Accelerated Long-Term Forgetting in Preclinical Alzheimer's Disease: An Updated Systematic Review

Objectives: Accelerated Long-Term Forgetting (ALF) refers to the unusually rapid loss of newly learned information over extended delays (e.g., 24 hours, 1 week, or longer), despite intact short-term recall. It reflects early disruption of memory consolidation processes, which are undetectable by standard neuropsychological assessments. ALF has been reported in individuals with Subjective Cognitive Decline (SCD) or Alzheimer’s disease (AD) biomarkers. This review synthesizes current findings on ALF in the preclinical stage of AD and explores its potential as a tool for early detection. Materials: We systematically reviewed studies on ALF in neurological populations, focusing on preclinical AD. Eligible studies included cognitively unimpaired individuals with SCD or those classified as at risk for AD based on early pathological markers. These included cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers (e.g., Aβ42, tau), Apolipoprotein E (APOE) ε4 status, hippocampal atrophy, altered functional connectivity, family history, or early metabolic changes. Method: This review followed a PICO-based protocol and was updated on February 16, 2025. Searches were conducted in PubMed, Scopus, and PsycINFO using a predefined search string. Inclusion criteria were neurological samples, ≥30-minute memory delay, presence of a control group, and quantitative memory outcomes. Exclusion criteria were animal studies, case reports, small samples, and non-English publications. Of approximately 700 records, 111 underwent full-text screening; 81 were included, of which 11 focused on ALF in individuals at risk for AD. Results: ALF was identified across all 11 studies in individuals with SCD or AD–related markers. Long-delay recall tasks exceeding 24 hours—particularly 7- and 14-day intervals—were the most sensitive, with 9 studies reporting significantly lower retention in at-risk groups than controls. Immediate recall was typically preserved. Protocols included free and cued recall. Five studies linked ALF to medial temporal lobe atrophy, posterior cingulate changes, or reduced functional connectivity. Two studies reported associations with abnormal CSF profiles, further supporting ALF as a marker of early cognitive vulnerability. Discussion: Current evidence suggests that ALF reflects early AD–related neural dysfunction that precedes measurable decline on standard cognitive assessments. Long-delay memory tasks appear particularly sensitive to such subtle impairments. Standardized testing protocols and normative benchmarks are needed to enhance comparability across studies and support clinical implementation. Conclusions: ALF represents a promising early cognitive marker in preclinical AD. When combined with biomarkers and genetic risk profiles, it may improve early diagnosis, support patient stratification, and inform preventive strategies. Its systematic inclusion in clinical research could facilitate early detection and enhance trial enrollment.