Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer's disease

Abstract

Objectives: Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD.

Methods: A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ-/ND-), Stage 1 (Aβ+/ND-), Stage 2 (Aβ+/ND+), and suspected non-Alzheimer's associated pathology (SNAP; Aβ-/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT).

Results: Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed.

Conclusions: Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design.

Keywords: Biomarker stages; Free and cued memory; Preclinical Alzheimer’s disease.

Figure 1

The Memory Capacity Test. In List Learning 1, subjects view 4 words per page. The examiner provides a semantic cue (e.g., which item is a country?) for each item and the subject selects the correct corresponding word (e.g. Spain). This is repeated for 3 more cards, for a total of 16 words comprising List1. This procedure is repeated for a 2^nd list of 16 new words but with equivalent semantic categories (List Learning 2). A semantic cue is provided and subjects are asked to produce both words from List 1 and 2 (Immediate Cued Recall). This is followed by Immediate Free Recall in which the subject produces items from both lists without a cue. The recall portion is repeated following a 30-minute delay with Delayed Free Recall (/32) followed by Delayed Cued Recall (/32).

Figure 2

Performance on Cognitive Composites by Preclinical AD Biomarker Stage. Estimated marginal means (z-scores) and standard errors by Stage controlled for age, sex, and education. *Brackets show the significant group differences (p< 0.05) between Stage 0 and Stage 2 on memory performance.

Figure 3

Memory Performance on Individual Tests (MCT, SRT) with Free and Cued Paradigms by Biomarker Stage. Estimated marginal means (z-scores) and standard errors (controlling for age, sex, and education) for MCT Delayed Recall (top) and SRT Delayed Recall by biomarker stage. *Brackets represent significant (p< 0.05) pairwise comparisons.