Abstract
Brain Commun. 2026 May 6;8(3):fcag163. doi: 10.1093/braincomms/fcag163. eCollection 2026.
ABSTRACT
A pivotal debate in Alzheimer's disease (AD) revolves around the clinical utility of a purely biomarker-based diagnostic framework, making it imperative to identify early functional signs that are both clinically meaningful and sensitive to biological biomarkers in the preclinical stages. While the development of the Preclinical Alzheimer's Cognitive Composite (PACC) addresses this need, its lack of language-specific markers might limit its sensitivity, given that language deficits are among the earliest manifestations of AD. To address this limitation, we developed PACC variants incorporating proper names delayed recall, a novel lexical-semantic marker robustly linked to PET and CSF biomarkers. We analysed 824 dementia-free participants (mean age ≈ 62 at baseline) from the Wisconsin Registry for Alzheimer's Prevention, stratifying them by plasma phosphorylated tau 217 (p-tau217) levels (using established amyloid PET positivity cut-offs: negative [<0.40 pg/mL; N = 539], intermediate [0.40-0.63 pg/mL; N = 163], positive [>0.63 pg/mL; N = 122]). We constructed six PACC variants: (1) traditional PACC4 (Rey Auditory Verbal Learning Test immediate learning, Logical Memory II [LM II; delayed recall], Digit Symbol, Mini-Mental State Examination [MMSE]); (2) PACC3 (excluding MMSE to mitigate ceiling effects); (3-4) PACC4_PN and PACC3_PN, replacing LM II's total score with proper-name recall; and (5-6) PACC4 + VF and PACC3 + VF, adding animal fluency. Cognitive composites were calculated as the equally weighted sum of component z-scores. We compared PACC variants'sensitivity (i.e. longitudinal decline rates) associated with plasma p-tau217, using linear mixed models adjusted for age, gender, literacy and practice (total visits minus one). We showed individuals with positive plasma p-tau217 status exhibited significantly faster cognitive decline across all PACCs. Notably, the proper name enhanced-PACC, especially the parsimonious PACC3_PN, demonstrated the steepest decline-6.4-19% faster than the traditional and animal fluency-appended versions. Our optimized measure offers critical advantages in clinical utility: an 82% reduction in scoring burden for clinicians (9-point proper names versus 50-point total LM score), finer semantic memory granularity within an episodic memory task and enhanced sensitivity to AD biomarkers. Our findings position proper name-enhanced PACC as a clinically practical tool for tracking longitudinal cognitive trajectories, highlighting proper names delayed recall as a sensitive marker due to AD-type brain changes. Future work will validate its utility for trial enrichment and clinical screening.
PMID:42183044 | PMC:PMC13195032 | DOI:10.1093/braincomms/fcag163
UK DRI Authors
