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Background: The asymptomatic at-risk phase might be the optimal time-window to establish clinically meaningful endpoints in Alzheimer's disease (AD). Objective: We investigated whether, compared with the Free and Cued Selective Reminding Test (FCSRT), the Memory Binding Test (MBT) can anticipate the diagnosis of emergent subtle episodic memory (EM) deficits to an at-risk phase. Methods: Five-year longitudinal FCSRT and MBT scores from 45 individuals matched for age, education, and gender, were divided into 3 groups of 15 subjects: Aβ-/controls, Aβ+/stable, and Aβ+/progressors (preclinical-AD). The MBT adds an associative memory component (binding), particularly sensitive to subtle EM decline. Results: In the MBT, EM decline started in the Aβ+/progressors (preclinical-AD) up to 4 years prior to diagnosis in delayed free recall (FR), followed by decline in binding-associated scores 1 year later. Conversely, in the FCSRT, EM-decline began later, up to 3 years prior to diagnosis, in the same group on both immediate and delayed versions of FR, while on total recall (TR) and intrusions decline started only 1 year prior to diagnosis. Conclusions: The MBT seems more sensitive than the FCSRT for early EM-decline detection, regarding the year of diagnosis and the number of scores showing AD-linked EM deficits (associated with the AD-characteristic amnesic hippocampal syndrome). Considering the MBT as a detection tool of early subtle EM-decline in an asymptomatic at-risk phase, and the FCSRT as a classification tool of stages of EM-decline from a preclinical phase, these tests ought to potentially become complementary diagnostic tools that can foster therapies to delay cognitive decline. Clinical trial registration title: Electrophysiological markers of the progression to clinical Alzheimer disease in asymptomatic at-risk individuals: a longitudinal event-related potential study of episodic memory in the INSIGHT pre-AD cohort (acronym: ePARAD). [ABSTRACT FROM AUTHOR]

Introduction: Anticipating the diagnosis of Alzheimer's disease (AD) at an early asymptomatic at-risk stage, where therapeutics can more effectively delay conscious cognitive decline, is currently among the biggest challenges in the field. Herein, we aimed to compare the capacity of the Memory Binding Test (MBT) with the official diagnostic tool, the Free and Cued Selective Reminding Test (FCSRT), to anticipate AD diagnosis at an early preclinical stage based on the associative memory component of MBT (binding), suggested as more sensitive to the emergence of subtle episodic memory (EM) deficits (AD hallmark)., Methods: We assessed the tests performance longitudinally (over 5 years) in 263 cognitively-normal elderly individuals at risk of AD (>6 months of subjective memory complaints) using linear mixed-effect models controlled for age, sex, and education. We stratified participants in 2 models: amyloid-β (Aβ)/neurodegeneration (N) model, assessing Aβ burden and neurodegeneration effect [3 groups: controls (Aβ-/N-); stable/N- (Aβ+); stable/N+ (Aβ+)]; and the stable/progressors model, assessing progression to prodromal-AD effect [2 groups: stable (Aβ+); progressors (Aβ+)], based on 15 subjects who progressed to AD during follow-up (excluded once diagnosed)., Results: Aβ burden was associated with significantly less MBT-intrusions, while Aβ burden and neurodegeneration together, with the most. Progression status had a strong negative effect on both tests performance. When compared with the FCSRT, the MBT seems to anticipate diagnosis based on a worst performance in a higher number of scores (including binding) in at least a year., Discussion: Anticipation of diagnosis to an asymptomatic at-risk stage, while participants remain cognitively-normal according to FCSRT cut-offs and unaware of objective EM deficits, has the potential to delay the onset of AD-linked cognitive decline by applying promising therapeutics before decline becomes too advanced., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Raposo Pereira, George, Dalla Barba, Dubois and La Corte.)