Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome

doi:10.1093/braincomms/fcae331

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome

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15 Scopus citations

Abstract

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Original language	English
Article number	fcae331
Journal	Brain Communications
Volume	6
Issue number	5
DOIs	https://doi.org/10.1093/braincomms/fcae331
State	Published - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Funding

The Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) is funded by the National Institute on Aging and the National Institute for Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054). The work contained in this publication was also supported through the following National Institutes of Health Programs: the Alzheimer's Disease Research Centers Program (P50 AG008702, P30 AG062421, P50 AG16537, P50 AG005133, P50 AG005681, P30 AG062715 and P30 AG066519), the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program (U54 HD090256, U54 HD087011 and P50 HD105353), the National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857 and UL1 TR002345), the National Centralized Repository for Alzheimer Disease and Related Dementias (U24 AG21886) and DS-Connect® (The Down Syndrome Registry) supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). In Cambridge, UK, this research was supported by the NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK. The authors are grateful to the ABC-DS study participants, their families and care providers and the ABC-DS research and support staff for their contributions to this study. This manuscript has been reviewed by ABC-DS investigators for scientific content and consistency of data interpretation with previous ABC-DS study publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the CPFT, the NIHR or the UK Department of Health and Social Care. The graphical abstract was created using BioRender.com. This work was supported by the US National Institutes of Health (NIH) grants RF1 AG079519, U19 AG068054, U01 AG051412, U01 AG051406, and F31 AG090091. The Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) is funded by the National Institute on Aging and the National Institute for Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054). The work contained in this publication was also supported through the following National Institutes of Health Programs: the Alzheimer’s Disease Research Centers Program (P50 AG008702, P30 AG062421, P50 AG16537, P50 AG005133, P50 AG005681, P30 AG062715 and P30 AG066519), the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program (U54 HD090256, U54 HD087011 and P50 HD105353), the National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857 and UL1 TR002345), the National Centralized Repository for Alzheimer Disease and Related Dementias (U24 AG21886) and DS-Connect® (The Down Syndrome Registry) supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). In Cambridge, UK, this research was supported by the NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK. The authors are grateful to the ABC-DS study participants, their families and care providers and the ABC-DS research and support staff for their contributions to this study. This manuscript has been reviewed by ABC-DS investigators for scientific content and consistency of data interpretation with previous ABC-DS study publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the CPFT, the NIHR or the UK Department of Health and Social Care. The graphical abstract was created using BioRender.com . This work was supported by the US National Institutes of Health (NIH) grants RF1 AG079519, U19 AG068054, U01 AG051412, U01 AG051406, and F31 AG090091.

Funders	Funder number
National Institute on Handicapped Research
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Windsor Research Unit
Fulbourn Hospital
UK Department of Health and Social Care
NIHR Cambridge Biomedical Research Centre
CPFT
National Institute on Aging
Down Syndrome Registry
National Centralized Repository for Alzheimer Disease and Related Dementias	U24 AG21886
National Institutes of Health (NIH)	RF1 AG079519, F31 AG090091
Office of Research Infrastructure Programs, National Institutes of Health	P50 AG008702, P50 AG16537, P30 AG062421, P50 AG005681, P50 AG005133, P30 AG062715, P30 AG066519
National Center for Advancing Translational Sciences (NCATS)	UL1 TR002373, UL1 TR001873, UL1 TR002345, UL1 TR001414, UL1 TR001857
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	U01 AG051412, U01 AG051406, U19 AG068054
Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program	U54 HD090256, U54 HD087011, P50 HD105353

Keywords

Alzheimer's disease
Down syndrome
biomarkers
cerebrovascular disease
magnetic resonance imaging

ASJC Scopus subject areas

Neurology
Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

UN SDGs

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

Access to Document

10.1093/braincomms/fcae331

Cite this

@article{267a5c38482c476796ed15da03e0ce10,

title = "Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome",

abstract = "By age 40 years, over 90\% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.",

keywords = "Alzheimer's disease, Down syndrome, biomarkers, cerebrovascular disease, magnetic resonance imaging",

author = "Edwards, \{Natalie C.\} and Lao, \{Patrick J.\} and Alshikho, \{Mohamad J.\} and Ericsson, \{Olivia M.\} and Batool Rizvi and Petersen, \{Melissa E.\} and Sid O'bryant and Aguilar, \{Lisi Flores\} and Sabrina Simoes and Mark Mapstone and Tudorascu, \{Dana L.\} and Shorena Janelidze and Oskar Hansson and Handen, \{Benjamin L.\} and Christian, \{Bradley T.\} and Lee, \{Joseph H.\} and Florence Lai and Rosas, \{H. Diana\} and Shahid Zaman and Lott, \{Ira T.\} and Yassa, \{Michael A.\} and Jos{\'e} Gutierrez and Wilcock, \{Donna M.\} and Elizabeth Head and Brickman, \{Adam M.\} and Aizenstein, \{Howard J.\} and Ances, \{Beau M.\} and Andrews, \{Howard F.\} and Karen Bell and Birn, \{Rasmus M.\} and Peter Bulova and Amrita Cheema and Kewei Chen and Isabel Clare and Cohen, \{Ann D.\} and Constantino, \{John N.\} and Doran, \{Eric W.\} and Anne Fagan and Eleanor Feingold and Foroud, \{Tatiana M.\} and Jordan Harp and Hartley, \{Sigan L.\} and Rachel Henson and Christy Hom and Lawrence Honig and Ikonomovic, \{Milos D.\} and Johnson, \{Sterling C.\} and Courtney Jordan and Kamboh, \{M. Ilyas\} and Frederick Schmitt",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2024",

doi = "10.1093/braincomms/fcae331",

language = "English",

volume = "6",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome

AU - Edwards, Natalie C.

AU - Lao, Patrick J.

AU - Alshikho, Mohamad J.

AU - Ericsson, Olivia M.

AU - Rizvi, Batool

AU - Petersen, Melissa E.

AU - O'bryant, Sid

AU - Aguilar, Lisi Flores

AU - Simoes, Sabrina

AU - Mapstone, Mark

AU - Tudorascu, Dana L.

AU - Janelidze, Shorena

AU - Hansson, Oskar

AU - Handen, Benjamin L.

AU - Christian, Bradley T.

AU - Lee, Joseph H.

AU - Lai, Florence

AU - Rosas, H. Diana

AU - Zaman, Shahid

AU - Lott, Ira T.

AU - Yassa, Michael A.

AU - Gutierrez, José

AU - Wilcock, Donna M.

AU - Head, Elizabeth

AU - Brickman, Adam M.

AU - Aizenstein, Howard J.

AU - Ances, Beau M.

AU - Andrews, Howard F.

AU - Bell, Karen

AU - Birn, Rasmus M.

AU - Bulova, Peter

AU - Cheema, Amrita

AU - Chen, Kewei

AU - Clare, Isabel

AU - Cohen, Ann D.

AU - Constantino, John N.

AU - Doran, Eric W.

AU - Fagan, Anne

AU - Feingold, Eleanor

AU - Foroud, Tatiana M.

AU - Harp, Jordan

AU - Hartley, Sigan L.

AU - Henson, Rachel

AU - Hom, Christy

AU - Honig, Lawrence

AU - Ikonomovic, Milos D.

AU - Johnson, Sterling C.

AU - Jordan, Courtney

AU - Kamboh, M. Ilyas

AU - Schmitt, Frederick

PY - 2024

Y1 - 2024

N2 - By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

AB - By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

KW - Alzheimer's disease

KW - Down syndrome

KW - biomarkers

KW - cerebrovascular disease

KW - magnetic resonance imaging

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UR - https://www.scopus.com/pages/publications/85207124318#tab=citedBy

U2 - 10.1093/braincomms/fcae331

DO - 10.1093/braincomms/fcae331

M3 - Article

AN - SCOPUS:85207124318

SN - 2632-1297

VL - 6

JO - Brain Communications

JF - Brain Communications

IS - 5

M1 - fcae331

ER -

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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