Accelerated long-term forgetting as a predictor of clinical onset in presymptomatic autosomal dominant Alzheimer's disease.

Background: In Alzheimer's disease (AD), sensitive measures of cognitive decline prior to overt symptoms are urgently needed. Accelerated long-term forgetting (ALF), where new information is retained normally over conventional testing intervals but is then lost at an accelerated rate over the following days and weeks, has been identified cross-sectionally in presymptomatic autosomal dominant and sporadic AD cohorts. We aimed to assess whether ALF testing is predictive of proximity to future symptom onset.

Methods: 20 asymptomatic autosomal dominant AD mutation carriers who performed normally on standard cognitive testing underwent ALF assessment with (1) a list, (2) a story and (3) a visual figure, with the testing of 30-min recall and 7-day recall. Participants were followed up annually for a median of 7 years and assessed each time with the Clinical Dementia Rating (CDR) scale.

Results: 9/20 participants developed symptoms (CDR global>0) during follow-up. Those who became symptomatic had lower baseline ALF scores for both the list (progressors=30 (IQR, 30-36.4) and non-progressors=58.3 (IQR, 33-66.7), p=0.03) and story (progressors=58.8 (IQR, 44-66) and non-progressors=81.2 (IQR, 69.1-87.8), p<0.001). Story ALF (area under curve (AUC)=0.82) and list ALF (AUC=0.73) discriminated between those who did and did not develop symptoms.

Conclusions: Severity of ALF is not only associated with the presence of AD pathology but also predictive of clinical onset, identifying those at the highest risk of imminent decline. ALF testing offers promise in aiding presymptomatic trial recruitment, as a presymptomatic cognitive endpoint and potentially as a screening tool in the wider population.