Lei Yu1, Michael W Lutz2, Robert S Wilson2, Daniel K Burns2, Allen D Roses2, Ann M Saunders2, Chris Gaiteri2, Philip L De Jager2, Lisa L Barnes2, David A Bennett2. 1. From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA. lei_yu@Rush.edu. 2. From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
Abstract
OBJECTIVE: To interrogate a poly-T variant (rs10524523, '523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD). METHODS: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM40'523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE ε3/3 carriers with different '523 genotypes. RESULTS: The 1,170 APOE ε3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the '523 variant were linked to APOE ε3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (p = 0.002). The same association was observed for episodic memory (p < 0.001) and semantic memory (p = 0.003) but not for working memory, perceptual speed, or visuospatial ability. CONCLUSIONS: Our data reveal an association of APOE ε3/3-TOMM40'523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.
OBJECTIVE: To interrogate a poly-T variant (rs10524523, '523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD). METHODS: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM40'523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE ε3/3 carriers with different '523 genotypes. RESULTS: The 1,170 APOE ε3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the '523 variant were linked to APOE ε3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (p = 0.002). The same association was observed for episodic memory (p < 0.001) and semantic memory (p = 0.003) but not for working memory, perceptual speed, or visuospatial ability. CONCLUSIONS: Our data reveal an association of APOE ε3/3-TOMM40'523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.
Authors: A Payton; P Sindrewicz; V Pessoa; H Platt; M Horan; W Ollier; V J Bubb; N Pendleton; J P Quinn Journal: Neurobiol Aging Date: 2015-12-08 Impact factor: 4.673
Authors: Lei Yu; Patricia Boyle; Robert S Wilson; Eisuke Segawa; Sue Leurgans; Philip L De Jager; David A Bennett Journal: Neuroepidemiology Date: 2012-07-17 Impact factor: 3.282
Authors: Richard J Caselli; Amylou C Dueck; David Osborne; Marwan N Sabbagh; Donald J Connor; Geoffrey L Ahern; Leslie C Baxter; Steven Z Rapcsak; Jiong Shi; Bryan K Woodruff; Dona E C Locke; Charlene Hoffman Snyder; Gene E Alexander; Rosa Rademakers; Eric M Reiman Journal: N Engl J Med Date: 2009-07-16 Impact factor: 91.245
Authors: Richard J Caselli; Amylou C Dueck; Matthew J Huentelman; Michael W Lutz; Ann M Saunders; Eric M Reiman; Allen D Roses Journal: Alzheimers Dement Date: 2012-11 Impact factor: 21.566
Authors: Robert S Wilson; Laurel A Beckett; Lisa L Barnes; Julie A Schneider; Julie Bach; Denis A Evans; David A Bennett Journal: Psychol Aging Date: 2002-06
Authors: Donald M Lyall; Sarah E Harris; Mark E Bastin; Susana Muñoz Maniega; Catherine Murray; Michael W Lutz; Ann M Saunders; Allen D Roses; Maria del C Valdés Hernández; Natalie A Royle; John M Starr; David J Porteous; Joanna M Wardlaw; Ian J Deary Journal: Neurobiol Aging Date: 2014-01-08 Impact factor: 4.673
Authors: Lei Yu; Michael W Lutz; Jose M Farfel; Robert S Wilson; Daniel K Burns; Ann M Saunders; Philip L De Jager; Lisa L Barnes; Julie A Schneider; David A Bennett Journal: Alzheimers Dement Date: 2017-06-15 Impact factor: 21.566
Authors: Melissa Lamar; Lei Yu; Leah H Rubin; Bryan D James; Lisa L Barnes; Jose Marcelo Farfel; Chris Gaiteri; Aron S Buchman; David A Bennett; Julie A Schneider Journal: Alzheimers Dement Date: 2018-10-12 Impact factor: 21.566
Authors: Heidi I L Jacobs; John A Becker; Kenneth Kwong; Nina Engels-Domínguez; Prokopis C Prokopiou; Kathryn V Papp; Michael Properzi; Olivia L Hampton; Federico d'Oleire Uquillas; Justin S Sanchez; Dorene M Rentz; Georges El Fakhri; Marc D Normandin; Julie C Price; David A Bennett; Reisa A Sperling; Keith A Johnson Journal: Sci Transl Med Date: 2021-09-22 Impact factor: 17.956
Authors: Shahram Oveisgharan; Zoe Arvanitakis; Lei Yu; Jose Farfel; Julie A Schneider; David A Bennett Journal: Acta Neuropathol Date: 2018-10-17 Impact factor: 17.088
Authors: David A Bennett; Aron S Buchman; Patricia A Boyle; Lisa L Barnes; Robert S Wilson; Julie A Schneider Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472
Authors: Kacie D Deters; Elizabeth C Mormino; Lei Yu; Michael W Lutz; David A Bennett; Lisa L Barnes Journal: Alzheimers Dement Date: 2021-02-13 Impact factor: 21.566
Authors: Shahram Oveisgharan; Aron S Buchman; Lei Yu; Jose Farfel; Vladimir Hachinski; Chris Gaiteri; Philip L De Jager; Julie A Schneider; David A Bennett Journal: Neurology Date: 2018-05-11 Impact factor: 9.910