Abstract
Late-onset Alzheimer's disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%-7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself.
Original language | English |
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Pages (from-to) | 115-121 |
Number of pages | 7 |
Journal | Neurobiology of Aging |
Volume | 41 |
DOIs | |
State | Published - May 1 2016 |
Bibliographical note
Publisher Copyright:© 2016.Published by Elsevier Inc.
Funding
EPAD: GRF. EPAD:GRF is funded by the National Institute on Aging , R01 AG 042437 (P Crane, PI). ADNI: Data collection and sharing for this project was funded by the Alzheimer's 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’s Association ; Alzheimer’s Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc. ; 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's Disease Cooperative Study at the University of Southern California . ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California . ADGC: The National Institutes of Health , National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, aU01 AG032984 , RC2 AG036528 ; Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant ( U24 AG21886 ) awarded by the National Institute on Aging (NIA) , were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania ( U24-AG041689-01 ); NACC , U01 AG016976 ; NIA LOAD , U24 AG026395 , R01AG041797 ; Banner Sun Health Research Institute P30 AG019610 ; Boston University , P30 AG013846 , U01 AG10483 , R01 CA129769 , R01 MH080295 , R01 AG017173 , R01 AG025259 , R01AG33193 ; Columbia University , P50 AG008702 , R37 AG015473 ; Duke University , P30 AG028377 , AG05128 ; Emory University , AG025688 ; Group Health Research Institute , UO1 AG006781 , UO1 HG004610 , UO1 HG006375 ; Indiana University , P30 AG10133 ; Johns Hopkins University , P50 AG005146 , R01 AG020688 ; Massachusetts General Hospital , P50 AG005134 ; Mayo Clinic , P50 AG016574 ; Mount Sinai School of Medicine , P50 AG005138 , P01 AG002219 ; New York University , P30 AG08051 , UL1 RR029893 , 5R01AG012101 , 5R01AG022374 , 5R01AG013616 , 1RC2AG036502 , 1R01AG035137 ; Northwestern University , P30 AG013854 ; Oregon Health & Science University , P30 AG008017 , R01 AG026916 ; Rush University , P30 AG010161 , R01 AG019085 , R01 AG15819 , R01 AG17917 , R01 AG30146 ; TGen , R01 NS059873 ; University of Alabama at Birmingham , P50 AG016582 ; University of Arizona , R01 AG031581 ; University of California, Davis , P30 AG010129 ; University of California, Irvine , P50 AG016573 ; University of California, Los Angeles , P50 AG016570 ; University of California, San Diego , P50 AG005131 ; University of California, San Francisco , P50 AG023501 , P01 AG019724 ; University of Kentucky , P30 AG028383 , AG05144 ; University of Michigan , P50 AG008671 ; University of Pennsylvania , P30 AG010124 ; University of Pittsburgh , P50 AG005133 , AG030653 , AG041718 , AG07562 , AG02365 ; University of Southern California , P50 AG005142 ; University of Texas Southwestern , P30 AG012300 ; University of Miami , R01 AG027944 , AG010491 , AG027944 , AG021547 , AG019757 ; University of Washington , P50 AG005136 ; University of Wisconsin , P50 AG033514 ; Vanderbilt University , R01 AG019085 ; and Washington University , P50 AG005681 , P01 AG03991 . The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764 , NIMH MH60451 and by Glaxo Smith Kline . Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council , local NHS trusts and Newcastle University ), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council ),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE) , Alzheimer’s Research Trust (ART) , BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN ), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research , Brain Net Europe , Hersenstichting Nederland Breinbrekend Werk , International Parkinson Fonds , Internationale Stiching Alzheimer Onderzoek ), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and 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’s Association ; Alzheimer’s Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc. ; 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's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720 ; MP-V, IIRG-05-14147 ) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program . P.S.G.-H. is supported by Wellcome Trust , Howard Hughes Medical Institute , and the Canadian Institute of Health Research . EPAD: GRF. EPAD:GRF is funded by the National Institute on Aging, R01 AG 042437 (P Crane, PI). ADNI: Data collection and sharing for this project was funded by the Alzheimer''s 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’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; 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''s Disease Cooperative Study at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ADGC: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, aU01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01); NACC, U01 AG016976; NIA LOAD, U24 AG026395, R01AG041797; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG006781, UO1 HG004610, UO1 HG006375; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718, AG07562, AG02365; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; University of Wisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer’s Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and 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’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; 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''s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.
Funders | Funder number |
---|---|
ADGC | RC2 AG036528, aU01 AG032984 |
Alzheimer’s Association, and Cure Alzheimer’s Fund | |
Alzheimer’s Research Trust | |
Araclon Biotech | |
Biomedical Laboratory Research Program | |
Canadian Health Research Institute | |
CereSpir, Inc. | |
DOD ADNI | |
Elan Pharmaceuticals, Inc. | |
Euroimmun | |
Glaxo Smith Kline | |
Hersenstichting Nederland Breinbrekend Werk | |
Institut de Neuropatologia | |
International Parkinson Fonds | |
Kronos Science | AG041232 |
MRC London Brain Bank for Neurodegenerative Diseases | |
NIA/NIH | |
National Cell Repository for Alzheimer’s Disease | U24 AG21886 |
Netherlands Brain Bank | |
Newcastle Brain Tissue Resource | |
South West Dementia Brain Bank | |
US Department of Veterans Affairs Administration | |
National Institutes of Health (NIH) | U01 AG024904, R01CA129769 |
National Institutes of Health (NIH) | |
U.S. Department of Defense | W81XWH-12-2-0012 |
U.S. Department of Defense | |
Howard Hughes Medical Institute | |
National Institute of Mental Health | MH60451 |
National Institute of Mental Health | |
National Institute on Aging | R01AG033193, R01 AG 042437, RC2AG036502, P50AG008671, P30AG019610 |
National Institute on Aging | |
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01NS059873, NS39764 |
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | |
National Institute of Biomedical Imaging and Bioengineering | |
Lance Armstrong Foundation | IIRG-05-14147, IIRG-08-89720 |
Lance Armstrong Foundation | |
Bristol-Myers Squibb | |
Alzheimer's Drug Discovery Foundation | |
Eli Lilly and Company | |
Roche Diagnostics | |
Biogen IDEC | |
Biomedical Laboratory Research and Development, VA Office of Research and Development | |
AbbVie | |
DoD Alzheimer's Disease Neuroimaging Initiative | |
Astrobiology Research Trust | |
BioClinica Inc. | |
Wellcome Trust | |
Banner Alzheimerâs Foundation | |
BRACE | |
Higher Education Funding Council for England | |
Medical Research Council | |
Newcastle University | |
Stichting MS Research | |
Eisai | |
North Bristol NHS Trust | |
Universitat de Barcelona | |
Internationale Stichting Alzheimer Onderzoek |
Keywords
- Atypical Alzheimer's disease
- Dysexecutive Alzheimer's disease
- Executive function
- Genetics
- Heritability
- Memory
ASJC Scopus subject areas
- Clinical Neurology
- Geriatrics and Gerontology
- Aging
- General Neuroscience
- Developmental Biology