Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome

Priyanka Gorijala; M Muaaz Aslam; Lam-Ha T Dang; L Xicota; Maria V Fernandez; Yun Ju Sung; Kang-Hsien Fan; Eleanor Feingold; Ezequiel I Surace; Jasmeer P Chhatwal; Christy L Hom; Dominantly Inherited Alzheimer Network (DIAN), the Alzheimer's Disease Neuroimaging Initiative (ADNI); NIA-LOAD family study, for the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) Investigators; Sigan L Hartley; Jason Hassenstab; Richard J Perrin; Mark Mapstone; Shahid H Zaman; Beau M Ances; M Ilyas Kamboh; Joseph H Lee; Carlos Cruchaga

doi:10.1002/alz.13506

Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome

Alzheimers Dement. 2024 Feb;20(2):1038-1049. doi: 10.1002/alz.13506. Epub 2023 Oct 19.

Authors

Priyanka Gorijala^{1

2}, M Muaaz Aslam³, Lam-Ha T Dang^{4

5}, L Xicota⁵, Maria V Fernandez^{1

2}, Yun Ju Sung^{1

2

6}, Kang-Hsien Fan³, Eleanor Feingold³, Ezequiel I Surace⁷, Jasmeer P Chhatwal⁸, Christy L Hom⁹; Dominantly Inherited Alzheimer Network (DIAN), the Alzheimer's Disease Neuroimaging Initiative (ADNI); NIA-LOAD family study, for the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) Investigators; Sigan L Hartley¹⁰, Jason Hassenstab¹¹, Richard J Perrin^{12

13

14}, Mark Mapstone¹⁵, Shahid H Zaman^{16

17}, Beau M Ances¹⁴, M Ilyas Kamboh³, Joseph H Lee^{4

5}, Carlos Cruchaga^{1

2

12}

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
² Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, Missouri, USA.
³ Department of Human Genetics, University of Pittsburgh, School of Public Health, Pittsburgh, Pennsylvania, USA.
⁴ Department of Epidemiology, Columbia University Irving Medical Center, New York, New York, USA.
⁵ Sergievsky Center, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
⁶ Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Laboratory of Neurodegenerative Diseases - Institute of Neurosciences (INEU-Fleni- CONICET), Buenos Aires, Argentina.
⁸ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Dept. of Psychiatry and Human Behavior, University of California, Irvine School of Medicine, California, USA.
¹⁰ Waisman Center and School of Human Ecology, University of Wisconsin- Madison, Madison, Wisconsin, USA.
¹¹ Department of Neurology and Psychological & Brain Sciences, Washington University, St. Louis, Missouri, USA.
¹² Hope Center for Neurologic Diseases, Washington University, St. Louis, Missouri, USA.
¹³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁴ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁵ Department of Neurology, University of California-Irvine, Irvine, California, USA.
¹⁶ Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Douglas House, Cambridge, UK.
¹⁷ Cambridgeshire and Peterborough NHS Foundation Trust, Elizabeth House, Fulbourn Hospital, Fulbourn, Cambridge, UK.

Abstract

Introduction: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers.

Methods: AD polygenic risk scores (PRS) were tested for association with DS-related traits.

Results: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRS_APOE , p = 2.84 × 10^-4 ; PRS excluding APOE, PRS_nonAPOE , p = 1.60 × 10^-2 ). PRS_APOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS.

Discussion: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits.

Highlights: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

Keywords: Dominantly Inherited Alzheimer Network; Down syndrome; PSEN1; PSEN2; amyloid precursor protein; apoliprotein E APOE; area under the curve; cerebrospinal fluid biomarkers; cognitive batteries; early-onset Alzheimer's disease; early-onset autosomal dominant; genetic architecture; genetic risk factor; late-onset Alzheimer's disease; polygenic risk score; sporadic late-onset Alzheimer's disease.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adult
Alzheimer Disease* / diagnosis
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoproteins E / genetics
Biomarkers / cerebrospinal fluid
Cognition
Cognitive Dysfunction* / diagnosis
Down Syndrome* / genetics
Genetic Risk Score
Humans
Memory Disorders
Phenotype

Substances

Apolipoproteins E
Biomarkers
Amyloid beta-Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding