Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume
Authors: Milicic Lidija , Vacher Michael , Porter Tenielle , Doré Vincent , Burnham Samantha C. , Bourgeat Pierrick , Shishegar Rosita , Doecke James , Armstrong Nicola J. , Tankard Rick , Maruff Paul , Masters Colin L. , Rowe Christopher C. , Villemagne Victor L. , Laws Simon M. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Weiner Michael , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John C. , Shaw Leslie M. , Liu Enchi , Montine Tom , Thomas Ronald G. , Donohue Michael , Walter Sarah , Gessert Devon , Sather Tamie , Jiminez Gus , Harvey Danielle , Bernstein Matthew , Fox Nick , Thompson Paul , Schuff Norbert , DeCArli Charles , Borowski Bret , Gunter Jeff , Senjem Matt , Vemuri Prashanthi , Jones David , Kantarci Kejal , Ward Chad , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Cairns Nigel J. , Householder Erin , Reinwald Lisa Taylor , Lee Virginia , Korecka Magdalena , Figurski Michal , Crawford Karen , Neu Scott , Foroud Tatiana M. , Potkin Steven , Shen Li , Kelley Faber , Kim Sungeun , Nho Kwangsik , Kachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Quinn Joseph , Lind Betty , Carter Raina , Dolen Sara , Schneider Lon S. , Pawluczyk Sonia , Beccera Mauricio , Teodoro Liberty , Spann Bryan M. , Brewer James , Vanderswag Helen , Fleisher Adam , Heidebrink Judith L. , Lord Joanne L. , Petersen Ronald , Mason Sara S. , Albers Colleen S. , Knopman David , Johnson Kris , Doody Rachelle S. , Meyer Javier Villanueva , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Ances Beau , Carroll Maria , Leon Sue , Householder Erin , Mintun Mark A. , Schneider Stacy , OliverNG Angela , Griffith Randall , Clark David , Geldmacher David , Brockington John , Roberson Erik , Grossman Hillel , Mitsis Effie , deToledo-Morrell Leyla , Shah Raj C. , Duara Ranjan , Varon Daniel , Greig Maria T. , Roberts Peggy , Albert Marilyn , Onyike Chiadi , Agostino Daniel D.’ , Kielb Stephanie , Galvin James E. , Pogorelec Dana M. , Cerbone Brittany , Michel Christina A. , Rusinek Henry , de Leon Mony J. , Glodzik Lidia , De Santi Susan , Doraiswamy P. Murali , Petrella Jeffrey R. , Wong Terence Z. , Arnold Steven E. , Karlawish Jason H. , Wolk David A. , Smith Charles D. , Jicha Greg , Hardy Peter , Sinha Partha , Oates Elizabeth , Conrad Gary , Lopez Oscar L. , Oakley Mary Ann , Simpson Donna M. , Porsteinsson Anton P. , Goldstein Bonnie S. , Martin Kim , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Mulnard Ruth A. , Thai Gaby , Mc Adams Ortiz Catherine , Womack Kyle , Mathews Dana , Quiceno Mary , Arrastia Ramon Diaz , King Richard , Weiner Myron , Cook Kristen Martin , DeVous Michael , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Anderson Heather S. , Swerdlow Russell H. , Apostolova Liana , Tingus Kathleen , Woo Ellen , Silverman Daniel H. S. , Lu Po H. , Bartzokis George , Radford Neill R. Graff , ParfittH Francine , Kendall Tracy , Johnson Heather , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Herring Scott , Hunt Cynthia , van Dyck Christopher H. , Carson Richard E. , MacAvoy Martha G. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Hsiung Ging Yuek Robin , Feldman Howard , Mudge Benita , Past Michele Assaly , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Munic Donna , Kerwin Diana , Mesulam Marek Marsel , Lipowski Kristine , Wu Chuang Kuo , Johnson Nancy , Sadowsky Carl , Martinez Walter , Villena Teresa , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A. , Johnson Keith A. , Marshall Gad , Frey Meghan , Yesavage Jerome , Taylor Joy L. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Sabbagh Marwan N. , Belden Christine M. , Jacobson Sandra A. , Sirrel Sherye A. , Kowall Neil , Killiany Ronald , Budson Andrew E. , Norbash Alexander , Johnson Patricia Lynn , Obisesan Thomas O. , Wolday Saba , Allard Joanne , Lerner Alan , Ogrocki Paula , Hudson Leon , Fletcher Evan , Carmichael Owen , Olichney John , DeCarli Charles , Kittur Smita , Borrie Michael , Lee T. Y. , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Preda Adrian , Nguyen Dana , Tariot Pierre , Fleisher Adam , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Scharre Douglas W. , Kataki Maria , Adeli Anahita , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Santulli Robert B. , Kitzmiller Tamar J. , Schwartz Eben S. , SinkS Kaycee M. , Williamson Jeff D. , Garg Pradeep , Watkins Franklin , Ott Brian R. , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J. , Miller Bruce L. , Mintzer Jacobo , Spicer Kenneth , Bachman David , Finger Elizabether , Pasternak Stephen , Rachinsky Irina , Rogers John , Kertesz Andrew , Drost Dick , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Schultz Susan K. , Boles Ponto Laura L. , Shim Hyungsub , Smith Karen Elizabeth , Relkin Norman , Chaing Gloria , Raudin Lisa , Smith Amanda , Fargher Kristin , Raj Balebail Ashok ,   Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Fowler Christopher , Rainey-Smith Stephanie R. , Bird Sabine , Bomke Julia , Bourgeat Pierrick , Brown Belinda M. , Burnham Samantha C. , Bush Ashley I. , Chadunow Carolyn , Collins Steven , Doecke James , Dore Vincent , Ellis Kathryn A. , Evered Lis , Fazlollahi Amir , Fripp Jurgen , Gardener Samantha L. , Gibson Simon , Grenfell Robert , Harrison Elise , Head Richard , Jin Liang , Kamer Adrian , Lamb Fiona , Lautenschlager Nicola T. , Laws Simon M. , Li Qiao-Xin , Lim Lucy , Lim Yen Ying , Louey Andrea , Macaulay S. Lance , Mackintosh Lucy , Martins Ralph N. , Maruff Paul , Masters Colin L. , McBride Simon , Milicic Lidija , Pertile Kelly , Porter Tenielle , Radler Morgan , Robertson Joanne , Rodrigues Mark , Rowe Christopher C. , Rumble Rebecca , Salvado Olivier , Savage Greg , Shishegar Rosita , Silbert Brendan , Soh Magdalene , Sohrabi Hamid R. , Taddei Kevin , Taddei Tania , Thai Christine , Trounson Brett , Tyrrel Regan , Vacher Michael , Varghese Shiji , Villemagne Victor L. , Weinborn Michael , Woodward Michael , Xia Ying , Ames David 
Published: April 2022

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.