Longitudinal cognitive performance of participants with sporadic early onset Alzheimer's disease from LEADS

Dustin B Hammers¹, Ani Eloyan², Alexander Taurone², Maryanne Thangarajah², Sujuan Gao³, Laurel Beckett⁴, Angelina J Polsinelli¹, Kala Kirby¹, Jeffrey L Dage¹, Kelly Nudelman⁵, Paul Aisen⁶, Rema Reman⁶, Renaud La Joie⁷, Julien Lagarde⁷, Alireza Atri⁸, David Clark¹, Gregory S Day⁹, Ranjan Duara¹⁰, Neill R Graff-Radford⁹, Ian Grant¹¹, Lawrence S Honig¹², Erik C B Johnson¹³, David T Jones¹⁴, Joseph C Masdeu¹⁵, Mario F Mendez¹⁶, Kyle Womack¹⁷, Erik Musiek¹⁷, Chiadi U Onyike¹⁸, Meghan Riddle¹⁹, Emily Rogalski²⁰, Steven Salloway¹⁹, Sharon J Sha²¹, Raymond Scott Turner²², Thomas S Wingo²³, David A Wolk²⁴, Maria C Carrillo²⁵, Gil D Rabinovici^{7

26}, Bradford C Dickerson²⁷, Liana G Apostolova^{1

5

28}; LEADS Consortium¹

Affiliations

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

PMID: 39713873
PMCID: PMC11848182
DOI: 10.1002/alz.14439

Longitudinal cognitive performance of participants with sporadic early onset Alzheimer's disease from LEADS

Dustin B Hammers et al. Alzheimers Dement. 2025 Feb.

. 2025 Feb;21(2):e14439.

doi: 10.1002/alz.14439. Epub 2024 Dec 23.

Authors

Affiliations

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

PMID: 39713873
PMCID: PMC11848182
DOI: 10.1002/alz.14439

Abstract

Introduction: Early-onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%-8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early-onset dementia.

Methods: Data from 307 cognitively normal (CN) volunteer participants and those with amyloid-positive EOAD or amyloid-negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed-effects modeling.

Results: The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD.

Discussion: EOAD declined 2-4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease-modifying medications.

Highlights: Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

Keywords: Alzheimer's disease; amnestic; atypical variant; early‐onset; longitudinal.

PubMed Disclaimer

Conflict of interest statement

No authors associated with this project have reported conflicts of interest that would impact these results. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Longitudinal trajectories of each diagnostic group across domains of cognitive performance. Performance bands around each line represent 95% confidence intervals. CN, cognitive normal; EOAD, early‐onset Alzheimer's disease; EOnonAD, early‐onset non‐Alzheimer's disease.

**FIGURE 2**
Annualized scores over time for select cognitive variables. Error bars reflect the 95% t‐distribution corrected confidence intervals. The y‐axis for each plot is unique based on the test's range of performance. The values listed within the plots reflect the sample size for the group at each time point. AVLT, Rey Auditory Verbal Learning Test Delayed Recall; CDR, Clinical Dementia Rating Scale; CN, cognitively normal; EOAD, early‐onset Alzheimer's disease; EOnonAD, early‐onset non‐Alzheimer's disease; MOCA, Montreal Cognitive Assessment.

See this image and copyright information in PMC

References

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Longitudinal cognitive performance of participants with sporadic early onset Alzheimer's disease from LEADS

Affiliations

Longitudinal cognitive performance of participants with sporadic early onset Alzheimer's disease from LEADS

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical