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<p>White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer’s disease (AD) progression (amyloid-β and <i>APOE-ε4</i> carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience.</p>

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Divergent white matter metabolic signature patterns indicate impending cognitive decline in aging and dementia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Wen Zhang,
  • Sheelakumari Raghavan,
  • Jianqiao Tian,
  • Scott A. Przybelski,
  • Heather J. Wiste,
  • Angela J. Fought,
  • Matthew L. Senjem,
  • Christopher G. Schwarz,
  • Robert I. Reid,
  • Mary M. Machulda,
  • Ronald C. Petersen,
  • Jonathan Graff-Radford,
  • Clifford R. Jack Jr.,
  • Val J. Lowe,
  • Michael Weiner,
  • Paul Aisen,
  • Ronald Petersen,
  • Clifford R. Jack Jr,
  • William Jagust,
  • Susan Landau,
  • Monica Rivera-Mindt,
  • Ozioma Okonkwo,
  • Leslie M. Shaw,
  • Edward B. Lee,
  • Arthur W. Toga,
  • Laurel Beckett,
  • Danielle Harvey,
  • Robert C. Green,
  • Andrew J. Saykin,
  • Kwangsik Nho,
  • Richard J. Perrin,
  • Duygu Tosun,
  • Pallavi Sachdev,
  • Erin Drake,
  • Tom Montine,
  • Catherine Conti,
  • Rachel Nosheny,
  • Diana Truran Sacrey,
  • Juliet Fockler,
  • Melanie J. Miller,
  • Winnie Kwang,
  • Chengshi Jin,
  • Adam Diaz,
  • Miriam Ashford,
  • Derek Flenniken,
  • Adrienne Kormos,
  • Michael Rafii,
  • Rema Raman,
  • Gustavo Jimenez,
  • Michael Donohue,
  • Jennifer Salazar,
  • Andrea Fidell,
  • Virginia Boatwright,
  • Justin Robison,
  • Caileigh Zimmerman,
  • Yuliana Cabrera,
  • Sarah Walter,
  • Taylor Clanton,
  • Elizabeth Shaffer,
  • Caitlin Webb,
  • Lindsey Hergesheimer,
  • Stephanie Smith,
  • Sheila Ogwang,
  • Olusegun Adegoke,
  • Payam Mahboubi,
  • Jeremy Pizzola,
  • Cecily Jenkins,
  • Naomi Saito,
  • Kedir Adem Hussen,
  • Hannatu Amaza,
  • Mai Seng Thao,
  • Shaniya Parkins,
  • Omobolanle Ayo,
  • Matt Glittenberg,
  • Isabella Hoang,
  • Kaori Kubo Germano,
  • Joe Strong,
  • Trinity Weisensel,
  • Fabiola Magana,
  • Lisa Thomas,
  • Vanessa Guzman,
  • Adeyinka Ajayi,
  • Joseph Di Benedetto,
  • Sandra Talavera,
  • Robert A. Koeppe,
  • Gil Rabinovici,
  • Victor Villemagne,
  • Brian LoPresti,
  • John Morris,
  • Erin Franklin,
  • Virginia M. Y. Lee,
  • Magdalena Korecka,
  • Magdalena Brylska,
  • Yang Wan,
  • J. Q. Trojanowki,
  • Karen Crawford,
  • Scott Neu,
  • Tatiana M. Foroud,
  • Taeho Jo,
  • Shannon L. Risacher,
  • Hannah Craft,
  • Liana G. Apostolova,
  • Kelly Nudelman,
  • Kelley Faber,
  • Zoë Potter,
  • Kaci Lacy,
  • Rima Kaddurah-Daouk,
  • Li Shen,
  • Jason Karlawish,
  • Claire Erickson,
  • Joshua Grill,
  • Emily Largent,
  • Kristin Harkins,
  • Zaven Kachaturian,
  • Richard Frank,
  • Peter J. Snyder,
  • Neil Buckholtz,
  • John K. Hsiao,
  • Laurie Ryan,
  • Susan Molchan,
  • Maria Carrillo,
  • William Potter,
  • Lisa Barnes,
  • Marie Bernard,
  • Hector González,
  • Carole Ho,
  • Jonathan Jackson,
  • Eliezer Masliah,
  • Donna Masterman,
  • Nina Silverberg,
  • Prashanthi Vemuri

摘要

White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer’s disease (AD) progression (amyloid-β and APOE-ε4 carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience.