A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease
Authors: Inglese Marianna , Patel Neva , Linton-Reid Kristofer , Loreto Flavia , Win Zarni , Perry Richard J. , Carswell Christopher , Grech-Sollars Matthew , Crum William R. , Lu Haonan , Malhotra Paresh A. ,   the Alzheimer’s Disease Neuroimaging Initiative, Silbert Lisa C. , Lind Betty , Crissey Rachel , Kaye Jeffrey A. , Carter Raina , Dolen Sara , Quinn Joseph , Schneider Lon S. , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M. , Brewer James , Vanderswag Helen , Fleisher Adam , Ziolkowski Jaimie , Heidebrink Judith L. , Zbizek-Nulph  , Lord Joanne L. , Zbizek-Nulph Lisa , Petersen Ronald , Mason Sara S. , Albers Colleen S. , Knopman David , Johnson Kris , Villanueva-Meyer Javier , Pavlik Valory , Pacini Nathaniel , Lamb Ashley , Kass Joseph S. , Doody Rachelle S. , Shibley Victoria , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S. , Mintz Akiva , Ances Beau , Morris John C. , Winkfield David , Carroll Maria , Stobbs-Cucchi Georgia , Oliver Angela , Creech Mary L. , Mintun Mark A. , Schneider Stacy , Geldmacher David , Love Marissa Natelson , Griffith Randall , Clark David , Brockington John , Marson Daniel , Grossman Hillel , Goldstein Martin A. , Greenberg Jonathan , Mitsis Effie , Shah Raj C. , Lamar Melissa , Sood Ajay , Blanchard Kimberly S. , Fleischman Debra , Arfanakis Konstantinos , Samuels Patricia , Duara Ranjan , Greig-Custo Maria T. , Rodriguez Rosemarie , Albert Marilyn , Varon Daniel , Onyike Chiadi , Farrington Leonie , Rudow Scott , Brichko Rottislav , Greig Maria T. , 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. , Singleton-Garvin Jamika , Doraiswamy P. Murali , Petrella Jeffrey R. , James Olga , Wong Terence Z. , 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. , Zmuda Michelle , Butters Meryl , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Martin Kim , Kowalski Nancy , Martin Kimberly S. , Keltz Melanie , Goldstein Bonnie S. , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Reist Christopher , Thai Gaby , Pierce Aimee , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Kelley Brendan , Nguyen Trung , Womack Kyle , Mathews Dana , Quiceno Mary , 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 , Lu Po H. , Bartzokis George , Woo Ellen , Teng Edmond , Graff-Radford Neill R. , Parfitt Francine , Poki-Walker Kim , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Brosch Jared 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 , Hsiung Ging-Yuek Robin , Kim Ellen , Mudge Benita , Sossi Vesna , Feldman Howard , Assaly Michele , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Kertesz Andrew , Drost Dick , Rogers John , Grant Ian , Muse Brittanie , Rogalski Emily , Mesulam Jordan Robson M. -Marsel , Kerwin Diana , Wu Chuang-Kuo , Johnson Nancy , Lipowski Kristine , Weintraub Sandra , Bonakdarpour Borna , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J. , Mackin Scott , Nelson Craig , Bickford David , Au Yiu Ho , Scherer Kelly , Catalinotto Daniel , Stark Samuel , Ong Elise , Fernandez Dariella , Miller Bruce L. , Rosen Howard , 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 , Rosen Allyson , Tinklenberg Jared , Belden Christine M. , Atri Alireza , Spann Bryan M. , Zamrini Kelly A. Clark Edward , Sabbagh Marwan , 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 , Capote Horacio , Rainka Michelle , Borrie Michael , Lee T. -Y , Bartha 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 , Lin Michael , Ravdin Lisa , Lee Athena , Sadowsky Carl , Martinez Walter , Villena Teresa , Peskind Elaine R. , Petrie Eric C. , Li Gail , Aboagye Eric O. 
Published: June 2022

Abstract
Background
Alzheimer’s disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care.

Methods
We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called “Alzheimer’s Predictive Vector” (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO).

Results
The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer’s related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype.

Conclusions
This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.