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5. Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Author

Xicota, Laura, Cosentino, Stephanie, Vardarajan, Badri, Mayeux, Richard, Perls, Thomas T, Andersen, Stacy L, Zmuda, Joseph M, Thyagarajan, Bharat, Yashin, Anatoli, Wojczynski, Mary K, Krinsky‐McHale, Sharon, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark E, Schupf, Nicole, Lee, Joseph H, Barral, Sandra, Study, the Long‐Life Family, Abner, Erin, Adams, Perrie M, Aguirre, Alyssa, Albert, Marilyn S, Albin, Roger L, Allen, Mariet, Alvarez, Lisa, Andrews, Howard, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Ayres, Gayle, Barber, Robert C, Barnes, Lisa L, Bartlett, Jackie, Beach, Thomas G, Becker, James T, Beecham, Gary W, Benchek, Penelope, Bennett, David A, Bertelson, John, Biber, Sarah A, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Brewer, James B, Burke, James R, Burns, Jeffrey M, Bush, William S, Buxbaum, Joseph D, Byrd, Goldie, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Chan, Kwun C, Chasse, Scott, Chen, Yen‐Chi, Chesselet, Marie‐Francoise, Chin, Nathaniel A, Chui, Helena C, Chung, Jaeyoon, Craft, Suzanne, Crane, Paul K, Cranney, Marissa, Cruchaga, Carlos, Cuccaro, Michael L, Culhane, Jessica, Cullum, C Munro, Darby, Eveleen, Davis, Barbara, De Jager, Philip L, DeCarli, Charles, DeToledo, John C, Dickson, Dennis W, Dobbins, Nic, Duara, Ranjan, Ertekin‐Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallin, Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Farrell, John, Farrer, Lindsay A, Fernandez‐Hernandez, Victoria, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gamboa, Adriana, Gauthreaux, Kathryn M, Gefen, Tamar, Geschwind, Daniel H, Ghetti, Bernardino, and Gilbert, John R

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Alzheimer's Disease, Human Genome, Biotechnology, Aging, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Genetic Predisposition to Disease, Genome-Wide Association Study, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, genetic risk, late-onset Alzheimer's disease, microtubule protein, MTUS2 gene, whole genome sequence, Long‐Life Family Study, Alzheimer's Disease Genetic Consortium, Alzheimer's Biomarkers Consortium‐Down Syndrome, late‐onset Alzheimer's disease, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Published
2024

6. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Author

Katsumata, Yuriko, Fardo, David W, Shade, Lincoln MP, Bowen, James D, Crane, Paul K, Jarvik, Gail P, Keene, C Dirk, Larson, Eric B, McCormick, Wayne C, McCurry, Susan M, Mukherjee, Shubhabrata, Kowall, Neil W, McKee, Ann C, Honig, Robert A, Lawrence, S, Vonsattel, Jean Paul, Williamson, Jennifer, Small, Scott, Burke, James R, Hulette, Christine M, Welsh-Bohmer, Kathleen A, Gearing, Marla, Lah, James J, Levey, Allan I, Wingo, Thomas S, Apostolova, Liana G, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Spina, Salvatore, Albert, Marilyn S, Lyketsos, Constantine G, Troncoso, Juan C, Frosch, Matthew P, Green, Robert C, Growdon, John H, Hyman, Bradley T, Tanzi, Rudolph E, Potter, Huntington, Dickson, Dennis W, Ertekin-Taner, Nilufer, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Duara, Ranjan, Buxbaum, Joseph D, Goate, Alison M, Sano, Mary, Masurkar, Arjun V, Wisniewski, Thomas, Bigio, Eileen H, Mesulam, Marsel, Weintraub, Sandra, Vassar, Robert, Kaye, Jeffrey A, Quinn, Joseph F, Woltjer, Randall L, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Yu, Lei, Henderson, Victor, Fallon, Kenneth B, Harrell, Lindy E, Marson, Daniel C, Roberson, Erik D, DeCarli, Charles, Jin, Lee-Way, Olichney, John M, Kim, Ronald, LaFerla, Frank M, Monuki, Edwin, Head, Elizabeth, Sultzer, David, Geschwind, Daniel H, Vinters, Harry V, Chesselet, Marie-Francoise, Galasko, Douglas R, Brewer, James B, Boxer, Adam, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, Rosen, Howard J, Seeley, William W, Burns, Jeffrey M, Swerdlow, Russell H, Abner, Erin, Van Eldik, Linda J, Albin, Roger L, Lieberman, Andrew P, Paulson, Henry L, Arnold, Steven E, Trojanowski, John Q, Van Deerlin, Vivianna M, Hamilton, Ronald L, Kamboh, M Ilyas, Lopez, Oscar L, and Becker, James T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Prevention, Aging, Minority Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Health Disparities, Genetics, 2.1 Biological and endogenous factors, Aetiology, Humans, Alleles, Polymorphism, Single Nucleotide, Alzheimer Disease, TDP-43 Proteinopathies, Progranulins, Membrane Proteins, Nerve Tissue Proteins, Sulfonylurea Receptors, Alzheimer’s Disease Genetics Consortium, KCNMB2, Diversity, Epidemiology, FTLD, Genome-Wide Association Studies, KATP, Neurology & Neurosurgery, Clinical sciences
Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Published
2023

12. Current and projected future economic burden of Parkinson’s disease in the U.S.

Author

Yang, Wenya, Hamilton, Jamie L, Kopil, Catherine, Beck, James C, Tanner, Caroline M, Albin, Roger L, Ray Dorsey, E, Dahodwala, Nabila, Cintina, Inna, Hogan, Paul, and Thompson, Ted

Subjects
Clinical Research, Brain Disorders, Parkinson's Disease, Burden of Illness, Neurosciences, Neurodegenerative, Aging, Health and social care services research, 2.4 Surveillance and distribution, Aetiology, 8.2 Health and welfare economics, Neurological, Health care economics, Neurological disorders
Abstract

Parkinson's disease (PD) is one of the world's fastest growing neurological disorders. Much is unknown about PD-associated economic burdens in the United States (U.S.) and other high-income nations. This study provides a comprehensive analysis of the economic burdens of PD in the U.S. (2017) and projections for the next two decades. Multiple data sources were used to estimate the costs of PD, including public and private administrative claims data, Medicare Current Beneficiary Survey, Medical Expenditure Panel Survey, and a primary survey (n = 4,548) designed for this study. We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson's disease in 2017 and a total economic burden of $51.9 billion. The total burden of PD includes direct medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of $14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and $4.8 billion due to disability income received by PWPs. The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65. Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037. The economic burden of PD was previously underestimated. Our findings underscore the substantial burden of PD to society, payers, patients, and caregivers. Interventions to reduce PD incidence, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD.

Published
2020

30. Improving efficacy of repetitive transcranial magnetic stimulation for treatment of Parkinson disease gait disorders.

Author

Panda, Rupsha, Deluisi, Joseph A., Lee, Taraz G., Davis, Sheeba, Muñoz-Orozco, Isabel, Albin, Roger L., and Vesia, Michael

Abstract

Parkinson disease (PD) is a neurodegenerative disorder that causes motor and cognitive deficits, presenting complex challenges for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulation that can produce plastic changes in neural activity. rTMS has been trialed as a therapy to treat motor and non-motor symptoms in persons with Parkinson disease (PwP), particularly treatment-refractory postural instability and gait difficulties such as Freezing of Gait (FoG), but clinical outcomes have been variable. We suggest improving rTMS neuromodulation therapy for balance and gait abnormalities in PwP by targeting brain regions in cognitivemotor control networks. rTMS studies in PwP often targeted motor targets such as the primary motor cortex (M1) or supplementary motor area (SMA), overlooking network interactions involved in posture-gait control disorders. We propose a shift in focus toward alternative stimulation targets in basal gangliacortex- cerebellum networks involved in posture-gait control, emphasizing the dorsolateral prefrontal cortex (dlPFC), cerebellum (CB), and posterior parietal cortex (PPC) as potential targets. rTMS might also be more effective if administered during behavioral tasks designed to activate posture-gait control networks during stimulation. Optimizing stimulation parameters such as dosage and frequency as used clinically for the treatment of depression may also be useful. A network-level perspective suggests new directions for exploring optimal rTMS targets and parameters to maximize neural plasticity to treat postural instabilities and gait difficulties in PwP. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Preface

Author

Narayanan, Nandakumar S., primary and Albin, Roger L., additional

Published
2022
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36. Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

Author

Jun, Gyungah R, Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W, Bennett, David A, Buxbaum, Joseph D, Byrd, Goldie S, Carrasquillo, Minerva M, Crane, Paul K, Cruchaga, Carlos, De Jager, Philip, Ertekin‐Taner, Nilufer, Evans, Denis, Fallin, M Danielle, Foroud, Tatiana M, Friedland, Robert P, Goate, Alison M, Graff‐Radford, Neill R, Hendrie, Hugh, Hall, Kathleen S, Hamilton‐Nelson, Kara L, Inzelberg, Rivka, Kamboh, M Ilyas, Kauwe, John SK, Kukull, Walter A, Kunkle, Brian W, Kuwano, Ryozo, Larson, Eric B, Logue, Mark W, Manly, Jennifer J, Martin, Eden R, Montine, Thomas J, Mukherjee, Shubhabrata, Naj, Adam, Reiman, Eric M, Reitz, Christiane, Sherva, Richard, St. George‐Hyslop, Peter H, Thornton, Timothy, Younkin, Steven G, Vardarajan, Badri N, Wang, Li‐San, Wendlund, Jens R, Winslow, Ashley R, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Barmada, Michjael M, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Green, Robert C, and Growdon, John H

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Apolipoprotein E4, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Membrane Glycoproteins, Molecular Chaperones, NFI Transcription Factors, Peroxisomal Bifunctional Enzyme, Polymorphism, Single Nucleotide, Receptors, GABA, Alzheimer's Disease Genetics Consortium, APOE interaction, Alzheimer's disease, Genome-wide association, Transethnic, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P

Published
2017

37. Internet-Based Conversational Engagement Randomized Controlled Clinical Trial (I-CONECT) Among Socially Isolated Adults 75+ Years Old With Normal Cognition or Mild Cognitive Impairment: Topline Results.

Author

Dodge, Hiroko H, Yu, Kexin, Wu, Chao-Yi, Pruitt, Patrick J, Asgari, Meysam, Kaye, Jeffrey A, Hampstead, Benjamin M, Struble, Laura, Potempa, Kathleen, Lichtenberg, Peter, Croff, Raina, Albin, Roger L, Silbert, Lisa C, and Team, the I-CONECT

Subjects
DEMENTIA prevention, HOME care services, ELDER care, MILD cognitive impairment, THERAPEUTICS, CONVERSATION, RESEARCH funding, MEDICAL care, STATISTICAL sampling, EXECUTIVE function, INTERNET, RANDOMIZED controlled trials, MAGNETIC resonance imaging, DESCRIPTIVE statistics, EXPERIMENTAL design, COMPUTERS in medicine, RESEARCH, INTERPERSONAL relations, COMPARATIVE studies, SOCIAL isolation, COGNITION, SOCIAL participation, COVID-19 pandemic, WELL-being, OLD age
Abstract

Background and Objectives Social isolation is a risk factor for cognitive decline and dementia. We conducted a randomized controlled clinical trial (RCT) of enhanced social interactions, hypothesizing that conversational interactions can stimulate brain functions among socially isolated older adults without dementia. We report topline results of this multisite RCT (Internet-based conversational engagement clinical trial [I-CONECT]; NCT02871921). Research Design and Methods The experimental group received cognitively stimulating semistructured conversations with trained interviewers via internet/webcam 4 times per week for 6 months (induction) and twice per week for an additional 6 months (maintenance). The experimental and control groups both received weekly 10 minutes telephone check-ins. Protocol modifications were required due to the coronavirus disease 2019 pandemic. Results A total of 186 participants were randomized. After the induction period, the experimental group had higher global cognitive test scores (Montreal Cognitive Assessment [primary outcome]; 1.75 points [ p  = .03]) compared with the control group. After induction, experimental group participants with normal cognition had higher language-based executive function (semantic fluency test [secondary outcome]; 2.56 points [ p  = .03]). At the end of the maintenance period, the experimental group of mild cognitive impairment subjects had higher encoding function (Craft Story immediate recall test [secondary outcome]; 2.19 points [ p  = .04]). Measure of emotional well-being improved in both control and experimental groups. Resting-state functional magnetic resonance imaging showed that the experimental group had increased connectivity within the dorsal attention network relative to the control group (p  = .02), but the sample size was limited. Discussion and Implications Providing frequent stimulating conversational interactions via the internet could be an effective home-based dementia risk-reduction strategy against social isolation and cognitive decline. Clinical Trials Registration Number NCT02871921 [ABSTRACT FROM AUTHOR]

Published
2024
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39. ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Author

Cukier, Holly N, Kunkle, Brian W, Vardarajan, Badri N, Rolati, Sophie, Hamilton-Nelson, Kara L, Kohli, Martin A, Whitehead, Patrice L, Dombroski, Beth A, Van Booven, Derek, Lang, Rosalyn, Dykxhoorn, Derek M, Farrer, Lindsay A, Cuccaro, Michael L, Vance, Jeffery M, Gilbert, John R, Beecham, Gary W, Martin, Eden R, Carney, Regina M, Mayeux, Richard, Schellenberg, Gerard D, Byrd, Goldie S, Haines, Jonathan L, Pericak-Vance, Margaret A, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barmada, M Michael, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cai, Guiqing, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fallin, M Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Go, Rodney CP, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Griffith, Patrick, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Haroutunian, Vahram, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, and Jin, Lee-Way

Subjects
Biological Sciences, Genetics, Human Genome, Neurodegenerative, Neurosciences, Dementia, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Genetics Consortium, Clinical sciences
Abstract

ObjectiveTo identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.MethodsCustom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.ResultsA 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.ConclusionsThis common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Published
2016

40. Assessment of the genetic variance of late-onset Alzheimer's disease

Author

Ridge, Perry G, Hoyt, Kaitlyn B, Boehme, Kevin, Mukherjee, Shubhabrata, Crane, Paul K, Haines, Jonathan L, Mayeux, Richard, Farrer, Lindsay A, Pericak-Vance, Margaret A, Schellenberg, Gerard D, Kauwe, John SK, Consortium, Alzheimer's Disease Genetics, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barber, Robert C, Barmada, Michael M, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Hardy, John, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M Ilyas, Karydas, Anna, Katz, Mindy J, Kaye, Jeffrey A, Kim, Ronald, and Kowall, Neil W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease, Human Genome, Aging, Brain Disorders, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Genetics, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Datasets as Topic, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Glycoproteins, Netrin Receptors, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Receptors, Immunologic, Risk, Alzheimer's Disease Genetics Consortium, Alzheimer's disease, Genetic variance, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Published
2016

41. Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database

Author

Ringman, John M, Monsell, Sarah, Ng, Denise W, Zhou, Yan, Nguyen, Andy, Coppola, Giovanni, Van Berlo, Victoria, Mendez, Mario F, Tung, Spencer, Weintraub, Sandra, Mesulam, Marek-Marsel, Bigio, Eileen H, Gitelman, Darren R, Fisher-Hubbard, Amanda O, Albin, Roger L, and Vinters, Harry V

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Aging, Alzheimer's Disease, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Apolipoproteins E, Databases, Factual, Female, Humans, Male, Middle Aged, Mutation, National Institute on Aging (U.S.), Neuropathology, Presenilin-1, Presenilin-2, United States, Alzheimer disease, Amyloid plaques, Autosomal dominant, Cerebral amyloid angiopathy, Neurofibrillary tangles, P267A, P267A., Neurology & Neurosurgery, Clinical sciences
Abstract

Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing.

Published
2016

45. Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States

Author

Wang, Li-San, Naj, Adam C, Graham, Robert R, Crane, Paul K, Kunkle, Brian W, Cruchaga, Carlos, Murcia, Josue D. Gonzalez, Cannon-Albright, Lisa, Baldwin, Clinton T, Zetterberg, Henrik, Blennow, Kaj, Kukull, Walter A, Faber, Kelley M, Schupf, Nicole, Norton, Maria C, Tschanz, JoAnn T, Munger, Ronald G, Corcoran, Christopher D, Rogaeva, Ekaterina, Lin, Chiao-Feng, Dombroski, Beth A, Cantwell, Laura B, Partch, Amanda, Valladares, Otto, Hakonarson, Hakon, St George-Hyslop, Peter, Green, Robert C, Goate, Alison M, Foroud, Tatiana M, Carney, Regina M, Larson, Eric B, Behrens, Timothy W, Kauwe, John S. K, Haines, Jonathan L, Farrer, Lindsay A, Pericak-Vance, Margaret A, Mayeux, Richard, Schellenberg, Gerard D, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Barber, Robert, Barmada, M. Michael, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, DeKosky, Steven T, Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Graff-Radford, Neill R, Growdon, John H, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, and Kaye, Jeffrey A

Published
2015

46. Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease

Author

Naj, Adam C, Jun, Gyungah, Reitz, Christiane, Kunkle, Brian W, Perry, William, Park, Yo Son, Beecham, Gary W, Rajbhandary, Ruchita A, Hamilton-Nelson, Kara L, Wang, Li-San, Kauwe, John S. K, Huentelman, Matthew J, Myers, Amanda J, Bird, Thomas D, Boeve, Bradley F, Baldwin, Clinton T, Jarvik, Gail P, Crane, Paul K, Rogaeva, Ekaterina, Barmada, M. Michael, Demirci, F. Yesim, Cruchaga, Carlos, Kramer, Patricia L, Ertekin-Taner, Nilufer, Hardy, John, Graff-Radford, Neill R, Green, Robert C, Larson, Eric B, St. George-Hyslop, Peter H, Buxbaum, Joseph D, Evans, Denis A, Schneider, Julie A, Lunetta, Kathryn L, Kamboh, M. Ilyas, Saykin, Andrew J, Reiman, Eric M, De Jager, Philip L, Bennett, David A, Morris, John C, Montine, Thomas J, Goate, Alison M, Blacker, Deborah, Tsuang, Debby W, Hakonarson, Hakon, Kukull, Walter A, Foroud, Tatiana M, Martin, Eden R, Haines, Jonathan L, Mayeux, Richard P, Farrer, Lindsay A, Schellenberg, Gerard D, Pericak-Vance, Margaret A, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Barber, Robert, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Beekly, Duane, Bigio, Eileen H, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, DeKosky, Steven T, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, and Hulette, Christine M

Published
2014

47. Development and validation of the automated imaging differentiation in parkinsonism (AID-P): a multicentre machine learning study

Author

Archer, Derek B, Bricker, Justin T, Chu, Winston T, Burciu, Roxana G, McCracken, Johanna L, Lai, Song, Coombes, Stephen A, Fang, Ruogu, Barmpoutis, Angelos, Corcos, Daniel M, Kurani, Ajay S, Mitchell, Trina, Black, Mieniecia L, Herschel, Ellen, Simuni, Tanya, Parrish, Todd B, Comella, Cynthia, Xie, Tao, Seppi, Klaus, Bohnen, Nicolaas I, Müller, Martijn LTM, Albin, Roger L, Krismer, Florian, Du, Guangwei, Lewis, Mechelle M, Huang, Xuemei, Li, Hong, Pasternak, Ofer, McFarland, Nikolaus R, Okun, Michael S, and Vaillancourt, David E

Published
2019
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49. Regionally selective atrophy of subcortical structures in prodromal HD as revealed by statistical shape analysis

Author

Younes, Laurent, Ratnanather, J Tilak, Brown, Timothy, Aylward, Elizabeth, Nopoulos, Peg, Johnson, Hans, Magnotta, Vincent A, Paulsen, Jane S, Margolis, Russell L, Albin, Roger L, Miller, Michael I, Ross, Christopher A, and Group, PREDICT‐HD Investigators and Coordinators of the Huntington Study

Subjects
Rare Diseases, Brain Disorders, Neurosciences, Neurodegenerative, Huntington's Disease, Neurological, Adult, Atrophy, Basal Ganglia, Female, Humans, Huntington Disease, Magnetic Resonance Imaging, Male, Middle Aged, Prodromal Symptoms, PREDICT-HD Investigators and Coordinators of the Huntington Study Group, diffeomorphic mapping, pallidus atrophy, striatal atrophy, surface registration, surface-based morphometry, Cognitive Sciences, Experimental Psychology
Abstract

Huntington disease (HD) is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this article, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through "Large Deformation Diffeomorphic Metric Mapping" of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. On the basis of the relation to cortico-basal ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

Published
2014

50. Blood‐based biomarkers for Alzheimer's disease and cognitive function from mid‐ to late life.

Author

Wang, Xin, Bakulski, Kelly M., Karvonen‐Gutierrez, Carrie A., Park, Sung Kyun, Morgan, David, Albin, Roger L., and Paulson, Henry L.

Abstract

INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid‐ to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid β (Aβ)42, the Aβ42/40 ratio, phosphorylated tau181 (p‐tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aβ42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p‐tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid‐life serum AD biomarkers could be associated with accelerated cognitive decline from mid‐ to late life in women. Future studies with larger samples are needed to validate and extend our findings. Highlights: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women.Mid‐life serum AD biomarkers are associated with accelerated cognitive decline.A decrease in the Aβ42/40 ratio was associated with a faster decline in the DSB score.A higher p‐tau181 concentration was associated with a faster decline in the SDMT score. [ABSTRACT FROM AUTHOR]

Published
2024
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