Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease

Sára Nemes; Paige E Logan; Mohit K Manchella; Nidhi S Mundada; Renaud La Joie; Angelina J Polsinelli; Dustin B Hammers; Robert A Koeppe; Tatiana M Foroud; Kelly N Nudelman; Ani Eloyan; Leonardo Iaccarino; Valérie Dorsant-Ardón; Alexander Taurone; Maryanne Thangarajah; Jeffery L Dage; Paul Aisen; Lea T Grinberg; Clifford R Jack Jr; Joel Kramer; Walter A Kukull; Melissa E Murray; Malia Rumbaugh; David N Soleimani-Meigooni; Arthur Toga; Alexandra Touroutoglou; Prashanthi Vemuri; Alireza Atri; Gregory S Day; Ranjan Duara; Neill R Graff-Radford; Lawrence S Honig; David T Jones; Joseph Masdeu; Mario F Mendez; Erik Musiek; Chiadi U Onyike; Meghan Riddle; Emily Rogalski; Stephen Salloway; Sharon J Sha; Raymond S Turner; Thomas S Wingo; Kyle B Womack; David A Wolk; Gil D Rabinovici; Maria C Carrillo; Bradford C Dickerson; Liana G Apostolova; LEADS Consortium

doi:10.1002/alz.13403

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease

Alzheimers Dement. 2023 Nov;19 Suppl 9(Suppl 9):S49-S63. doi: 10.1002/alz.13403. Epub 2023 Jul 26.

Authors

Sára Nemes¹, Paige E Logan¹, Mohit K Manchella^{1

2}, Nidhi S Mundada³, Renaud La Joie³, Angelina J Polsinelli^{1

4}, Dustin B Hammers¹, Robert A Koeppe⁵, Tatiana M Foroud⁶, Kelly N Nudelman⁶, Ani Eloyan⁷, Leonardo Iaccarino³, Valérie Dorsant-Ardón⁶, Alexander Taurone⁷, Maryanne Thangarajah⁷, Jeffery L Dage¹, Paul Aisen⁸, Lea T Grinberg^{3

9}, Clifford R Jack Jr¹⁰, Joel Kramer³, Walter A Kukull¹¹, Melissa E Murray¹², Malia Rumbaugh⁶, David N Soleimani-Meigooni³, Arthur Toga¹³, Alexandra Touroutoglou¹⁴, Prashanthi Vemuri¹⁰, Alireza Atri¹⁵, Gregory S Day¹², Ranjan Duara^{16

17}, Neill R Graff-Radford¹², Lawrence S Honig¹⁸, David T Jones^{10

19}, Joseph Masdeu²⁰, Mario F Mendez²¹, Erik Musiek²², Chiadi U Onyike²³, Meghan Riddle²⁴, Emily Rogalski²⁵, Stephen Salloway²⁴, Sharon J Sha²⁶, Raymond S Turner²⁷, Thomas S Wingo²⁸, Kyle B Womack²², David A Wolk^{29

30}, Gil D Rabinovici³, Maria C Carrillo³¹, Bradford C Dickerson¹⁴, Liana G Apostolova^{1

4

6}; LEADS Consortium

Affiliations

¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Department of Chemistry, University of Southern Indiana, Evansville, Indiana, USA.
³ Department of Neurology, University of California, San Francisco, California, USA.
⁴ Indiana Alzheimer's Disease Research Center, Indianapolis, Indiana, USA.
⁵ Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁷ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
⁸ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
⁹ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹² Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹³ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁶ Department of Neurology, Center for Mind/Brain Medicine, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts, USA.
¹⁷ Wein Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA.
¹⁸ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
¹⁹ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁰ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²¹ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²² Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
²³ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁴ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²⁶ Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA.
²⁷ Department of Neurology, Georgetown Universit, Washington, District of Columbia, USA.
²⁸ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁹ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁰ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³¹ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.

PMID: 37496307
PMCID: PMC10811272 (available on 2024-11-01)
DOI: 10.1002/alz.13403

Abstract

Introduction: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD).

Methods: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.

Results: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers.

Discussion: The effects of sex and APOE ε4 must be considered when studying these populations.

Highlights: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

Keywords: APOE ε4; MRI; amyloid PET; early-onset Alzheimer's disease; early-onset non-Alzheimer's disease; genetics; imaging biomarkers; neuroimaging; sex differences; tau PET.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Amyloid beta-Peptides
Amyloidogenic Proteins
Apolipoprotein E4 / genetics
Atrophy
Biomarkers
Female
Humans
Male
Neuroimaging

Substances

Apolipoprotein E4
Biomarkers
Amyloidogenic Proteins
Amyloid beta-Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding