Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Vincent Chouraki; Sarah R. Preis; Qiong Yang; Alexa Beiser; Shuo Li; Martin G. Larson; Galit Weinstein; Thomas J. Wang; Robert E. Gerszten; Ramachandran S. Vasan; Sudha Seshadri

doi:10.1016/j.jalz.2017.04.009

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Vincent Chouraki, Sarah R. Preis, Qiong Yang, Alexa Beiser, Shuo Li, Martin G. Larson, Galit Weinstein, Thomas J. Wang, Robert E. Gerszten, Ramachandran S. Vasan, Sudha Seshadri

School of Public Health

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: The identification of novel biomarkers associated with Alzheimer's disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. Methods: Plasma levels of 217 metabolites were assessed in 2067 dementia-free Framingham Offspring Cohort participants (mean age = 55.9 ± 9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. Results: Ninety-three participants developed incident dementia (mean follow-up = 15.6 ± 5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (hazard ratio [HR] = 1.40; 95% confidence interval [CI] = [1.15–1.70]; P = 8.08 × 10⁻⁴). Glutamic acid (HR = 1.38; 95% CI = [1.11–1.72]), taurine (HR = 0.74; 95% CI = [0.60–0.92]), and hypoxanthine (HR = 0.74; 95% CI = [0.60–0.92]) levels also showed suggestive associations with dementia risk. Discussion: We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

Original language	English
Pages (from-to)	1327-1336
Number of pages	10
Journal	Alzheimer's and Dementia
Volume	13
Issue number	12
DOIs	https://doi.org/10.1016/j.jalz.2017.04.009
State	Published - Dec 2017

Bibliographical note

Funding Information:
This work was supported by the dedication of the Framingham Heart Study participants. This work received support from the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and HHSN268201500001I) and grants from the National Institute of Neurological Disorders and Stroke ( NS17950 ), the National Institute on Aging ( AG008122 , AG016495 , AG049505 , AG049607 , and AG033193 ), and the National Institute of Diabetes and Digestive and Kidney Diseases ( R01-DK-HL081572 ). Role of the sponsors: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke; the National Heart, Lung, and Blood Institute; the National Institute of Aging; the National Institute of Diabetes and Digestive and Kidney Diseases; or the National Institutes of Health. The information contained in this article does not necessarily reflect the position or the policy of the US government, and no official endorsement should be inferred. Authors' contribution: V.C. and S.S helped in preparing the study design and drafting the manuscript. R.S.V. helped in study supervision and funding. Metabolites assessment was done by R.E.G. and T.J.W. Critical review of the manuscript was by all authors. Statistical methods and analysis was by S.R.P., A.B., S.L., and Q.Y.

Publisher Copyright:
© 2017 the Alzheimer's Association

Keywords

Alzheimer's disease
Anthranilic acid
Cohort studies
Dementia
Epidemiology
Glutamic acid
Hypoxanthine
Kynurenines
Metabolomics
Plasma biomarkers
Taurine
Uric acid

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jalz.2017.04.009

Cite this

@article{c175a132973b4c669c71b18f4c529c01,

title = "Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study",

abstract = "Introduction: The identification of novel biomarkers associated with Alzheimer's disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. Methods: Plasma levels of 217 metabolites were assessed in 2067 dementia-free Framingham Offspring Cohort participants (mean age = 55.9 ± 9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. Results: Ninety-three participants developed incident dementia (mean follow-up = 15.6 ± 5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (hazard ratio [HR] = 1.40; 95% confidence interval [CI] = [1.15–1.70]; P = 8.08 × 10−4). Glutamic acid (HR = 1.38; 95% CI = [1.11–1.72]), taurine (HR = 0.74; 95% CI = [0.60–0.92]), and hypoxanthine (HR = 0.74; 95% CI = [0.60–0.92]) levels also showed suggestive associations with dementia risk. Discussion: We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.",

keywords = "Alzheimer's disease, Anthranilic acid, Cohort studies, Dementia, Epidemiology, Glutamic acid, Hypoxanthine, Kynurenines, Metabolomics, Plasma biomarkers, Taurine, Uric acid",

author = "Vincent Chouraki and Preis, {Sarah R.} and Qiong Yang and Alexa Beiser and Shuo Li and Larson, {Martin G.} and Galit Weinstein and Wang, {Thomas J.} and Gerszten, {Robert E.} and Vasan, {Ramachandran S.} and Sudha Seshadri",

note = "Funding Information: This work was supported by the dedication of the Framingham Heart Study participants. This work received support from the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and HHSN268201500001I) and grants from the National Institute of Neurological Disorders and Stroke ( NS17950 ), the National Institute on Aging ( AG008122 , AG016495 , AG049505 , AG049607 , and AG033193 ), and the National Institute of Diabetes and Digestive and Kidney Diseases ( R01-DK-HL081572 ). Role of the sponsors: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke; the National Heart, Lung, and Blood Institute; the National Institute of Aging; the National Institute of Diabetes and Digestive and Kidney Diseases; or the National Institutes of Health. The information contained in this article does not necessarily reflect the position or the policy of the US government, and no official endorsement should be inferred. Authors' contribution: V.C. and S.S helped in preparing the study design and drafting the manuscript. R.S.V. helped in study supervision and funding. Metabolites assessment was done by R.E.G. and T.J.W. Critical review of the manuscript was by all authors. Statistical methods and analysis was by S.R.P., A.B., S.L., and Q.Y. Publisher Copyright: {\textcopyright} 2017 the Alzheimer's Association",

year = "2017",

month = dec,

doi = "10.1016/j.jalz.2017.04.009",

language = "English",

volume = "13",

pages = "1327--1336",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

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TY - JOUR

T1 - Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

AU - Chouraki, Vincent

AU - Preis, Sarah R.

AU - Yang, Qiong

AU - Beiser, Alexa

AU - Li, Shuo

AU - Larson, Martin G.

AU - Weinstein, Galit

AU - Wang, Thomas J.

AU - Gerszten, Robert E.

AU - Vasan, Ramachandran S.

AU - Seshadri, Sudha

N1 - Funding Information: This work was supported by the dedication of the Framingham Heart Study participants. This work received support from the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and HHSN268201500001I) and grants from the National Institute of Neurological Disorders and Stroke ( NS17950 ), the National Institute on Aging ( AG008122 , AG016495 , AG049505 , AG049607 , and AG033193 ), and the National Institute of Diabetes and Digestive and Kidney Diseases ( R01-DK-HL081572 ). Role of the sponsors: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke; the National Heart, Lung, and Blood Institute; the National Institute of Aging; the National Institute of Diabetes and Digestive and Kidney Diseases; or the National Institutes of Health. The information contained in this article does not necessarily reflect the position or the policy of the US government, and no official endorsement should be inferred. Authors' contribution: V.C. and S.S helped in preparing the study design and drafting the manuscript. R.S.V. helped in study supervision and funding. Metabolites assessment was done by R.E.G. and T.J.W. Critical review of the manuscript was by all authors. Statistical methods and analysis was by S.R.P., A.B., S.L., and Q.Y. Publisher Copyright: © 2017 the Alzheimer's Association

PY - 2017/12

Y1 - 2017/12

N2 - Introduction: The identification of novel biomarkers associated with Alzheimer's disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. Methods: Plasma levels of 217 metabolites were assessed in 2067 dementia-free Framingham Offspring Cohort participants (mean age = 55.9 ± 9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. Results: Ninety-three participants developed incident dementia (mean follow-up = 15.6 ± 5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (hazard ratio [HR] = 1.40; 95% confidence interval [CI] = [1.15–1.70]; P = 8.08 × 10−4). Glutamic acid (HR = 1.38; 95% CI = [1.11–1.72]), taurine (HR = 0.74; 95% CI = [0.60–0.92]), and hypoxanthine (HR = 0.74; 95% CI = [0.60–0.92]) levels also showed suggestive associations with dementia risk. Discussion: We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

AB - Introduction: The identification of novel biomarkers associated with Alzheimer's disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. Methods: Plasma levels of 217 metabolites were assessed in 2067 dementia-free Framingham Offspring Cohort participants (mean age = 55.9 ± 9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. Results: Ninety-three participants developed incident dementia (mean follow-up = 15.6 ± 5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (hazard ratio [HR] = 1.40; 95% confidence interval [CI] = [1.15–1.70]; P = 8.08 × 10−4). Glutamic acid (HR = 1.38; 95% CI = [1.11–1.72]), taurine (HR = 0.74; 95% CI = [0.60–0.92]), and hypoxanthine (HR = 0.74; 95% CI = [0.60–0.92]) levels also showed suggestive associations with dementia risk. Discussion: We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

KW - Alzheimer's disease

KW - Anthranilic acid

KW - Cohort studies

KW - Dementia

KW - Epidemiology

KW - Glutamic acid

KW - Hypoxanthine

KW - Kynurenines

KW - Metabolomics

KW - Plasma biomarkers

KW - Taurine

KW - Uric acid

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U2 - 10.1016/j.jalz.2017.04.009

DO - 10.1016/j.jalz.2017.04.009

M3 - Article

C2 - 28602601

AN - SCOPUS:85021339243

SN - 1552-5260

VL - 13

SP - 1327

EP - 1336

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 12

ER -

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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