Episodic memory (EM) decline is a hallmark of Alzheimer’s disease (AD) and one of the first cognitive symptoms to accelerate at a preclinical stage. Official diagnosis tools (i.e., Free and Cued Selective Reminding Test [FCSRT]) can detect AD-linked EM deficits at this stage. However, meaningful AD-therapies that can delay clinical symptomology are more effective at the earliest stages of disease progression. New alternative tools (i.e., Memory Binding Test [MBT]) are suggested as capable of anticipating diagnosis to an at-risk stage of AD based on a higher sensitivity to very subtle EM deficits. Our aim was to assess the efficacy of the MBT vs. the FCSRT in detecting the emergent AD-linked EM impairment in individuals at-risk to AD associated with: 1) amyloid-β burden (Aβ+) or neurodegeneration (N); 2) progression to prodromal-AD (defined as an amnestic syndrome of the hippocampal type).

Data of 265 cognitively functional individuals at-risk for AD (≥6months of subjective memory complaints) from the INSIGHTpreAD cohort were collected yearly during a 5-year follow-up period. To assess Aβ burden and neurodegeneration effect we considered 3 groups of non-progressors to prodromal AD: 177 controls/Aβ-/N-; 57 stable/Aβ+/N-; 16 stable/Aβ+/N+. To assess Aβ+ effect we contrasted the first 2 groups, to assess N effect we contrasted the last 2 groups. During follow-up, 15 individuals progressed to prodromal-AD but were considered in the study only until their diagnosis. Therefore, we assessed progression to prodromal-AD differences by considering 2 groups of Aβ+ individuals: 73 Aβ+/stable vs. 15 Aβ+/progressors (preclinical-AD). We assessed FCSRT and MBT data with mixed effect models including age, gender, and education as covariates. In both tests free recall (FR) and total (cued) recall (TR) are the most relevant scores for EM evaluation. However, while the FCSRT uses 1-list of words to remember, the MBT uses 2-lists, adding a biding component more sensitive to very subtle EM alterations.

In both tests the Aβ+/progressors group scored significantly lower longitudinally than the Aβ+/stable group on FR and TR-linked scores. However, decline in AD-specific scores (TR and binding) was detected by the MBT 1-year prior to the FCSRT and until 5-years prior to prodromal diagnosis. In the MBT the stable/Aβ-/N- group scored significantly higher than the stable/Aβ+/N- in the total number and extra list of intrusions -Aβ+ effect-. The stable/Aβ+/N+ scored higher than the stable/Aβ+/N- in the total number of intrusions but scored lower in source memory at session M48 -N+ effect-.

At an at-risk stage, the MBT surpassed the FCRST in the year of detection and in the number of scores detecting AD-specific EM-impairment. The MBT seems a promising complementary tool of AD-diagnosis to the FCSRT, for its capacity to detect emerging subtle EM deficits at an-at-risk stage. Currently this appears to be the optimal time-window to apply meaningful therapies that can at best delay cognitive decline, in a disease that still has no cure.