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Multicenter Study
. 2025 Jun;21(6):e70307.
doi: 10.1002/alz.70307.

Discrepancies in assessing intellectual disability levels in adults with Down syndrome: Implications for dementia diagnosis

Laura Del Hoyo Soriano  1   2 , Katja Sandkühler  3 , Laura Videla  1   2   4 , Bessy Benejam  1   2   4 , Maria Carmona-Iragui  1   2   4 , Elisabeth Wlasich  3 , Julia Kustermann  3 , Isabel Barroeta  1   2 , Lídia Vaqué-Alcázar  1   5   6 , Íñigo Rodríguez-Baz  1   2 , Alexandre Bejanin  1   2 , Susana Fernández  4 , Javier Arranz  1   2 , Jose Enrique Arriola-Infante  1   2 , Lucia Maure-Blesa  1   2 , Aida San Juan  1 , Georg Nübling  3   7 , Olivia Wagemann  3   7 , Anna Stockbauer  3   7 , Jason Hassenstab  8 , Johannes Levin  3   8   9 , Juan Fortea  1   3   4
Affiliations
Multicenter Study

Discrepancies in assessing intellectual disability levels in adults with Down syndrome: Implications for dementia diagnosis

Laura Del Hoyo Soriano et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: Cut-offs derived from baseline cognitive assessments, stratified by intellectual disability (ID) level, have been proposed to diagnose symptomatic Alzheimer's disease (AD) in Down syndrome (DS). However, discrepancies in ID classification risk misclassification when applying cut-offs across sites.

Methods: This dual-center cohort study included 673 adults with mild to moderate ID at different AD stages. We assessed ID classification discrepancies across sites and the impact on Cambridge Cognitive Examination for Older Adults with Down's Syndrome (CAMCOG-DS) cut-offs for AD dementia diagnosis derived from receiver operating characteristic analysis.

Results: Inter-rater agreement for ID level classification was 95% within sites but 60% between sites. While CAMCOG-DS score distributions in the whole cohort were similar across sites, ID classification discrepancies caused higher cut-offs in Barcelona for mild and moderate ID compared to Munich. Applying site-specific cut-offs to another cohort reduced sensitivity and specificity.

Discussion: Standardizing ID classification is critical for generalizable cut-offs to accurately diagnose AD dementia based on neuropsychological assessments in DS.

Highlights: CAMCOG-DS cut-offs by intellectual disability level classify dementia in Down syndrome. ID classification discrepancies between sites impact CAMCOG-DS diagnostic cut-offs. Applying site-specific cut-offs to other cohorts reduces sensitivity and specificity. Standardized ID classification is essential for generalizable cognitive cut-offs. Use site-specific cut-offs until ID classification is standardized.

Keywords: AD21; Alzheimer's disease; Cambridge Cognitive Examination for Older Adults with Down Syndrome; Down Alzheimer Barcelona Neuroimaging Initiative; Down syndrome; Down syndrome–associated Alzheimer's disease; cut‐off points; dementia; diagnostic performance; intellectual disability.

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Conflict of interest statement

J.F. has received personal fees for service on advisory boards, adjudication committees, or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, and Roche, outside the submitted work. J.F. also holds a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Esteve, Merck, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme Medical Publishers and W. Kohlhammer GmbH medical publishers; and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4‐Repeat Tauopathies” (PCT/EP2024/053388) filed by LMU Munich. In addition, J.L. reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH, and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. The other authors report no relevant disclosures. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
A, Density plot of the CAMCOG‐DS total scores for the total asymptomatic (aDS) sample (not matched) in both sites (N = 420 Barcelona, N = 78 Munich) and density plots split by ID level with density curves for (B) Barcelona and (C) Munich. Dashed lines represent the means. D, Density plot of the CAMCOG‐DS for the aDS samples matched on CAMCOG‐DS scores (N = 77 Barcelona, N = 77 Munich) and density plots split by ID level with density curves for (E) Barcelona and (F) Munich. aDS, asymptomatic Down syndrome; CAMCOG‐DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; ID, intellectual disability.
FIGURE 2
FIGURE 2
A, Histogram of the CAMCOG‐DS total scores only for individuals with a dementia diagnosis (dDS) at first visit for both sites (N = 84 Barcelona, N = 26 Munich) and split by ID level for (B) Barcelona and (C) Munich. Dashed lines represent the means. CAMCOG‐DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; dDS, dementia stage Down syndrome; ID, intellectual disability.
FIGURE 3
FIGURE 3
CAMCOG‐DS total scores by ID level and AD dDiagnosis across sites. Boxplots illustrate the CAMCOG‐DS performance by ID level (mild and moderate) and AD diagnosis (asymptomatic, prodromal AD, AD dementia) for Barcelona and Munich. The figure shows that ID level exerts a stronger influence on CAMCOG‐DS scores than AD diagnosis, with a clear decline in scores from mild to moderate ID regardless of AD status. This highlights the significant role of ID classification in interpreting cognitive decline at a cross‐sectional level. AD, Alzheimer's disease; CAMCOG‐DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; ID, intellectual disability.
FIGURE 4
FIGURE 4
ROC CAMCOG‐DS diagnostic performance. ROC curves illustrating the CAMCOG‐DS diagnostic performance for AD dementia in individuals with mild and moderate ID across sites (Munich and Barcelona). The AUC values, ranging from 0.89 to 0.95, indicate high diagnostic accuracy, with confidence intervals provided for each threshold. Barcelona's data show higher CAMCOG‐DS cut‐off points for mild and moderate ID compared to Munich's cohort. AD, Alzheimer's disease; AUC, area under the curve; CAMCOG‐DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; ID, intellectual disability; ROC, receiver operating characteristic.
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