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; 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

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, Sigan L. Hartley, Jason Hassenstab, Richard J. Perrin, Mark Mapstone, Shahid H. Zaman, Beau M. Ances, M. Ilyas Kamboh, Joseph H. Lee, Carlos Cruchaga

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2 Scopus citations

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.

Original language	English
Pages (from-to)	1038-1049
Number of pages	12
Journal	Alzheimer's and Dementia
Volume	20
Issue number	2
DOIs	https://doi.org/10.1002/alz.13506
State	Published - Feb 2024

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

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10.1002/alz.13506

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Gorijala, P., Aslam, M. M., Dang, L. H. T., Xicota, L., Fernandez, M. V., Sung, Y. J., Fan, K. H., Feingold, E., Surace, E. I., Chhatwal, J. P., Hom, C. L., Hartley, S. L., Hassenstab, J., Perrin, R. J., Mapstone, M., Zaman, S. H., Ances, B. M., Kamboh, M. I., Lee, J. H., & Cruchaga, C. (2024). Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome. Alzheimer's and Dementia, 20(2), 1038-1049. https://doi.org/10.1002/alz.13506

@article{db9f31b5637b4c11918bbc73add29ee1,

title = "Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome",

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, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE 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",

author = "Priyanka Gorijala and Aslam, {M. Muaaz} and Dang, {Lam Ha T.} and L. Xicota and Fernandez, {Maria V.} and Sung, {Yun Ju} and Fan, {Kang Hsien} and Eleanor Feingold and Surace, {Ezequiel I.} and Chhatwal, {Jasmeer P.} and Hom, {Christy L.} and Hartley, {Sigan L.} and Jason Hassenstab and Perrin, {Richard J.} and Mark Mapstone and Zaman, {Shahid H.} and Ances, {Beau M.} and Kamboh, {M. Ilyas} and Lee, {Joseph H.} and Carlos Cruchaga",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = feb,

doi = "10.1002/alz.13506",

language = "English",

volume = "20",

pages = "1038--1049",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

number = "2",

}

Gorijala, P, Aslam, MM, Dang, LHT, Xicota, L, Fernandez, MV, Sung, YJ, Fan, KH, Feingold, E, Surace, EI, Chhatwal, JP, Hom, CL, Hartley, SL, Hassenstab, J , Perrin, RJ, Mapstone, M, Zaman, SH, Ances, BM, Kamboh, MI, Lee, JH & Cruchaga, C 2024, 'Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome', Alzheimer's and Dementia, vol. 20, no. 2, pp. 1038-1049. https://doi.org/10.1002/alz.13506

TY - JOUR

T1 - Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome

AU - Gorijala, Priyanka

AU - Aslam, M. Muaaz

AU - Dang, Lam Ha T.

AU - Xicota, L.

AU - Fernandez, Maria V.

AU - Sung, Yun Ju

AU - Fan, Kang Hsien

AU - Feingold, Eleanor

AU - Surace, Ezequiel I.

AU - Chhatwal, Jasmeer P.

AU - Hom, Christy L.

AU - Hartley, Sigan L.

AU - Hassenstab, Jason

AU - Perrin, Richard J.

AU - Mapstone, Mark

AU - Zaman, Shahid H.

AU - Ances, Beau M.

AU - Kamboh, M. Ilyas

AU - Lee, Joseph H.

AU - Cruchaga, Carlos

PY - 2024/2

Y1 - 2024/2

N2 - 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, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE 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.

AB - 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, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE 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.

KW - Dominantly Inherited Alzheimer Network

KW - Down syndrome

KW - PSEN1

KW - PSEN2

KW - amyloid precursor protein

KW - apoliprotein E APOE

KW - area under the curve

KW - cerebrospinal fluid biomarkers

KW - cognitive batteries

KW - early-onset Alzheimer's disease

KW - early-onset autosomal dominant

KW - genetic architecture

KW - genetic risk factor

KW - late-onset Alzheimer's disease

KW - polygenic risk score

KW - sporadic late-onset Alzheimer's disease

UR - http://www.scopus.com/inward/record.url?scp=85174415945&partnerID=8YFLogxK

U2 - 10.1002/alz.13506

DO - 10.1002/alz.13506

M3 - Article

C2 - 37855447

AN - SCOPUS:85174415945

SN - 1552-5260

VL - 20

SP - 1038

EP - 1049

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 2

ER -

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

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