Added value of neuropsychological norms derived from amyloid‐negative cognitively normal adults

• DOI: 10.1002/alz.091523
• Publication Date: 2025-01-03T14:28:27Z
• Authors: Sara Rubio‐Guerra; María Belén Sánch...; Isabel Sala; Alexandre Bejanin; Ainara Estanga; Mirian Ecay‐Torres; Carolina Lopez de...; Lorena Rami; Adrià Tort‐Merino; Magdalena Castellví; Ana Pozueta; María García‐Mart...; David Gómez‐Andrés; Carmen Lage; Sara López‐García; Pascual Sánchez‐Juan; Mircea Balasa; Albert Lladó; Miren Altuna; Mikel Tainta; Javier Arranz; Nuole Zhu; Daniel Alcolea; Alberto Lleo; Juan Fortea; Eloy Rodríguez Ro...; Raquel Sánchez‐Valle; Pablo Martínez‐Lage; Ignacio Illán‐Gala
• Keywords: Concordance; Clinical Dementia Rating

Abstract Background Neuropsychological performance guides diagnostic and therapeutic decision‐making on Alzheimer’s disease (AD) related disorders. Despite broad recognition that amyloid‐beta (Aβ) impacts cognition during preclinical AD, the added value of Aβ‐negative norms remains uncertain. Furthermore, normative modeling is constrained by limitations inherent to traditional methods. Here, we derived next‐generation (NGN) for a comprehensive neuropsychological battery compared their utility with (TN). Methods This multicenter study included 2405 non‐demented participants conventionally identified as cognitively normal (CN, n = 987) or mild cognitive impairment (MCI, 1418) ( Table 1 ). All had extensive data CSF AD biomarkers at baseline. Based 774 CN individuals, NGN using generalized additive models location, scale, shape (GAMLSS). First, accuracy TN discriminate Aβ‐positive from MCI participants. Next, actuarially reclassified all according both NGN, examined concordance these classifications biomarkers. For subset clinical follow‐up (n 1318), linear mixed‐effects was used capture longitudinal change in Clinical Dementia Rating Scale‐Sum Boxes. The Akaike Information Criteria (AIC) employed select best model. Results Age‐, education‐, sex‐adjusted percentiles were obtained 14 measures across main domains (memory, language, attention, executive functioning, visuospatial skills) 2 outperformed detecting prodromal verbal memory measures, but one differences reaching statistical significance (p<0.05). Most either (43%) (52%) based NGN. Among conflicting diagnoses (5%), MCI/CN group (3%) ‐individuals diagnosed considered per NGN‐ analogous CN/CN group, while CN/MCI (2%) paralleled MCI/MCI rates Aβ‐positivity Figure Cognitive status better predicted progression than (AIC 5195.5 vs 5206.1, respectively). Conclusion incorporating Aβ GAMLSS yield stronger associations TN. has direct implications practice research.