This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2025 Apr 3:2025.03.31.25324964.

doi: 10.1101/2025.03.31.25324964.

Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research

Mark Sanderson-Cimino¹, Alden L Gross², Leslie S Gaynor^{3

4}, Emily W Paolillo¹, Rowan Saloner¹, Marilyn S Albert⁵, fLiana G Apostolova⁶, Brooke Boersema⁷, Adam L Boxer¹, Bradley F Boeve⁷, Kaitlin B Casaletto¹, Savannah R Hallgarth¹, Valentina E Diaz¹, Lindsay R Clark⁸, Pauline Maillard⁹, Ani Eloyan¹⁰, Sarah Tomaszewski Farias⁹, Mitzi M Gonzales¹¹, Dustin B Hammers⁶, Renaud La Joie¹, Yann Cobigo¹, Amy Wolf¹, Benjamin M Hampstead¹², Dawn Mechanic-Hamilton¹³, Bruce L Miller¹, Gil D Rabinovici¹, John M Ringman¹⁴, Howie J Rosen¹, Sephira G Ryman¹⁵, Jillian L Prestopnik¹⁵, David P Salmon¹⁶, Glenn E Smith^{17

18}, Charles DeCarli⁹, Kumar B Rajan¹⁹, Lee-Way Jin²⁰, Jason Hinman²¹, David K Johnson⁹, Danielle Harvey²², Myriam Fornage²³, Joel H Kramer¹, Adam M Staffaroni¹

Affiliations

¹ Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94158, USA.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
³ Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁴ Vanderbilt Memory and Aging Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁶ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
⁷ Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53726, USA.
⁹ Department of Neurology, University of California at Davis, Sacramento, CA, 95816, USA.
¹⁰ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, 02912, USA.
¹¹ Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA.
¹² Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
¹³ Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
¹⁴ Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA, 90033, USA.
¹⁵ Center for Memory & Aging, University of New Mexico, Albuquerque, NM, 87110, USA.
¹⁶ Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92161, USA.
¹⁷ 1Florida Alzheimer's Disease Research Center, Gainesville, FL, 32610, USA.
¹⁸ Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, 32603, USA.
¹⁹ Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, 60612, USA.
²⁰ Department of Pathology and Laboratory Medicine University of California, Davis, CA, 95817, USA.
²¹ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, 90095, United States.
²² Department of Public Health Sciences University of California, Davis, CA, 95616, USA.
²³ Brown Foundation Institute of Molecular Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

PMID: 40236433
PMCID: PMC11998833
DOI: 10.1101/2025.03.31.25324964

Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research

Mark Sanderson-Cimino et al. medRxiv. 2025.

[Preprint]. 2025 Apr 3:2025.03.31.25324964.

doi: 10.1101/2025.03.31.25324964.

Authors

Affiliations

¹ Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94158, USA.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
³ Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁴ Vanderbilt Memory and Aging Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁶ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
⁷ Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53726, USA.
⁹ Department of Neurology, University of California at Davis, Sacramento, CA, 95816, USA.
¹⁰ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, 02912, USA.
¹¹ Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA.
¹² Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
¹³ Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
¹⁴ Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA, 90033, USA.
¹⁵ Center for Memory & Aging, University of New Mexico, Albuquerque, NM, 87110, USA.
¹⁶ Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92161, USA.
¹⁷ 1Florida Alzheimer's Disease Research Center, Gainesville, FL, 32610, USA.
¹⁸ Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, 32603, USA.
¹⁹ Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, 60612, USA.
²⁰ Department of Pathology and Laboratory Medicine University of California, Davis, CA, 95817, USA.
²¹ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, 90095, United States.
²² Department of Public Health Sciences University of California, Davis, CA, 95616, USA.
²³ Brown Foundation Institute of Molecular Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

PMID: 40236433
PMCID: PMC11998833
DOI: 10.1101/2025.03.31.25324964

Abstract

Introduction: List-learning tasks are important for characterizing memory in ADRD research, but the Uniform Data Set neuropsychological battery (UDS-NB) lacks a list-learning paradigm; thus, sites administer a range of tests. We developed a harmonized memory composite that incorporates UDS memory tests and multiple list-learning tasks.

Methods: Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogenous sample (n=5943) who completed the UDS-NB and one of five list-learning tasks. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, and plasma phosphorylated tau (p-tau181 and p-tau217). Test-retest reliability was assessed. Analyses were replicated in a racially/ethnically diverse cohort (n=1058).

Results: Fit indices, loadings, distributions, and test-retest reliability were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity.

Discussion: This composite enables researchers to incorporate multiple list-learning tasks with other UDS measures to create a single metric.

Keywords: Alzheimer’s Dementia and Related Disorders; Co-calibration; Cognition; Harmonization; Memory; Neurodegeneration; Neuropsychology.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest B.F.B. has served as an investigator for clinical trials sponsored by Alector, Biogen, Transposon and Cognition Therapeutics. He serves on the Scientific Advisory Board of the Tau Consortium, which is funded by the Rainwater Charitable Foundation. He receives research support from NIH. A.L.B. receives research support from the NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding and Wave and received research support from Biogen, Eisai and Regeneron. M.M.G. reports personal stock in Abbvie. R.C.P. reports personal fees from Roche, no personal fees from Eisai, and personal fees from Genentech, personal fees from Eli Lilly and personal fees from Nestle, outside the submitted work. B.L.M reported serving on the scientific advisory board of the Bluefield Project to Cure Frontotemporal Dementia; the John Douglas French Alzheimer’s Foundation; Fundación Centro de Investigación Enfermedades Neurológicas, Madrid, Spain; Genworth; the Kissick Family Foundation; the Larry L. Hillblom Foundation; and the Tau Consortium of the Rainwater Charitable Foundation; serving as a scientific advisor for the Arizona Alzheimer’s Consortium; Massachusetts General Hospital Alzheimer’s Disease Research Center; and the Stanford University Alzheimer’s Disease Research Center; receiving royalties from Cambridge University Press, Elsevier, Guilford Publications, Johns Hopkins Press, Oxford University Press, and the Taylor & Francis Group; serving as editor for Neurocase and section editor for Frontiers in Neurology; and receiving grants for the University of California San Francisco Frontotemporal Dementia Core, from the Bluefield Project to Cure Frontotemporal Dementia, and from the National Institute on Aging for the US–South American Initiative for Genetic-Neural-Behavioral Interactions in Human Neurodegenerative Diseases. G.D.R. reported grants from National Institutes of Health during the conduct of the study; consulting fees from C2N, Eli Lilly, Alector, Merck, Roche, and Novo Nordisk; data safety monitoring board fees from Johnson & Johnson; and grants from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech outside the submitted work; and served as Associate Editor at JAMA Neurology. A.M.S. reported grants from the National Institutes of Health, the Bluefield Project to Cure Frontotemporal Dementia, and the Association for Frontotemporal Degeneration; personal fees from Alector, Prevail Therapuetics/Eli Lilly, Passage Bio, Takeda, and the Alzheimer’s Drug Discovery Foundation; and other from Datacubed Health (licensing fees) outside the submitted work. H. J. R. reported consulting fees from Genentech and Eisai outside the submitted work. Dr Staffaroni reported grants from the National Institutes of Health, the Bluefield Project to Cure Frontotemporal Dementia, and the Association for Frontotemporal Degeneration; personal fees from Alector, Prevail Therapuetics/Eli Lilly, Passage Bio, Takeda, and the Alzheimer’s Drug Discovery Foundation; and other from Datacubed Health (licensing fees) outside the submitted work. C.D. serves as a consultant to Norvo Nordisk and Eisai Pharmaceuticals. D.K.J. has stock holdings in Sage Cerebrovascular Diagnostics, serves as President for Sage Cerebrovascular Diagnostics, and has a patent pending for Serologic assay for silent brain ischemia licensed to Sage Cerebrovascular Diagnostics

Figures

**Figure 1:**
UDS-M+ by list-learning task sample within Development cohort The histograms display the distribution and mean UDS-M+ score (red dashed line) for subsamples delineated by which list-learning task was administered. All subsamples were derived from the Developmental Cohort. T-tests compared UDS-M+ scores (adjusted for age, Clinical Dementia Rating Scale (CDR) sum of boxes, sex, and education) between list-learning subgroups. All combinations of pairwise comparisons were completed. Cohen’s ds were calculated for each comparison, and the average Cohen’s d is presented above each histogram; for example, −0.085 is the average Cohen’s d for pairwise comparisons of the AVLT group and all other list-learning groups. **Abbreviations**: **AVLT**: Rey-Auditory Verbal Learning Test; **CERAD**: Consortium to Establish a Registry for Alzheimer’s Disease; **CVLT-II:** California Verbal Learning Task-II Standard form; **CVLT-SF**: CVLT-II Short form; **HVLT**: Hopkins Verbal Learning Task; **UDS-Only**: Participants who only completed a subset of linking items but were not administered a list-learning task.

**Figure 2:**
Marginal reliability Presents marginal reliability within a sample that combines the Development cohort. The left graph includes all participants. The right graph separates participants based on which list-learning task they completed. Horizonal dashed lines indicate when the marginal reliability is at 0.8 and 0.9. Abbreviations: AVLT: Rey-Auditory Verbal Learning Test; CERAD: Consortium to Establish a Registry for Alzheimer’s Disease; CVLT-II: California Verbal Learning Task-II Standard form; CVLT-SF: CVLT Short form; HVLT: Hopkins Verbal Learning Task; UDS-Only: Participants who only completed a subset of anchor items.

**Figure 3:**
Convergent and discriminant validation Forest plot presenting standardized regression betas in the Development (circle) and DVCID cohorts (triangle), after controlling for CDR Sum of boxes (CDR Sb), with the exception of the CDR Sb row. Confidence intervals (95%) are shown via the horizontal lines. Variables are color coded by domain. * indicates reverse scoring. Abbreviations: MoCA: Montreal Cognitive Assessment total score; TabCAT: Tablet-based Cognitive Assessment Tool; UDS-EF: Uniform Data Set (v3.0) executive function composite score; DS: Digit Span; Words: Lexical Fluency; MINT= Multilingual Naming Task

**Figure 4:**
Known Group Validity: UDS-M+ by Clinical Dementia Rating Scale These graphs illustrate the stepwise decline in UDS-M+ scores that was observed with increasing disease stage (p<.001) in two independent cohorts. Abbreviations: UDS-M+: Uniform Data Set Version 3 Memory plus List-Learning score; CDR: Clinical Dementia Rating Scale

**Figure 5:**
Association between UDS-M+ and plasma phosphorylated tau levels Each graph presents the association between UDS-M+ and plasma phosphorylated tau levels (Development cohort: p-tau217; DVCID: p-tau181), after controlling for age, sex, education, and CDR sum of boxes. Graphs on the left present the results for the full sample within Development cohort (A) and DVCID (B). The stacked graphs on the right display the same results, separated by CDR global scores. p-tau levels were log transformed then Z scored. Abbreviations: UDS-M+: Uniform Data Set Memory plus List-Learning score; CDR: Clinical Dementia Rating Scale

See this image and copyright information in PMC

References

1. Weintraub S., et al., Version 3 of the Alzheimer Disease Centers’ neuropsychological test battery in the Uniform Data Set (UDS). Alzheimer disease and associated disorders, 2018. 32(1): p. 10. - PMC - PubMed
1. Rabin L.A., Paolillo E., and Barr W.B., Stability in test-usage practices of clinical neuropsychologists in the United States and Canada over a 10-year period: A follow-up survey of INS and NAN members. Archives of Clinical Neuropsychology, 2016. 31(3): p. 206–230. - PubMed
1. Mansbach W.E., Mace R.A., and Clark K.M., Story recall and word lists: Differential and combined utilities in predicting cognitive diagnosis. Journal of Clinical and Experimental Neuropsychology, 2014. 36(6): p. 569–576. - PubMed
1. De Simone M.S., et al., Different deficit patterns on word lists and short stories predict conversion to Alzheimer’s disease in patients with amnestic mild cognitive impairment. Journal of Neurology, 2017. 264: p. 2258–2267. - PubMed
1. Tremont G., et al., Comparison of verbal memory impairment rates in mild cognitive impairment. Journal of Clinical and Experimental Neuropsychology, 2010. 32(6): p. 630–636. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

This is a preprint.

Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research

Affiliations

Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources