Characterizing and validating 12-month reliable cognitive change in Early-Onset Alzheimer's Disease for use in clinical trials - 27/03/25

Doi : 10.1016/j.tjpad.2025.100075

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

^⁎Correspondence authors at: Department of Neurology, Indiana University School of Medicine, Department of Neurology, 355 West 16th Street (GH4027), Indianapolis, IN, 46202, USA.Department of Neurology, Indiana University School of MedicineDepartment of Neurology355 West 16th Street (GH4027)IndianapolisIN46202USA

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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

Plan

Calculation of development sample SRBs

Characterization of 12-month change in early-onset dementia

Individual distributions of stability versus decline

Prediction of 12-month change with ad biomarkers

Discussion

Funding

Consent

CRediT authorship contribution statement

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Vol 12 - N° 4

Article 100075- avril 2025 Retour au numéro

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Characterizing and validating 12-month reliable cognitive change in Early-Onset Alzheimer's Disease for use in clinical trials - 27/03/25

Abstract

Background

Objectives

Design

Setting

Participants

Measurement

Results

Conclusions

Plan

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