Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology

Sarah E. Monsell; Charles Mock; David W. Fardo; Sarah Bertelsen; Nigel J. Cairns; Catherine M. Roe; Sally R. Ellingson; John C. Morris; Alison M. Goate; Walter A. Kukull

doi:10.1097/WAD.0000000000000179

Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology

Sarah E. Monsell, Charles Mock, David W. Fardo, Sarah Bertelsen, Nigel J. Cairns, Catherine M. Roe, Sally R. Ellingson, John C. Morris, Alison M. Goate, Walter A. Kukull

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

12 Scopus citations

Abstract

Objective: The objective was to determine whether symptomatic and asymptomatic persons with Alzheimer disease (AD) neuropathology have different allele counts for single-nucleotide polymorphisms that have been associated with clinical late-onset AD. Methods: Data came from the National Alzheimer's Coordinating Center Uniform Data Set and Neuropathology Data Set, and the Alzheimer's Disease Genetics Consortium (ADGC). Participants had low to high AD neuropathologic change. The 22 known/suspected genes associated with late-onset AD were considered. "Symptomatic" was defined as Clinical Dementia Rating global score >0. Results: Sixty-eight asymptomatic and 521 symptomatic participants met inclusion criteria. Single-nucleotide polymorphisms associated with ABCA7 [odds ratio (OR)=1.66; 95% confidence interval (CI), 1.03-2.85] and MAPT (OR=2.18; CI, 1.26-3.77) were associated with symptomatic status. In stratified analyses, loci containing CD2AP (OR=0.35; 95% CI, 0.16-0.74), ZCWPW1 (OR=2.98; 95% CI, 1.34-6.86), and MAPT (OR=3.73, 95% CI, 1.30-11.76) were associated with symptomatic status in APOE e4 carriers. Conclusions: These findings potentially explain some of the variation in whether a person with AD neuropathology expresses symptoms. Understanding why some people remain cognitively normal despite having AD neuropathology could identify pathways to disease heterogeneity and guide treatment trials.

Original language	English
Pages (from-to)	232-238
Number of pages	7
Journal	Alzheimer Disease and Associated Disorders
Volume	31
Issue number	3
DOIs	https://doi.org/10.1097/WAD.0000000000000179
State	Published - 2017

Bibliographical note

Funding Information:
The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD). The Alzheimer's Disease Genetics Consortium (ADGC) supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The ADGC also generated and kindly provided genotype data. 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 NIA, were used in this study. Support was also provided by the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24 AG041689). D.W.F. is supported by NIH grant K25-AG043546. S.E. reports support from the National Institutes of Health (NIH). National Center for Advancing Translational Science grant KL2TR000116. J.C.M.: Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.C.M. is currently participating in clinical trials of antidementia drugs (A4 trial: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease), funded by the National Institute on Aging, Eli Lilly and Company, and several philanthropic organizations. J.C.M. has served as a consultant for Lilly, USA and Takeda Pharmaceuticals. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276; and UF01AG032438. A.M.G. has served as a consultant for Cognition Therapeutics, Denali Therapeutics, AbbVie, and Amgen. She also was a speaker at Eli Lilly. She is funded by NIH grants R01 AG035083 and U01AG049508. The remaining authors declare no conflicts of interest.

Funding Information:
The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD).The Alzheimer’s Disease Genetics Consortium (ADGC) supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The ADGC also generated and kindly provided genotype data. 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 NIA, were used in this study.Support was also provided by the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24 AG041689).

Funding Information:
D.W.F. is supported by NIH grant K25-AG043546. S.E. reports support from the National Institutes of Health (NIH). National Center for Advancing Translational Science grant KL2TR000116. J.C.M.: Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.C.M. is currently participating in clinical trials of antidementia drugs (A4 trial: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease), funded by the National Institute on Aging, Eli Lilly and Company, and several philanthropic organizations. J.C.M. has served as a consultant for Lilly, USA and Takeda Phar-maceuticals. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276; and UF01AG032438. A.M.G. has served as a consultant for Cognition Therapeutics, Denali Therapeutics, AbbVie, and Amgen. She also was a speaker at Eli Lilly. She is funded by NIH grants R01 AG035083 and U01AG049508. The remaining authors declare no conflicts of interest.

Publisher Copyright:
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Keywords

APOE
Alzheimer disease
Alzheimer disease genetics
genetic risk score
preclinical Alzheimer disease

ASJC Scopus subject areas

Clinical Psychology
Gerontology
Geriatrics and Gerontology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1097/WAD.0000000000000179

Cite this

@article{b33b7db12a2b4e42837378a1afff56e9,

title = "Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology",

abstract = "Objective: The objective was to determine whether symptomatic and asymptomatic persons with Alzheimer disease (AD) neuropathology have different allele counts for single-nucleotide polymorphisms that have been associated with clinical late-onset AD. Methods: Data came from the National Alzheimer's Coordinating Center Uniform Data Set and Neuropathology Data Set, and the Alzheimer's Disease Genetics Consortium (ADGC). Participants had low to high AD neuropathologic change. The 22 known/suspected genes associated with late-onset AD were considered. {"}Symptomatic{"} was defined as Clinical Dementia Rating global score >0. Results: Sixty-eight asymptomatic and 521 symptomatic participants met inclusion criteria. Single-nucleotide polymorphisms associated with ABCA7 [odds ratio (OR)=1.66; 95% confidence interval (CI), 1.03-2.85] and MAPT (OR=2.18; CI, 1.26-3.77) were associated with symptomatic status. In stratified analyses, loci containing CD2AP (OR=0.35; 95% CI, 0.16-0.74), ZCWPW1 (OR=2.98; 95% CI, 1.34-6.86), and MAPT (OR=3.73, 95% CI, 1.30-11.76) were associated with symptomatic status in APOE e4 carriers. Conclusions: These findings potentially explain some of the variation in whether a person with AD neuropathology expresses symptoms. Understanding why some people remain cognitively normal despite having AD neuropathology could identify pathways to disease heterogeneity and guide treatment trials.",

keywords = "APOE, Alzheimer disease, Alzheimer disease genetics, genetic risk score, preclinical Alzheimer disease",

author = "Monsell, {Sarah E.} and Charles Mock and Fardo, {David W.} and Sarah Bertelsen and Cairns, {Nigel J.} and Roe, {Catherine M.} and Ellingson, {Sally R.} and Morris, {John C.} and Goate, {Alison M.} and Kukull, {Walter A.}",

note = "Funding Information: The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD). The Alzheimer's Disease Genetics Consortium (ADGC) supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The ADGC also generated and kindly provided genotype data. 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 NIA, were used in this study. Support was also provided by the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24 AG041689). D.W.F. is supported by NIH grant K25-AG043546. S.E. reports support from the National Institutes of Health (NIH). National Center for Advancing Translational Science grant KL2TR000116. J.C.M.: Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.C.M. is currently participating in clinical trials of antidementia drugs (A4 trial: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease), funded by the National Institute on Aging, Eli Lilly and Company, and several philanthropic organizations. J.C.M. has served as a consultant for Lilly, USA and Takeda Pharmaceuticals. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276; and UF01AG032438. A.M.G. has served as a consultant for Cognition Therapeutics, Denali Therapeutics, AbbVie, and Amgen. She also was a speaker at Eli Lilly. She is funded by NIH grants R01 AG035083 and U01AG049508. The remaining authors declare no conflicts of interest. Funding Information: The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD).The Alzheimer{\textquoteright}s Disease Genetics Consortium (ADGC) supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The ADGC also generated and kindly provided genotype data. Samples from the National Cell Repository for Alzheimer{\textquoteright}s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the NIA, were used in this study.Support was also provided by the NIA Genetics of Alzheimer{\textquoteright}s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24 AG041689). Funding Information: D.W.F. is supported by NIH grant K25-AG043546. S.E. reports support from the National Institutes of Health (NIH). National Center for Advancing Translational Science grant KL2TR000116. J.C.M.: Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.C.M. is currently participating in clinical trials of antidementia drugs (A4 trial: The Anti-Amyloid Treatment in Asymptomatic Alzheimer{\textquoteright}s Disease), funded by the National Institute on Aging, Eli Lilly and Company, and several philanthropic organizations. J.C.M. has served as a consultant for Lilly, USA and Takeda Phar-maceuticals. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276; and UF01AG032438. A.M.G. has served as a consultant for Cognition Therapeutics, Denali Therapeutics, AbbVie, and Amgen. She also was a speaker at Eli Lilly. She is funded by NIH grants R01 AG035083 and U01AG049508. The remaining authors declare no conflicts of interest. Publisher Copyright: Copyright {\textcopyright} 2016 Wolters Kluwer Health, Inc. All rights reserved.",

year = "2017",

doi = "10.1097/WAD.0000000000000179",

language = "English",

volume = "31",

pages = "232--238",

number = "3",

}

TY - JOUR

T1 - Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology

AU - Monsell, Sarah E.

AU - Mock, Charles

AU - Fardo, David W.

AU - Bertelsen, Sarah

AU - Cairns, Nigel J.

AU - Roe, Catherine M.

AU - Ellingson, Sally R.

AU - Morris, John C.

AU - Goate, Alison M.

AU - Kukull, Walter A.

N1 - Funding Information: The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD). The Alzheimer's Disease Genetics Consortium (ADGC) supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The ADGC also generated and kindly provided genotype data. 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 NIA, were used in this study. Support was also provided by the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24 AG041689). D.W.F. is supported by NIH grant K25-AG043546. S.E. reports support from the National Institutes of Health (NIH). National Center for Advancing Translational Science grant KL2TR000116. J.C.M.: Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.C.M. is currently participating in clinical trials of antidementia drugs (A4 trial: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease), funded by the National Institute on Aging, Eli Lilly and Company, and several philanthropic organizations. J.C.M. has served as a consultant for Lilly, USA and Takeda Pharmaceuticals. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276; and UF01AG032438. A.M.G. has served as a consultant for Cognition Therapeutics, Denali Therapeutics, AbbVie, and Amgen. She also was a speaker at Eli Lilly. She is funded by NIH grants R01 AG035083 and U01AG049508. The remaining authors declare no conflicts of interest. Funding Information: The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD).The Alzheimer’s Disease Genetics Consortium (ADGC) supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The ADGC also generated and kindly provided genotype data. 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 NIA, were used in this study.Support was also provided by the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24 AG041689). Funding Information: D.W.F. is supported by NIH grant K25-AG043546. S.E. reports support from the National Institutes of Health (NIH). National Center for Advancing Translational Science grant KL2TR000116. J.C.M.: Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.C.M. is currently participating in clinical trials of antidementia drugs (A4 trial: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease), funded by the National Institute on Aging, Eli Lilly and Company, and several philanthropic organizations. J.C.M. has served as a consultant for Lilly, USA and Takeda Phar-maceuticals. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276; and UF01AG032438. A.M.G. has served as a consultant for Cognition Therapeutics, Denali Therapeutics, AbbVie, and Amgen. She also was a speaker at Eli Lilly. She is funded by NIH grants R01 AG035083 and U01AG049508. The remaining authors declare no conflicts of interest. Publisher Copyright: Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

PY - 2017

Y1 - 2017

N2 - Objective: The objective was to determine whether symptomatic and asymptomatic persons with Alzheimer disease (AD) neuropathology have different allele counts for single-nucleotide polymorphisms that have been associated with clinical late-onset AD. Methods: Data came from the National Alzheimer's Coordinating Center Uniform Data Set and Neuropathology Data Set, and the Alzheimer's Disease Genetics Consortium (ADGC). Participants had low to high AD neuropathologic change. The 22 known/suspected genes associated with late-onset AD were considered. "Symptomatic" was defined as Clinical Dementia Rating global score >0. Results: Sixty-eight asymptomatic and 521 symptomatic participants met inclusion criteria. Single-nucleotide polymorphisms associated with ABCA7 [odds ratio (OR)=1.66; 95% confidence interval (CI), 1.03-2.85] and MAPT (OR=2.18; CI, 1.26-3.77) were associated with symptomatic status. In stratified analyses, loci containing CD2AP (OR=0.35; 95% CI, 0.16-0.74), ZCWPW1 (OR=2.98; 95% CI, 1.34-6.86), and MAPT (OR=3.73, 95% CI, 1.30-11.76) were associated with symptomatic status in APOE e4 carriers. Conclusions: These findings potentially explain some of the variation in whether a person with AD neuropathology expresses symptoms. Understanding why some people remain cognitively normal despite having AD neuropathology could identify pathways to disease heterogeneity and guide treatment trials.

AB - Objective: The objective was to determine whether symptomatic and asymptomatic persons with Alzheimer disease (AD) neuropathology have different allele counts for single-nucleotide polymorphisms that have been associated with clinical late-onset AD. Methods: Data came from the National Alzheimer's Coordinating Center Uniform Data Set and Neuropathology Data Set, and the Alzheimer's Disease Genetics Consortium (ADGC). Participants had low to high AD neuropathologic change. The 22 known/suspected genes associated with late-onset AD were considered. "Symptomatic" was defined as Clinical Dementia Rating global score >0. Results: Sixty-eight asymptomatic and 521 symptomatic participants met inclusion criteria. Single-nucleotide polymorphisms associated with ABCA7 [odds ratio (OR)=1.66; 95% confidence interval (CI), 1.03-2.85] and MAPT (OR=2.18; CI, 1.26-3.77) were associated with symptomatic status. In stratified analyses, loci containing CD2AP (OR=0.35; 95% CI, 0.16-0.74), ZCWPW1 (OR=2.98; 95% CI, 1.34-6.86), and MAPT (OR=3.73, 95% CI, 1.30-11.76) were associated with symptomatic status in APOE e4 carriers. Conclusions: These findings potentially explain some of the variation in whether a person with AD neuropathology expresses symptoms. Understanding why some people remain cognitively normal despite having AD neuropathology could identify pathways to disease heterogeneity and guide treatment trials.

KW - APOE

KW - Alzheimer disease

KW - Alzheimer disease genetics

KW - genetic risk score

KW - preclinical Alzheimer disease

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UR - http://www.scopus.com/inward/citedby.url?scp=84995450887&partnerID=8YFLogxK

U2 - 10.1097/WAD.0000000000000179

DO - 10.1097/WAD.0000000000000179

M3 - Article

C2 - 27849641

AN - SCOPUS:84995450887

VL - 31

SP - 232

EP - 238

IS - 3

ER -

Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology

Abstract

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UN SDGs

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