Accelerated long-term forgetting and relevant biomarkers for early detection in preclinical Alzheimer's disease

Alzheimer's disease (AD) commences with the preclinical stage where individuals remain cognitively unimpaired but already have AD pathology. As fluid and neuroimaging biomarker research progresses, AD has become defined biologically rather than based on traditional clinical symptoms. While the diagnosis of AD has been conceptually advanced by the AT(N) classification framework according to core biomarker profiles of amyloid-β (A), tau (T) and neurodegeneration (N), solely relying on biological diagnosis at an asymptomatic stage has limitations with potential ethical and psychosocial issues. Accelerated long-term forgetting (ALF) characterized by higher forgetting rates over longer delays (a week to months) captures substantial interest as one of the sensitive mnemonic measures. Remarkably, ALF assays have been increasingly applied to detecting subtle cognitive declines in preclinical AD individuals who are still normal on standard memory tests, which typically use ∼ 30 min delays to assess classical hippocampal amnesia. The findings suggest that ALF may reflect the impairment of systems memory consolidation, a process that is required to gradually transform memory traces temporarily stored in the hippocampus into cortical networks for long-term storage. This review provides an overview of recent progress in ALF research including the underlying mechanisms and fluid-based or brain imaging biomarkers, which have been explored not only in individuals at risk for developing AD but also in relevant animal models. The findings have important implications for how we can optimize the earlier and precise identification of patients at a preclinical stage of AD that is essential for designing effective preventive interventions.