Associations between accelerated forgetting, amyloid deposition and brain atrophy in older adults
Authors: Lu Kirsty , Baker John , Nicholas Jennifer M , Street Rebecca E , Keuss Sarah E , Coath William , James Sarah-Naomi , Keshavan Ashvini , Weston Philip S J , Murray-Smith Heidi , Cash David M , Malone Ian B , Wong Andrew , Fox Nick C , Richards Marcus , Crutch Sebastian J , Schott Jonathan M 
Published: October 2024

Abstract
Accelerated long-term forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (e.g. minutes) but forgotten abnormally rapidly over longer periods (days or weeks). ALF might be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer’s disease pathology and how memory selectivity might influence which material is forgotten.
We assessed ALF in ‘Insight 46’, a sub-study of the MRC National Survey of Health and Development (a population-based cohort born during the same week in 1946) (n = 429; 47% female; assessed at age ∼73 years). ALF assessment comprised visual and verbal memory tests: complex figure drawing and the face–name associative memory exam (FNAME). ALF scores were calculated as the percentage of material retained after 7 days, relative to 30 min. In 306 cognitively normal participants, we investigated effects on ALF of β-amyloid pathology (quantified using 18F-Florbetapir-PET, classified as positive/negative) and whole-brain and hippocampal atrophy rate (quantified from serial T1-MRI over ∼2.4 years preceding the ALF assessment), in addition to interactions between these pathologies. We categorized complex figure drawing items as ‘outline’ or ‘detail’, to test our hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. We also investigated associations between ALF and subjective cognitive decline, measured with the MyCog questionnaire.
Complex figure ‘outline’ items were better retained than ‘detail’ items (mean retention over 7 days = 94% versus 72%). Amyloid-positive participants showed greater forgetting of the complex figure outline compared with amyloid-negative participants (90% versus 95%; P &lt; 0.01). There were interactions between amyloid pathology and cerebral atrophy, such that whole-brain and hippocampal atrophy predicted greater ALF on complex figure drawing among amyloid-positive participants only [e.g. 1.9 percentage-points lower retention per ml/year of whole-brain atrophy (95% confidence intervals 0.5, 3.7); P &lt; 0.05]. Greater ALF on FNAME was associated with increased rate of hippocampal atrophy. ALF on complex figure drawing was also correlated with subjective cognitive decline [−0.45 percentage-points per MyCog point (−0.85, −0.05); P &lt; 0.05].
These results provide evidence of associations between some measures of ALF and biomarkers of brain pathologies and subjective cognitive decline in cognitively normal older adults. On complex figure drawing, ‘outline’ items were better remembered than ‘detail’ items, illustrating the strategic role of memory selectivity, but ‘outline’ items were also relatively more vulnerable to ALF in individuals with amyloid pathology. Overall, our findings suggest that ALF might be a sensitive marker of cognitive changes in preclinical Alzheimer’s disease.