Amyloid PET in Sporadic Early- Versus Late-Onset Alzheimer's Disease: Comparison of the LEADS and ADNI Cohorts

Julien Lagarde¹, Piyush Maiti¹, Daniel R Schonhaut¹, Ganna Blazhenets¹, Jiaxiuxiu Zhang¹, Ani Eloyan², Maryanne Thangarajah², Alexander Taurone², Isabel Elaine Allen³, David N Soleimani-Meigooni¹, Ehud Zeltzer¹, Charles Windon¹, Maison Abu Raya^{1

4}, Agathe Vrillon¹, Karen Smith¹, Ranjani Shankar¹, Alinda Amuiri¹, Salma Rocha¹, Dustin B Hammers⁵, Jeffrey L Dage⁵, Kelly N Nudelman⁶, Kala Kirby⁵, Paul Aisen⁷, Robert Koeppe⁸, Susan M Landau⁹, Maria C Carrillo¹⁰, Alexandra Touroutoglou¹¹, Michael Brickhouse¹¹, Prashanthi Vemuri¹², Laurel Beckett¹³, Rema Raman⁷, Alireza Atri¹⁴, Gregory S Day¹⁵, Ranjan Duara¹⁶, Neill R Graff-Radford¹⁵, Lawrence S Honig¹⁷, David T Jones¹⁸, Joseph C Masdeu¹⁹, Mario F Mendez²⁰, Kyle Womack²¹, Erik Musiek²¹, Chiadi U Onyike²², Meghan Riddle²³, Ian M Grant²⁴, Emily Rogalski²⁵, Erik C B Johnson²⁶, Stephen Salloway²³, Sharon Sha²⁷, R Scott Turner²⁸, Thomas S Wingo^{26

29}, David A Wolk³⁰, Bradford C Dickerson¹¹, Liana G Apostolova^{5

6

31}, Renaud La Joie¹, Gil D Rabinovici^{1

32}; LEADS Consortium for the Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco, CA.
² Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI.
³ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
⁴ Global Brain Health Institute, The university of California, San Francisco, California, CA.
⁵ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
⁷ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, CA.
⁸ Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI.
⁹ Department of Neuroscience, University of California, Berkeley, Berkeley, CA.
¹⁰ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, IL.
¹¹ Frontotemporal Disorders Unit and Massachusetts Alzheimer's Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
¹² Department of Radiology, Mayo Clinic, Rochester, MN.
¹³ Department of Public Health Sciences, University of California, Davis, Davis, CA.
¹⁴ Banner Sun Health Research Institute, Sun City, AZ.
¹⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL.
¹⁶ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL.
¹⁷ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY.
¹⁸ Department of Neurology, Mayo Clinic, Rochester, MN.
¹⁹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX.
²⁰ Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
²¹ Department of Neurology, Washington University in St. Louis, St. Louis, MO.
²² Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
²³ Department of Neurology, Alpert Medical School, Brown University, Providence, RI.
²⁴ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL.
²⁵ Healthy Aging & Alzheimer's Research Care Center, Department of Neurology, University of Chicago, Chicago, IL.
²⁶ Department of Neurology, Emory University School of Medicine, Atlanta, GA.
²⁷ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA.
²⁸ Department of Neurology, Georgetown University, Washington, DC.
²⁹ Department of Neurology, UC Davis Alzheimer's Disease Research Center, University of California, Davis, Davis, CA.
³⁰ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
³¹ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN.
³² Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA.

PMID: 40091774
PMCID: PMC12406739 (available on 2026-08-01)
DOI: 10.1002/ana.27233

Comparative Study

Amyloid PET in Sporadic Early- Versus Late-Onset Alzheimer's Disease: Comparison of the LEADS and ADNI Cohorts

Julien Lagarde et al. Ann Neurol. 2025 Aug.

. 2025 Aug;98(2):236-248.

doi: 10.1002/ana.27233. Epub 2025 Mar 17.

Authors

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco, CA.
² Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI.
³ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
⁴ Global Brain Health Institute, The university of California, San Francisco, California, CA.
⁵ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
⁷ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, CA.
⁸ Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI.
⁹ Department of Neuroscience, University of California, Berkeley, Berkeley, CA.
¹⁰ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, IL.
¹¹ Frontotemporal Disorders Unit and Massachusetts Alzheimer's Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
¹² Department of Radiology, Mayo Clinic, Rochester, MN.
¹³ Department of Public Health Sciences, University of California, Davis, Davis, CA.
¹⁴ Banner Sun Health Research Institute, Sun City, AZ.
¹⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL.
¹⁶ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL.
¹⁷ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY.
¹⁸ Department of Neurology, Mayo Clinic, Rochester, MN.
¹⁹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX.
²⁰ Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
²¹ Department of Neurology, Washington University in St. Louis, St. Louis, MO.
²² Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
²³ Department of Neurology, Alpert Medical School, Brown University, Providence, RI.
²⁴ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL.
²⁵ Healthy Aging & Alzheimer's Research Care Center, Department of Neurology, University of Chicago, Chicago, IL.
²⁶ Department of Neurology, Emory University School of Medicine, Atlanta, GA.
²⁷ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA.
²⁸ Department of Neurology, Georgetown University, Washington, DC.
²⁹ Department of Neurology, UC Davis Alzheimer's Disease Research Center, University of California, Davis, Davis, CA.
³⁰ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
³¹ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN.
³² Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA.

PMID: 40091774
PMCID: PMC12406739 (available on 2026-08-01)
DOI: 10.1002/ana.27233

Abstract

Objective: Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large-scale comparative studies.

Methods: Three hundred ninety-nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition.

Results: The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74-82) than in ADNI (71%, 95% CI = 67-75, p = 0.02). Lower Mini-Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid-positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD.

Interpretation: Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236-248.

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Conflict of interest statement

Potential Conflicts of Interest

E.M. is an Assistant Editor for Annals of Neurology. G.D.R. receives research support from Avid Radiopharmaceuticals, GE Healthcare, Genentech, Life Molecular Imaging. The other authors have no competing interests to disclose.

References

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1. Olivieri P, Hamelin L, Lagarde J, et al. Characterization of the initial complaint and care pathways prior to diagnosis in very young sporadic Alzheimer’s disease. Alzheimers Res Ther 2021;13(1):90. - PMC - PubMed
1. Tort-Merino A, Falgàs N, Allen IE, et al. Early-onset Alzheimer’s disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late-onset. Ann Clin Transl Neurol 2022;9(12):1962–1973. - PMC - PubMed
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Amyloid PET in Sporadic Early- Versus Late-Onset Alzheimer's Disease: Comparison of the LEADS and ADNI Cohorts

Affiliations

Amyloid PET in Sporadic Early- Versus Late-Onset Alzheimer's Disease: Comparison of the LEADS and ADNI Cohorts

Authors

Affiliations

Abstract

Conflict of interest statement

References

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