Abstract

BackgroundHere, we address a pivotal factor in Alzheimer’s prevention—identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer’s disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer’s disease. We also expected hippocampal subfield volumes to improve predictive accuracy.MethodsForty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke’s Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months.ResultsFifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R2 = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001).ConclusionsWe show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer’s-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

Highlights

  • IntroductionAnother study showed that a delay of 6 weeks on story and complex figure recall tasks could identify significant impairment in a group of people who report ‘subjective’ memory impairment but who have no objective memory deficit on standard cognitive tests including delayed recall after 30 min [5]

  • We address a pivotal factor in Alzheimer’s prevention—identifying those at risk early, when dementia can still be avoided

  • Scores at either time point of the story (30m: R2 = .006, p = .629; 4w R2 = .027, p = .289) and complex figure tasks (30m: R2 = .0003, p = .912; 4w: R2 = .045, p = .171) could not predict ΔACE-III. In this healthy cohort, neither whole hippocampal volume nor volume of any single hippocampal subfield or medial temporal lobe (MTL) cortical region was correlated with change in performance over the year (Table 1)

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Summary

Introduction

Another study showed that a delay of 6 weeks on story and complex figure recall tasks could identify significant impairment in a group of people who report ‘subjective’ memory impairment but who have no objective memory deficit on standard cognitive tests including delayed recall after 30 min [5]. This highlights that people with ‘subjective’ memory impairment may, in some cases, have impairment for which standard tests lack sufficient sensitivity. 1-week verbal memory is impaired in otherwise asymptomatic APOE ε4 homozygotes compared to people with one or no ε4 alleles [7]

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