Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease

Alzheimer’s Disease Neuroimaging Initiative Consortium

doi:10.1007/s11357-024-01151-x

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease

Alzheimer’s Disease Neuroimaging Initiative Consortium

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer’s disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer’s disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer’s participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

Original language	English (US)
Pages (from-to)	6071-6084
Number of pages	14
Journal	GeroScience
Volume	46
Issue number	6
DOIs	https://doi.org/10.1007/s11357-024-01151-x
State	Published - Dec 2024

Funding

Data collection and sharing for this project was funded by the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer\u2019s Association; Alzheimer\u2019s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer\u2019s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was also partially supported by the American Heart Association (AHA834339) and the National Institute on Aging of National Institutes of Health (R01AG075834) awards. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

Alzheimer’s disease (AD)
Apolipoprotein E
Functional connectivity
Sex difference

ASJC Scopus subject areas

Aging
veterinary (miscalleneous)
Complementary and alternative medicine
Geriatrics and Gerontology
Cardiology and Cardiovascular Medicine

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10.1007/s11357-024-01151-x

Cite this

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title = "Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer{\textquoteright}s disease",

abstract = "As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer{\textquoteright}s disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer{\textquoteright}s disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer{\textquoteright}s participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.",

keywords = "Alzheimer{\textquoteright}s disease (AD), Apolipoprotein E, Functional connectivity, Sex difference",

author = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative Consortium} and Williamson, {Jordan N.} and James, {Shirley A.} and Mullen, {Sean P.} and Sutton, {Bradley P.} and Tracey Wszalek and Beni Mulyana and Peter Mukli and Andriy Yabluchanskiy and Raj, {Balebail Ashok} and Kristin Fargher and Amanda Smith and Lisa Raudin and Gloria Chaing and Norman Relkin and Smith, {Karen Elizabeth} and Hyungsub Shim and Ponto, {Laura L.Boles} and Schultz, {Susan K.} and Antero Sarrael and Raymundo Hernando and Nunzio Pomara and Dick Drost and Andrew Kertesz and John Rogers and Irina Rachinsky and Stephen Pasternak and Elizabether Finger and David Bachman and Kenneth Spicer and Jacobo Mintzer and Miller, {Bruce L.} and Rosen, {Howard J.} and Stephen Correia and Paul Malloy and Stephen Salloway and Geoffrey Tremont and Henry Querfurth and Ott, {Brian R.} and Franklin Watkins and Pradeep Garg and Williamson, {Jeff D.} and Sink, {Kaycee M.} and Schwartz, {Eben S.} and Kitzmiller, {Tamar J.} and Santulli, {Robert B.} and Karen Anderson and Karen Blank and Pearlson, {Godfrey D.} and Mesulam, {Marek Marsel} and Yuan Yang",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to American Aging Association 2024.",

year = "2024",

month = dec,

doi = "10.1007/s11357-024-01151-x",

language = "English (US)",

volume = "46",

pages = "6071--6084",

journal = "GeroScience",

issn = "2509-2715",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "6",

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T1 - Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease

AU - Alzheimer’s Disease Neuroimaging Initiative Consortium

AU - Williamson, Jordan N.

AU - James, Shirley A.

AU - Mullen, Sean P.

AU - Sutton, Bradley P.

AU - Wszalek, Tracey

AU - Mulyana, Beni

AU - Mukli, Peter

AU - Yabluchanskiy, Andriy

AU - Raj, Balebail Ashok

AU - Fargher, Kristin

AU - Smith, Amanda

AU - Raudin, Lisa

AU - Chaing, Gloria

AU - Relkin, Norman

AU - Smith, Karen Elizabeth

AU - Shim, Hyungsub

AU - Ponto, Laura L.Boles

AU - Schultz, Susan K.

AU - Sarrael, Antero

AU - Hernando, Raymundo

AU - Pomara, Nunzio

AU - Drost, Dick

AU - Kertesz, Andrew

AU - Rogers, John

AU - Rachinsky, Irina

AU - Pasternak, Stephen

AU - Finger, Elizabether

AU - Bachman, David

AU - Spicer, Kenneth

AU - Mintzer, Jacobo

AU - Miller, Bruce L.

AU - Rosen, Howard J.

AU - Correia, Stephen

AU - Malloy, Paul

AU - Salloway, Stephen

AU - Tremont, Geoffrey

AU - Querfurth, Henry

AU - Ott, Brian R.

AU - Watkins, Franklin

AU - Garg, Pradeep

AU - Williamson, Jeff D.

AU - Sink, Kaycee M.

AU - Schwartz, Eben S.

AU - Kitzmiller, Tamar J.

AU - Santulli, Robert B.

AU - Anderson, Karen

AU - Blank, Karen

AU - Pearlson, Godfrey D.

AU - Mesulam, Marek Marsel

AU - Yang, Yuan

PY - 2024/12

Y1 - 2024/12

N2 - As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer’s disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer’s disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer’s participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

AB - As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer’s disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer’s disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer’s participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

KW - Alzheimer’s disease (AD)

KW - Apolipoprotein E

KW - Functional connectivity

KW - Sex difference

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SN - 2509-2715

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JO - GeroScience

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ER -

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease

Abstract

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Keywords

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