Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis
Authors: Bocancea Diana I , Svenningsson Anna L , van Loenhoud Anna C , Groot Colin , Barkhof Frederik , Strandberg Olof , Smith Ruben ,   for the Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael W , Aisen Paul , Petersen Ronald , 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 , Perrin Richard J , Shaw Leslie M , Khachaturian Zaven , Carrillo Maria , Potter William , Barnes Lisa , Bernard Marie , González Hector , Ho Carole , Hsiao John K , Jackson Jonathan , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Ryan Laurie , Silverberg Nina , Fleisher Adam , Weiner Michael W , Sacrey Diana Truran , Fockler Juliet , Conti Cat , Veitch Dallas , Neuhaus John , Jin Chengshi , Nosheny Rachel , Ashford Miriam , Flenniken Derek , Kormo Adrienne , Green Robert C , Montine Tom , Conti Cat B , Petersen Ronald , Aisen Paul , Rafii Michael , Raman Rema , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Cabrera Yuliana , Walter Sarah , Miller Garrett , Coker Godfrey , Clanton Taylor , Hergesheimer Lindsey , Smith Stephanie , Adegoke Olusegun , Mahboubi Payam , Moore Shelley , Pizzola Jeremy , Shaffer Elizabeth , Beckett Laurel , Harvey Danielle , Donohue Michael , Jack Clifford R , Forghanian-Arani Arvin , Borowski Bret , Ward Chad , Schwarz Christopher , Jones David , Gunter Jeff , Kantarci Kejal , Senjem Matthew , Vemuri Prashanthi , Reid Robert , Fox Nick C , Malone Ian , Thompson Paul , Thomopoulos Sophia I , Nir Talia M , Jahanshad Neda , DeCarli Charles , Knaack Alexander , Fletcher Evan , Harvey Danielle , Tosun-Turgut Duygu , Chen Stephanie Rossi , Choe Mark , Crawfor Karen , Yushkevich Paul A , Das Sandhitsu , Jagust William , Koeppe Robert A , Reiman Eric M , Chen Kewei , Mathis Chet , Landau Susan , Morris John C , Perrin Richard , Cairns Nigel J , Bernhardt Haley , Shaw Leslie M , Figurski Michal , Toga Arthur W , Crawfor Karen , Neu Scott , Saykin Andrew J , Nho Kwangsik , Risacher Shannon L , Apostolova Liana G , Shen Li , Foroud Tatiana M , Nudelman Kelly , Faber Kelley , Weiner Michael W , Hsiao John K , Silbert Lisa C , Kaye Jeffrey A , Dolen Sara , Schneider Lon S , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M , Brewer James , Vanderswag Helen , Ziolkowski Jaimie , Heidebrink Judith L , Zbizek-Nulph Lisa , Lord Joanne L , Zbizek-Nulph Lisa , Petersen Ronald , Mason Sara S , Albers Colleen S , Knopman David , Johnson Kris , Villanueva-Meyer Javier , Pacini Nathaniel , Lamb Ashley , Kass Joseph S , Doody Rachelle S , Chowdhury Munir , Dang Mimi , Stern Yaakov , Honig Lawrence S , Mintz Akiva , Ances Beau , Morris John C , Winkfield David , Carroll Maria , Oliver Angela , Schneider Stacy , Geldmacher David , Love Marissa Natelson , Griffith Randall , Brockington John , Grossman Hillel , Goldstein Martin A , Greenberg Jonathan , Mitsis Effie , Shah Raj C , Lamar Melissa , Samuel Patricia , Duara Ranjan , Greig-Custo Maria T , Rodriguez Rosemarie , Albert Marilyn , Onyike Chiadi , Farrington Leonie , Rudow Scott , Brichko Rottislav , Kielb Stephanie , Smith Amanda , Raj Balebail Ashok , Fargher Kristin , Sadowski Martin , Wisniewski Thomas , Shulman Melanie , Faustin Arline , Rao Julia , Castro Karen M , Ulysse Anaztasia , Chen Shannon , Sheikh Mohammed O , Doraiswamy P Murali , Petrella Jeffrey R , James Olga , Borges-Neto Salvador , Karlawish Jason H , Wolk David A , Vaishnavi Sanjeev , Clark Christopher M , Arnold Steven E , Smith Charles D , Jicha Gregory A , El Khouli Riham , Raslau Flavius D , Lopez Oscar L , Oakley MaryAnn , Simpson Donna M , Porsteinsson Anton P , Martin Kim , Kowalski Nancy , Keltz Melanie , Goldstein Bonnie S , Makino Kelly M , Ismail M Saleem , Brand Connie , Thai Gaby , Pierce Aimee , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Kelley Brendan , Nguyen Trung , Womack Kyle , Mathews Dana , Levey Allan I , Lah James J , Hajjar Ihab , Cellar Janet S , Burns Jeffrey M , Swerdlow Russell H , Brooks William M , Silverman Daniel H S , Kremen Sarah , Apostolova Liana , Tingus Kathleen , Teng Edmond , Graff-Radford Neill R , Parfitt Francine , Poki-Walker Kim , Farlow Martin R , Hake Ann Marie , Matthews Brandy R , Herring Scott , van Dyck Christopher H , Mecca Adam P , Good Susan P , MacAvoy Martha G , Carson Richard E , Varma Pradeep , Chertkow Howard , Vaitekunis Susan , Hosein Chris , Black Sandra , Stefanovic Bojana , Heyn Chris (Chinthaka) , Mudge Benita , Sossi Vesna , Feldman Howard , Assaly Michele , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Kertesz Andrew , Drost Dick , Grant Ian , Muse Brittanie , Rogalski Emily , Robso Jordan , Mesulam M-Marsel , Wu Chuang-Kuo , Johnson Nancy , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J , Miller Bruce L , Perry David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Sperling Reisa A , Johnson Keith A , Marshall Gad A , Yesavage Jerome , Taylor Joy L , Chao Steven , Coleman Jaila , White Jessica D , Lane Barton , Belden Christine M , Atri Alireza , Spann Bryan M , Clar Kelly A , Killiany Ronald , Stern Robert , Mez Jesse , Kowall Neil , Budson Andrew E , Obisesan Thomas O , Ntekim Oyonumo E , Wolday Saba , Khan Javed I , Nwulia Evaristus , Nadarajah Sheeba , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fatica Parianne , Fletcher Evan , Maillard Pauline , Olichney John , DeCarli Charles , Carmichael Owen , Bates Vernice , Rainka Michelle , Borrie Michael , Lee ChB T-Y , Bartha Dr Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M , Perrin Allison , Burke Anna , Scharre Douglas W , Kataki Maria , Tarawneh Rawan , Kelley Brendan , Hart David , Zimmerman Earl A , Celmins Dzintra , Miller Delwyn D , Ponto Laura L Boles , Smith Karen Ekstam , Koleva Hristina , Shim Hyungsub , Nam Ki Won , Schultz Susan K , Williamson Jeff D , Craft Suzanne , Cleveland Jo , Yang Mia , Sink Kaycee M , Ott Brian R , Drake Jonathan , Tremont Geoffrey , Daiello Lori A , Drake Jonathan D , Sabbagh Marwan , Ritter Aaron , Bernick Charles , Munic Donna , Mintz Akiva , O'Connelll Abigail , Mintzer Jacobo , Wiliams Arthur , Masdeu Joseph , Shi Jiong , Garcia Angelica , Sabbagh Marwan , Newhouse Paul , Potkin Steven , Salloway Stephen , Malloy Paul , Correia Stephen , Kittur Smita , Pearlson Godfrey D , Blank Karen , Anderson Karen , Flashman Laura A , Seltzer Marc , Hynes Mary L , Santulli Robert B , Relkin Norman , Chiang Gloria , Lee Athena , Lin Michael , Ravdin Lisa , Weiner Michael W , Aisen Paul , Weiner Michael W , Aisen Paul , Petersen Ronald , Green Robert C , Harvey Danielle , Jagust William , Morris John C , Saykin Andrew J , Shaw Leslie M , Toga Arthur W , Trojanowki John Q , Neylan Thomas , Grafman Jordan , Green Robert C , Montine Tom , Weiner Michael W , Petersen Ronald , Aisen Paul , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Walter Sarah , Adegoke Olusegun , Mahboubi Payam , Danowski Sarah , Coker Godfrey , Clanton Taylor , Pizzola Jeremy , Shaffer Elizabeth , Neylan Thomas , Hayes Jacqueline , Finley Shannon , Harvey Danielle , Donohue Michael , Bernstein Matthew , Borowski Bret , Gunter Jeff , Senjem Matt , Kantarci Kejal , Ward Chad , Tosun-Turgut Duygu , Chen Stephanie Rossi , Landau Susan , Koeppe Robert A , Foster Norm , Reiman Eric M , Chen Kewei , Morris John C , Perrin Richard J , Franklin Erin , Shaw Leslie M , Trojanowki John Q , Korecka Magdalena , Toga Arthur W , Crawfor Karen , Saykin Andrew J , Foroud Tatiana M , Potkin Steven , Shen Li , Faber Kelley , Kim Sungeun , Nho Kwangsik , Wilmes Kristi , Schneider Lon S , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M , Brewer James , Vanderswag Helen , Fleisher Adam , Stern Yaakov , Honig Lawrence S , Mintz Akiva , Shah Raj C , Sood Ajay , Blanchard Kimberly S , Fleischman Debra , Arfanakis Konstantinos , Duara Dr Ranjan , Varon Dr Daniel , Doraiswamy P Murali , Petrella Jeffrey R , James Olga , Borges-Neto Salvador , Wong Terence Z , Porsteinsson Anton P , Goldstein Bonnie , Martin Kimberly S , Thai Gaby , Pierce Aimee , Reist Christopher , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Sadowsky Carl , Martinez Walter , Villena Teresa , Rosen Howard , Perr David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Sperling Reisa A , Johnson Keith A , Belden Christine M , Atri Alireza , Spann Bryan M , Clar Kelly A , Zamrini Edward , Sabbagh Marwan , Obisesan Thomas O , Ntekim Oyonumo E , Wolday Saba , Nwulia Evaristus , Nadarajah Sheeba , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M , Peskind Elaine R , Petrie Eric C , Li Gail , Yesavage Jerome , Taylor Joy L , Chao Steven , Coleman Jaila , White Jessica D , Lane Barton , Rosen Allyson , Tinklenberg Jared , Lin Michael , Chiang Gloria , Ravdin Lisa , Relkin Norman , O'Connelll Abigail , Mintzer Jacobo , Wiliams Arthur , Mackin Scott , Aisen Paul , Raman Rema , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Walter Sarah , Adegoke Olusegun , Mahboubi Payam , Mackin Scott , Weiner Michael W , Aisen Paul , Raman Rema , Landau Susan , Saykin Andrew J , Toga Arthur W , DeCarli Charles , Koeppe Robert A , Green Robert C , Drake Erin , Weiner Michael W , Aisen Paul , Raman Rema , Donohue Mike , Mackin Scott , Nelson Craig , Bickford David , Butters Meryl , Zmuda Michelle , Bernstein Matthew , Borowski Bret , Gunter Jeff , Senjem Matt , Kantarci Kejal , Ward Chad , Reyes Denise , Koeppe Robert A , Landau Susan , Toga Arthur W , Crawfor Karen , Neu Scott , Saykin Andrew J , Foroud Tatiana M , Faber Kelley M , Nho Kwangsik , Nudelman Kelly N , Mackin Scott , Rosen Howard , Nelson Craig , Bickford David , Au Yiu Ho , Scherer Kelly , Catalinotto Daniel , Stark Samuel , Ong Elise , Fernandez Dariella , Butters Meryl , Zmuda Michelle , Lopez Oscar L , Oakley MaryAnn , Simpson Donna M , La Joie Renaud , Rosen Howard J , Pontecorvo Michael J , Rabinovici Gil D , van der Flier Wiesje M , Hansson Oskar , Ossenkoppele Rik 
Published: March 2023

Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET.

In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning.

We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = −0.062, P = 0.032), higher education level (Stβinteraction = −0.072, P = 0.011) and higher intracranial volume (Stβinteraction = −0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness.

In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.