the baseline examination (from 1989 to 1990 for the first wave of participants and 1992 to 1993 for the second wave). The first brain MRI (for the quantification of white matter grade) was performed from 1992 to 1994 and the second (for hippocampal volume) from 1997 to 1999.

**Figure 2. Association of soluble cluster of differentiation 14 (sCD14) with incident dementia**
Both the top decile and top quintile are compared to the remainder of the sample. All estimates are adjusted for age, sex, systolic blood pressure, treatment for hypertension, prevalent diabetes, prevalent atrial fibrillation, prevalent cardiovascular disease, total cholesterol, high-density lipoprotein cholesterol, smoking status, body mass index, and positivity for an *APOE* ε4 allele. Estimates for the Cardiovascular Health Study (CHS) are further adjusted for race and clinic site. CI = confidence interval; FHS = Framingham Heart Study; HR = hazard ratio; SDU = SD increase.

See this image and copyright information in PMC

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Association of CD14 with incident dementia and markers of brain aging and injury

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Association of CD14 with incident dementia and markers of brain aging and injury

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