Characterizing and validating 12-month reliable cognitive change in Early-Onset Alzheimer's Disease for use in clinical trials - 07/02/25

Doi : 10.1016/j.tjpad.2025.100075

Dustin B. Hammers ^1,^⁎ , Jane Musema ¹, Ani Eloyan ², Maryanne Thangarajah ², Alexander Taurone ², Renaud La Joie ³, Alexandra Touroutoglou ⁴, Prashanthi Vemuri ⁵, Joel Kramer ³, Paul Aisen ⁶, Jeffrey L. Dage ¹, Kelly N. Nudelman ⁷, Kala Kirby ¹, Alireza Atri ⁸, David Clark ¹, Gregory S. Day ⁹, Ranjan Duara ¹⁰, Neill R. Graff-Radford ⁹, Ian Grant ¹¹, Lawrence S. Honig ¹², Erik C.B. Johnson ¹³, David T. Jones ⁵, Joseph C. Masdeu ¹⁴, Mario F. Mendez ¹⁵, Kyle Womack ¹⁶, Erik Musiek ¹⁶, Chiadi U. Onyike ¹⁷, Meghan Riddle ¹⁸, Emily Rogalski ¹⁹, Steven Salloway ¹⁸, Sharon J. Sha ²⁰, Raymond Scott Turner ²¹, Thomas S. Wingo ²², David A. Wolk ²³, Maria C. Carrillo ²⁴, Gil D. Rabinovici ³, Bradford C. Dickerson ⁴, Liana G. Apostolova ^1,^7,²⁵
the LEADS Consortium¹
¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA, 46202
² Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA, 02912
³ Department of Neurology, University of California – San Francisco, San Francisco, California, USA, 94143
⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, 02114
⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA, 55905
⁶ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA, 92121
⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA, 46202
⁸ Banner Sun Health Research Institute, Sun City, Arizona, USA, 85351
⁹ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA, 32224
¹⁰ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA, 33140
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, 60611
¹² Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA, 10032
¹³ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA, 30307
¹⁴ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA, 77030
¹⁵ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA, 90095
¹⁶ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA, 63130
¹⁷ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 21205
¹⁸ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA, 02912
¹⁹ Healthy Aging & Alzheimer's Research Care Center, Department of Neurology, University of Chicago, Chicago, Illinois, USA, 60637
²⁰ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA, 94304
²¹ Department of Neurology, Georgetown University, Washington D.C., USA, 20057
²² Department of Neurology, UC Davis Alzheimer's Disease Research Center, University of California – Davis, Davis, California, USA, 95816
²³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA, 19104
²⁴ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA, 60603
²⁵ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA, 46202

^⁎Correspondences to Dustin B. Hammers, PhD, Department of Neurology, Indiana University School of Medicine, Department of Neurology, 355 West 16th Street (GH4027), Indianapolis, IN, 46202.Department of Neurology, Indiana University School of MedicineDepartment of Neurology355 West 16th Street (GH4027)IndianapolisIN46202

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Abstract

BACKGROUND

As literature suggests that Early-Onset Alzheimer's Disease (EOAD) and late-onset AD may differ in important ways, need exists for randomized clinical trials for treatments tailored to EOAD. Accurately measuring reliable cognitive change in individual patients with EOAD will have great value for these trials.

OBJECTIVES

The current study sought to characterize and validate 12-month reliable change from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) neuropsychological battery.

DESIGN

Standardized regression-based (SRB) prediction equations were developed from age-matched cognitively intact participants within LEADS, and applied to clinically impaired participants from LEADS.

SETTING

Participants were recruited from outpatient academic medical centers.

PARTICIPANTS

Participants were enrolled in LEADS and diagnosed with amyloid-positive EOAD (n=189) and amyloid-negative early-onset cognitive impairment not related to AD (EOnonAD; n=43).

MEASUREMENT

12-month reliable change (Z-scores) was compared between groups across cognitive domain composites, and distributions of individual participant trajectories were examined. Prediction of Z-scores by common AD biomarkers was also considered.

RESULTS

Both EOAD and EOnonAD displayed significantly lower 12-month follow-up scores than were predicted based on SRB equations, with declines more pronounced for EOAD across several domains. AD biomarkers of cerebral β-amyloid, tau, and EOAD-specific atrophy were predictive of 12-month change scores.

CONCLUSIONS

The current results support including EOAD patients in longitudinal clinical trials, and generate evidence of validation for using 12-month reliable cognitive change as a clinical outcome metric in clinical trials in EOAD cohorts like LEADS. Doing so will enhance the success of EOAD trials and permit a better understanding of individual responses to treatment.

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Keywords : Cognition, Longitudinal, Early-Onset Alzheimer's Disease, Memory, Non-Amnestic