Long-term forgetting, sleep, and tau in autosomal-dominant Alzheimer's disease.

INTRODUCTION: Accelerated long-term forgetting (ALF) may represent one of the earliest cognitive changes in Alzheimer's disease (AD). However, whether ALF emerges in the preclinical stage of autosomal-dominant AD (ADAD) is unclear, and its underlying mechanisms are poorly understood. METHODS: We assessed ALF via long-term memory testing, sleep physiology via overnight electroencephalography, and AD neuropathology burden via positron emission tomography in 28 non-demented PSEN1 E280A mutation carriers and 24 healthy non-carriers from a Colombian ADAD kindred. RESULTS: Non-demented carriers exhibited ALF despite having intact short-term memory. They also demonstrated isolated reduction in parietal sleep spindle (SS) power, whereas other aspects of sleep remained intact. Reduced parietal SS power was associated with both ALF and greater tau burden in the precuneus. DISCUSSION: ALF is among the earliest cognitive changes in preclinical ADAD, and the specific disruption of parietal SS power may be a key neurophysiologic mechanism linking early tau accumulation to ALF.