. 2025 Oct;21(10):e70726.

doi: 10.1002/alz.70726.

Alzheimer's disease diagnostic progression is associated with cerebrovascular disease and neuroinflammation in adults with Down syndrome

Natalie C Edwards^{1

2

3}, Patrick J Lao^{1

2}, Mohamad J Alshikho^{1

2}, Olivia M Ericsson^{1

2}, Batool Rizvi⁴, Melissa E Petersen⁵, Sid O'Bryant⁵, Lisi Flores-Aguilar⁶, Sabrina Simoes^{1

2}, Mark Mapstone⁷, Dana L Tudorascu⁸, Shorena Janelidze⁹, Oskar Hansson^{9

10}, Benjamin L Handen⁸, Bradley T Christian¹¹, Joseph H Lee^{1

2}, Florence Lai¹², H Diana Rosas^{12

13}, Shahid Zaman¹⁴, Ira T Lott¹⁵, Michael A Yassa^{4

16}; Alzheimer's Biomarkers Consortium–Down Syndrome (ABC‐DS) Investigators; José Gutierrez², Donna M Wilcock^{17

18

19}, Elizabeth Head⁶, Adam M Brickman^{1

2}

Affiliations

¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York City, New York, USA.
² Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York City, New York, USA.
³ Department of Neuroscience, Columbia University, New York City, New York, USA.
⁴ Department of Neurobiology & Behavior, University of California, Irvine, California, USA.
⁵ University of North Texas Health Science Center, Fort Worth, Texas, USA.
⁶ Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, University of California, Irvine, California, USA.
⁷ Department of Neurology, University of California, Irvine, California, USA.
⁸ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁹ Department of Clinical Sciences Malmö, Clinical Memory Research Unit, Lund University, Lund, Sweden.
¹⁰ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
¹¹ Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹² Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹³ Department of Radiology, Center for Neuroimaging of Aging and Neurodegenerative Diseases, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, USA.
¹⁴ Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁵ Department of Pediatrics and Neurology, School of Medicine, University of California, Irvine, California, USA.
¹⁶ Center for the Neurobiology of Learning and Memory, University of California, Irvine, California, USA.
¹⁷ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁸ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁹ Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 41014048
PMCID: PMC12475832
DOI: 10.1002/alz.70726

Alzheimer's disease diagnostic progression is associated with cerebrovascular disease and neuroinflammation in adults with Down syndrome

Natalie C Edwards et al. Alzheimers Dement. 2025 Oct.

. 2025 Oct;21(10):e70726.

doi: 10.1002/alz.70726.

Authors

Affiliations

¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York City, New York, USA.
² Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York City, New York, USA.
³ Department of Neuroscience, Columbia University, New York City, New York, USA.
⁴ Department of Neurobiology & Behavior, University of California, Irvine, California, USA.
⁵ University of North Texas Health Science Center, Fort Worth, Texas, USA.
⁶ Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, University of California, Irvine, California, USA.
⁷ Department of Neurology, University of California, Irvine, California, USA.
⁸ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁹ Department of Clinical Sciences Malmö, Clinical Memory Research Unit, Lund University, Lund, Sweden.
¹⁰ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
¹¹ Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹² Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹³ Department of Radiology, Center for Neuroimaging of Aging and Neurodegenerative Diseases, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, USA.
¹⁴ Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁵ Department of Pediatrics and Neurology, School of Medicine, University of California, Irvine, California, USA.
¹⁶ Center for the Neurobiology of Learning and Memory, University of California, Irvine, California, USA.
¹⁷ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁸ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁹ Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 41014048
PMCID: PMC12475832
DOI: 10.1002/alz.70726

Abstract

Introduction: Despite having few vascular risk factors, people with Down syndrome (DS) have MRI evidence of cerebrovascular disease (CVD) and neuroinflammation that worsens with Alzheimer's disease (AD) severity. We investigated whether markers of CVD and inflammation are associated with AD-related diagnostic progression in people with DS.

Methods: We included 149 participants (mean age [SD] = 44.6 [9]) from the Alzheimer's Biomarkers Consortium-Down Syndrome who had two (n = 24) or three follow-up visits (n = 125). We derived white matter hyperintensity (WMH) volume and plasma biomarker (glial fibrillary acidic protein [GFAP], amyloid beta [Aβ]42/Aβ40, hyperphosphorylated tau-217 [p-tau217], and neurofilament light [NfL]) concentrations at baseline and examined their association with progression in clinical diagnosis.

Results: Higher baseline WMH volume and higher GFAP were associated with a greater likelihood of diagnostic progression. Combining WMH and GFAP with p-tau217 improved clinical conversion classification accuracy over AD biomarkers alone. Among individuals with evidence of amyloidosis, both WMH and GFAP were associated with clinical progression.

Discussion: In DS, markers of CVD and inflammation are independently and synergistically associated with clinical AD progression.

Highlights: Higher baseline white matter hyperintensity (WMH) volume and plasma glial fibrillary acidic protein (GFAP) concentration were associated with a higher likelihood of progressing from cognitively stable to either mild cognitive impairment or clinical Alzheimer's disease in Down syndrome. WMH volume and GFAP concentration discriminated between those who progressed and those who did not. Models including the independent and interactive effects of WMH and GFAP more accurately discriminated between participants who progressed diagnostically from those who did not. Individuals with evidence of amyloid pathology were more likely to progress if they also had elevated WMH or GFAP.

Keywords: Alzheimer's disease progression; biomarker; dementia; white matter hyperintensity.

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Conflict of interest statement

Oskar Hansson has received consulting fees for AC Immune, Amylyx, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. Shahid Zaman has received consulting fees from Lundbeck. Donna M. Wilcock has received consulting fees from Biohaven Therapeutics. Michael A. Yassa has received consulting fees from Eisai Cognito Terapeutics, LLC, CuraSen Terapeutics, Inc, and Enthorin Terapeutics, LLC. Elizabeth Head has received consulting fees for Alzheon and Cyclo Therapeutics. Adam Brickman receives compensation for consultation to Cognition Terapeutics and Cognito Terapeutics. He is on the Scientific Advisory Board of CogState. He is an inventor of a patent for white matter hyperintensity quantification (US Patent US9867566B2) and serves on a Data Safety Monitoring Board for the University of Illinois, Urbana‐Champaign. All other authors do not have competing interests to declare. Any author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Frequency map of white matter hyperintensities (WMH) in adults with Down syndrome. A voxel‐wise frequency map of WMH was created by summing voxels labeled across all 149 individual 3D masks and dividing by 149. Each voxel's value represents the percentage each voxel was labeled as WMH across the 149 masks from lower frequency (blue) to higher frequency (red).

**FIGURE 2**
Receiver‐operating characteristic (ROC) curves demonstrate how well each model discriminates between participants who progressed diagnostically from those who did not. Aβ, amyloid beta; WMH, white matter hyperintensities; p‐tau217, phosphorylated tau‐217; GFAP, glial fibrillary acidic protein; NfL, neurofilament light.

**FIGURE 3**
Proportion of subjects who diagnostically progressed. The y‐axis represents the percentage of individuals in each group who progressed. * indicates a statistically significant difference between the two proportion percentages. Aβ, amyloid beta; WMH, white matter hyperintensity; GFAP, glial fibrillary acidic protein.

See this image and copyright information in PMC

References

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Alzheimer's disease diagnostic progression is associated with cerebrovascular disease and neuroinflammation in adults with Down syndrome

Affiliations

Alzheimer's disease diagnostic progression is associated with cerebrovascular disease and neuroinflammation in adults with Down syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous