Long-term forgetting in preclinical Alzheimer's disease
Authors: Eric M Reiman
Journal: The Lancet Neurology (2018)

Alzheimer's disease is characterised by progressive pathophysiological changes that correspond roughly to preclinical (ie, cognitively unimpaired), mild cognitive impairment, and dementia stages.1Sperling RA Aisen PS Beckett LA et al.Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.Alzheimers Dement. 2011; 7: 280-292Summary Full Text Full Text PDF PubMed Scopus (4644) Google Scholar Biomarkers continue to be developed, tested, and used to detect and track the pathophysiological manifestations of this disease. Although neuropsychological tests, clinical ratings, and composite cognitive test scores have shown initial promise,2Caselli RJ Dueck AC Osborne D et al.Longitudinal modeling of age-related memory decline and the APOE ɛ4 effect.N Engl J Med. 2009; 361: 255-263Crossref PubMed Scopus (394) Google Scholar, 3Langbaum JB Hendrix S Ayutyanont N et al.An empirically derived composite test score with improved power to track and evaluate treatments for preclinical Alzheimer's disease.Alzheimers Dement. 2014; 10: 666-674Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 4Fleisher AS Chen K Quiroz YT et al.Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study.JAMA Neurol. 2015; 71: 316-324Crossref Scopus (121) Google Scholar, 5Donohue MC Sperling RA Petersen R et al.Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons.JAMA. 2017; 317: 2305-2316Crossref PubMed Scopus (222) Google Scholar the field would benefit from additional ways to detect and track cognitive, behavioural, and functional manifestations of Alzheimer's disease with optimal power, ease, and availability, particularly in the preclinical and early clinical stages. In this issue of The Lancet Neurology, Philip Weston and colleagues6Weston PSJ Nicholas JM Henley SMD et al.Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study.Lancet Neurol. 2018; 17: 123-132Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar show the promise of a baseline and 7-day follow-up assessment strategy to measure accelerated long-term forgetting in presymptomatic Alzheimer's disease. 35 cognitively unimpaired autosomal dominant Alzheimer's disease mutation carriers and non-carriers were studied on average 7 years before their affected parents' age at symptom onset. Standard 15-item word list, short story, and complex figure learning and recall memory tests were done during an initial in-person assessment. Recall and recognition memory tests were done during a 7-day follow-up telephone call. Although the groups did not differ in their learning or 30-min recall memory scores, carriers did less well in measures of recall and recognition memory 7 days later. 7-day forgetting was associated with subjective memory concerns and proximity to age at symptom onset in the carriers. On the basis of these findings, the authors suggest that accelerated long-term forgetting might provide a more sensitive indicator of cognitive decline than do standard learning or 30-min memory tests in presymptomatic Alzheimer's disease; they suggest that accelerated long-term forgetting reflects an early decline in mediated memory consolidation and associated Alzheimer's disease pathology in the hippocampus, contributes to some of the earliest subjective memory concerns in at-risk persons, and has the potential to help evaluate preclinical treatments.6Weston PSJ Nicholas JM Henley SMD et al.Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study.Lancet Neurol. 2018; 17: 123-132Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar Additional research is needed, not only to confirm the study findings in the presymptomatic stages of autosomal dominant early-onset Alzheimer's disease, but also to show generalisability to the preclinical stages of late-onset disease and to consider how these results might be affected by ageing and other age-related disorders. Additional studies are also needed to clarify the extent to which accelerated long-term forgetting is related to biomarker measurements of amyloid burden, tau, and neurodegenerative pathology, other preclinical cognitive changes, and subsequent clinical progression. Refinements in the long-term forgetting framework might be needed to extend the findings of this study to later Alzheimer's disease stages, account for any initial learning and memory declines, minimise potentially confounding rehearsal and learning effects associated with longitudinal assessments, and provide an indicator of progressive cognitive decline that could be used as an endpoint in preclinical trials. Refinements to the framework might also be needed to minimise participant burden in longitudinal studies and preclinical Alzheimer's disease trials and support the study of long-term forgetting in observational studies and therapeutic trials. Interest in use of mobile and other digital technologies to detect and track cognitive, behavioural, and functional changes with greater ease, real-world value, and statistical power is growing, and there could be a chance to leverage these technologies in assessment of long-term forgetting.7Harvey PD Cosentino S Curiel R et al.Performance-based and observational assessments in clinical trials across the Alzheimer's disease spectrum.Innov Clin Neurosci. 2017; 14: 30-39PubMed Google Scholar This elegant study illustrates the opportunity now at hand to develop, test, and use new methods to detect and track the earliest cognitive changes associated with Alzheimer's disease, monitor a person's risk, and help evaluate promising prevention therapies. I declare no competing interests. Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional studyAccelerated long-term forgetting is an early presymptomatic feature of autosomal dominant Alzheimer's disease, which appears to pre-date other amnestic deficits and might underpin subjective memory complaints in Alzheimer's disease. Accelerated long-term forgetting testing might be useful in presymptomatic Alzheimer's disease trials. Full-Text PDF Open Access