Michael E Belloy1, Valerio Napolioni1, Summer S Han2,3, Yann Le Guen1, Michael D Greicius1. 1. Department of Neurology and Neurological Sciences, Functional Imaging in Neuropsychiatric Disorders (FIND) Lab, Stanford University, Stanford, California. 2. Department of Neurosurgery, Stanford University, Stanford, California. 3. Quantitative Sciences Unit, Stanford Medicine, Stanford, California.
Abstract
Importance: Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear. Objectives: To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4. Design, Setting, and Participants: This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019. Main Outcomes and Measures: The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling. Results: Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04). Conclusions and Relevance: The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.
Importance: Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear. Objectives: To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4. Design, Setting, and Participants: This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019. Main Outcomes and Measures: The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling. Results: Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04). Conclusions and Relevance: The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.
Authors: Ci-Di Chen; Sonia Podvin; Earl Gillespie; Susan E Leeman; Carmela R Abraham Journal: Proc Natl Acad Sci U S A Date: 2007-12-03 Impact factor: 11.205
Authors: Richard D Semba; Abhay R Moghekar; Jason Hu; Kai Sun; Randi Turner; Luigi Ferrucci; Richard O'Brien Journal: Neurosci Lett Date: 2013-11-07 Impact factor: 3.046
Authors: Ingrid S van Maurik; Stephanie J Vos; Isabelle Bos; Femke H Bouwman; Charlotte E Teunissen; Philip Scheltens; Frederik Barkhof; Lutz Frolich; Johannes Kornhuber; Jens Wiltfang; Wolfgang Maier; Oliver Peters; Eckart Rüther; Flavio Nobili; Giovanni B Frisoni; Luiza Spiru; Yvonne Freund-Levi; Asa K Wallin; Harald Hampel; Hilkka Soininen; Magda Tsolaki; Frans Verhey; Iwona Kłoszewska; Patrizia Mecocci; Bruno Vellas; Simon Lovestone; Samantha Galluzzi; Sanna-Kaisa Herukka; Isabel Santana; Ines Baldeiras; Alexandre de Mendonça; Dina Silva; Gael Chetelat; Stephanie Egret; Sebastian Palmqvist; Oskar Hansson; Pieter Jelle Visser; Johannes Berkhof; Wiesje M van der Flier Journal: Lancet Neurol Date: 2019-09-13 Impact factor: 44.182
Authors: L A Farrer; L A Cupples; J L Haines; B Hyman; W A Kukull; R Mayeux; R H Myers; M A Pericak-Vance; N Risch; C M van Duijn Journal: JAMA Date: 1997 Oct 22-29 Impact factor: 56.272
Authors: Adam C Naj; Gyungah Jun; Gary W Beecham; Li-San Wang; Badri Narayan Vardarajan; Jacqueline Buros; Paul J Gallins; Joseph D Buxbaum; Gail P Jarvik; Paul K Crane; Eric B Larson; Thomas D Bird; Bradley F Boeve; Neill R Graff-Radford; Philip L De Jager; Denis Evans; Julie A Schneider; Minerva M Carrasquillo; Nilufer Ertekin-Taner; Steven G Younkin; Carlos Cruchaga; John S K Kauwe; Petra Nowotny; Patricia Kramer; John Hardy; Matthew J Huentelman; Amanda J Myers; Michael M Barmada; F Yesim Demirci; Clinton T Baldwin; Robert C Green; Ekaterina Rogaeva; Peter St George-Hyslop; Steven E Arnold; Robert Barber; Thomas Beach; Eileen H Bigio; James D Bowen; Adam Boxer; James R Burke; Nigel J Cairns; Chris S Carlson; Regina M Carney; Steven L Carroll; Helena C Chui; David G Clark; Jason Corneveaux; Carl W Cotman; Jeffrey L Cummings; Charles DeCarli; Steven T DeKosky; Ramon Diaz-Arrastia; Malcolm Dick; Dennis W Dickson; William G Ellis; Kelley M Faber; Kenneth B Fallon; Martin R Farlow; Steven Ferris; Matthew P Frosch; Douglas R Galasko; Mary Ganguli; Marla Gearing; Daniel H Geschwind; Bernardino Ghetti; John R Gilbert; Sid Gilman; Bruno Giordani; Jonathan D Glass; John H Growdon; Ronald L Hamilton; Lindy E Harrell; Elizabeth Head; Lawrence S Honig; Christine M Hulette; Bradley T Hyman; Gregory A Jicha; Lee-Way Jin; Nancy Johnson; Jason Karlawish; Anna Karydas; Jeffrey A Kaye; Ronald Kim; Edward H Koo; Neil W Kowall; James J Lah; Allan I Levey; Andrew P Lieberman; Oscar L Lopez; Wendy J Mack; Daniel C Marson; Frank Martiniuk; Deborah C Mash; Eliezer Masliah; Wayne C McCormick; Susan M McCurry; Andrew N McDavid; Ann C McKee; Marsel Mesulam; Bruce L Miller; Carol A Miller; Joshua W Miller; Joseph E Parisi; Daniel P Perl; Elaine Peskind; Ronald C Petersen; Wayne W Poon; Joseph F Quinn; Ruchita A Rajbhandary; Murray Raskind; Barry Reisberg; John M Ringman; Erik D Roberson; Roger N Rosenberg; Mary Sano; Lon S Schneider; William Seeley; Michael L Shelanski; Michael A Slifer; Charles D Smith; Joshua A Sonnen; Salvatore Spina; Robert A Stern; Rudolph E Tanzi; John Q Trojanowski; Juan C Troncoso; Vivianna M Van Deerlin; Harry V Vinters; Jean Paul Vonsattel; Sandra Weintraub; Kathleen A Welsh-Bohmer; Jennifer Williamson; Randall L Woltjer; Laura B Cantwell; Beth A Dombroski; Duane Beekly; Kathryn L Lunetta; Eden R Martin; M Ilyas Kamboh; Andrew J Saykin; Eric M Reiman; David A Bennett; John C Morris; Thomas J Montine; Alison M Goate; Deborah Blacker; Debby W Tsuang; Hakon Hakonarson; Walter A Kukull; Tatiana M Foroud; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Gerard D Schellenberg Journal: Nat Genet Date: 2011-04-03 Impact factor: 38.330
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Giovanni B Frisoni; Daniele Altomare; Dietmar Rudolf Thal; Federica Ribaldi; Rik van der Kant; Rik Ossenkoppele; Kaj Blennow; Jeffrey Cummings; Cornelia van Duijn; Peter M Nilsson; Pierre-Yves Dietrich; Philip Scheltens; Bruno Dubois Journal: Nat Rev Neurosci Date: 2021-11-23 Impact factor: 34.870
Authors: Sarah M Neuner; Maria Telpoukhovskaia; Vilas Menon; Kristen M S O'Connell; Timothy J Hohman; Catherine C Kaczorowski Journal: Trends Neurosci Date: 2022-03-17 Impact factor: 16.978
Authors: Philip Scheltens; Bart De Strooper; Miia Kivipelto; Henne Holstege; Gael Chételat; Charlotte E Teunissen; Jeffrey Cummings; Wiesje M van der Flier Journal: Lancet Date: 2021-03-02 Impact factor: 79.321
Authors: Michael E Belloy; Sarah J Eger; Yann Le Guen; Valerio Napolioni; Kacie D Deters; Hyun-Sik Yang; Marzia A Scelsi; Tenielle Porter; Sarah-Naomi James; Andrew Wong; Jonathan M Schott; Reisa A Sperling; Simon M Laws; Elisabeth C Mormino; Zihuai He; Summer S Han; Andre Altmann; Michael D Greicius Journal: Neurobiol Aging Date: 2021-01-23 Impact factor: 4.673