Clinical Manifestations.

Abstract

Accelerated Long-term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer's disease pathology in older adults, and how memory selectivity may influence which material is forgotten. Participants in 'Insight 46', a sub-study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed cognitive and neuroimaging assessments at two time-points (baseline at age ∼70; follow-up ∼2.4 years later). At follow-up, we assessed Complex Figure Drawing (copy; immediate recall; 30-minute recall; 7-day recall). Complex Figure items were categorized as 'outline' or 'detail' (Fig1), to test the hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. ALF scores were calculated as the proportion of material retained after 7 days, relative to 30 minutes. Rates of cerebral atrophy between baseline and follow-up were quantified from T1-weighted MRI using the Brain Boundary Shift Integral (BBSI). β-amyloid status (positive/negative) was determined from 18F-Florbetapir-PET. Baseline serum neurofilament light (NfL) was quantified (Quanterix Simoa assay). Multivariable regression models were used to investigate the effects (mutually adjusted) of β-amyloid status, BBSI and NfL on ALF in n = 316 clinically-normal individuals (50% female; 22% β-amyloid positive; 30% APOE-ε4 carriers), and to explore interactions between these predictors, adjusting for potential confounders including prospectively-collected childhood cognitive ability and education. 'Outline' items were better retained than 'detail' (Fig1). β-amyloid-positive participants had poorer ALF scores for 'outline' (but not 'detail') items (Fig1C; Table 1). Unexpectedly, higher NfL was associated with scores for 'outline' items (Table 1). Greater rate of cerebral atrophy predicted poorer retention among participants with elevated β-amyloid and higher NfL (Table 1; Fig2). These results provide evidence of associations between biomarkers of brain pathologies and ALF in 73-year-olds. Interactions between different biomarkers merit further exploration. ALF may be a sensitive outcome measure for therapeutic trials in preclinical AD. Better retention of 'outline' (vs. 'detail') items illustrates the strategic role of memory selectivity.