Cerebrovascular disease emerges with age and Alzheimer's disease in adults with Down syndrome

Patrick Lao^{1

2}, Natalie Edwards¹, Lisi Flores-Aguilar³, Mohamad Alshikho¹, Batool Rizvi⁴, Dana Tudorascu⁵, H Diana Rosas⁶, Michael Yassa⁴, Bradley T Christian⁷, Mark Mapstone⁴, Benjamin Handen⁵, Molly E Zimmerman⁸, Jose Gutierrez², Donna Wilcock⁹, Elizabeth Head^{3

10}, Adam M Brickman^{11

12}

Affiliations

¹ Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PS Box 16, New York, NY, 10032, USA.
² Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, 92697, USA.
⁴ Department of Neurology, University of California, Irvine, Irvine, CA, 92697, USA.
⁵ Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
⁶ Department of Neurology, Massachusetts General Hospital, Harvard Medical Center, Boston, MA, 02114, USA.
⁷ Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁸ Department of Psychology, Fordham University, Bronx, NY, 10458, USA.
⁹ Departments of Neurology and Anatomy, Cell Biology, and Physiology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, 92697, USA.
¹¹ Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PS Box 16, New York, NY, 10032, USA. amb2139@columbia.edu.
¹² Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. amb2139@columbia.edu.

PMID: 38811657
PMCID: PMC11137035
DOI: 10.1038/s41598-024-61962-y

Cerebrovascular disease emerges with age and Alzheimer's disease in adults with Down syndrome

Patrick Lao et al. Sci Rep. 2024.

. 2024 May 29;14(1):12334.

doi: 10.1038/s41598-024-61962-y.

Authors

Affiliations

¹ Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PS Box 16, New York, NY, 10032, USA.
² Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, 92697, USA.
⁴ Department of Neurology, University of California, Irvine, Irvine, CA, 92697, USA.
⁵ Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
⁶ Department of Neurology, Massachusetts General Hospital, Harvard Medical Center, Boston, MA, 02114, USA.
⁷ Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁸ Department of Psychology, Fordham University, Bronx, NY, 10458, USA.
⁹ Departments of Neurology and Anatomy, Cell Biology, and Physiology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, 92697, USA.
¹¹ Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PS Box 16, New York, NY, 10032, USA. amb2139@columbia.edu.
¹² Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. amb2139@columbia.edu.

PMID: 38811657
PMCID: PMC11137035
DOI: 10.1038/s41598-024-61962-y

Abstract

Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

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Conflict of interest statement

Michael A. Yassa has received consulting fees from Eisai Cognito Therapeutics, LLC, CuraSen Therapeutics, Inc, and Enthorin Therapeutics, LLC. Adam Brickman receives compensation for consultation to Cognition Therapeutics and Cognito Therapeutics and for his role on the Scientific Advisory Board of CogState. He is an inventor a patent for white matter hyperintensity quantification (US Patent US9867566B2) and serves on a Data Safety Monitoring Board for University of Illinois, Urbana-Champaign. All other authors do not have competing interests to declare.

Figures

**Figure 1**
Representative MRI scans for white matter hyperintensity volume, enlarged perivascular spaces, microbleeds, and infarcts across the lifespan of adults with Down syndrome.

**Figure 2**
Piecewise left-null regressions of (A) cerebrovascular biomarkers, (B) regional white matter hyperintensity volume, and (C) traditional AD biomarkers against age across the lifespan in adults with Down syndrome. Inflection point estimates, their 95% confidence interval, and their p-value are displayed at the top.

See this image and copyright information in PMC

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Cerebrovascular disease emerges with age and Alzheimer's disease in adults with Down syndrome

Affiliations

Cerebrovascular disease emerges with age and Alzheimer's disease in adults with Down syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

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