Non-demented PSEN1 E280A mutation carriers exhibited accelerated long-term forgetting despite intact short-term memory, alongside isolated reduction in parietal sleep spindle power, which was associated with both accelerated long-term forgetting and greater tau burden in the precuneus.
Study included 28 non-demented PSEN1 E280A mutation carriers and 24 healthy non-carriers from a Colombian autosomal-dominant Alzheimer's disease (ADAD) kindred.
ALF was assessed via long-term memory testing, distinguishing it from short-term memory performance.
Carriers showed memory performance deficits specifically at long-term retention intervals while short-term memory remained intact.
The findings indicate ALF is among the earliest cognitive changes in preclinical ADAD.
Results
Non-demented mutation carriers showed an isolated reduction in parietal sleep spindle (SS) power while other aspects of sleep remained intact.
Sleep physiology was assessed via overnight electroencephalography (EEG).
The reduction in sleep spindle power was specific to the parietal region.
Other sleep parameters were not significantly disrupted in carriers compared to non-carriers.
This selective disruption suggests a regionally specific neurophysiologic change in preclinical ADAD.
Results
Reduced parietal sleep spindle power was associated with accelerated long-term forgetting in non-demented mutation carriers.
The association between parietal SS power and ALF was identified in the context of preclinical ADAD.
This relationship suggests parietal sleep spindle disruption as a neurophysiologic mechanism underlying ALF.
The finding links a measurable sleep physiology marker to an early cognitive deficit in preclinical disease.
Results
Reduced parietal sleep spindle power was associated with greater tau burden in the precuneus.
AD neuropathology burden was assessed via positron emission tomography (PET).
The association was specifically localized to the precuneus, a region known to be affected early in AD.
This links tau accumulation in a specific brain region to disruption of parietal sleep spindles.
The precuneus tau–sleep spindle relationship provides a potential mechanistic pathway from neuropathology to sleep disruption to cognitive decline.
Discussion
The specific disruption of parietal sleep spindle power may be a key neurophysiologic mechanism linking early tau accumulation to accelerated long-term forgetting.
The paper proposes a chain of associations: tau accumulation in the precuneus → reduced parietal sleep spindle power → accelerated long-term forgetting.
This mechanistic framework was observed in non-demented individuals, indicating it operates in the preclinical stage.
Sleep spindles are known to play a role in memory consolidation, providing a biological basis for this proposed mechanism.
The findings suggest disrupted sleep-dependent memory consolidation as an early pathophysiologic process in ADAD.
Methods
The study population was drawn from a Colombian ADAD kindred carrying the PSEN1 E280A mutation, providing a well-defined genetic model of preclinical Alzheimer's disease.
28 non-demented PSEN1 E280A mutation carriers and 24 healthy non-carriers were included.
All participants were non-demented at the time of assessment.
The PSEN1 E280A Colombian kindred is one of the largest known ADAD families, allowing study of preclinical stages with genetic certainty.
Use of a genetic model allows comparison of carriers and non-carriers with known disease trajectories before clinical symptom onset.
What This Means
This research suggests that memory problems in Alzheimer's disease may begin much earlier than previously recognized, and that disrupted sleep may play a role in this early decline. The study examined people from a large Colombian family who carry a genetic mutation (PSEN1 E280A) that causes Alzheimer's disease, testing their memory, sleep brain activity, and brain protein accumulation using specialized brain scans. Even though the mutation carriers had not yet developed dementia and performed normally on short-term memory tests, they showed a specific pattern of forgetting information over longer periods of time — a phenomenon called accelerated long-term forgetting.
The study also found that these same mutation carriers had a very specific type of sleep disruption: reduced activity of 'sleep spindles' — brief bursts of brain activity during sleep that are important for locking memories into long-term storage — but only in the parietal region at the back of the brain. Importantly, this reduction in parietal sleep spindle activity was linked both to the memory forgetting problems and to greater buildup of tau protein (a hallmark of Alzheimer's disease) in a brain region called the precuneus. Other aspects of sleep appeared normal, making this a notably targeted finding.
This research suggests a possible chain of events in the very early stages of Alzheimer's disease: tau protein accumulates in the brain, which disrupts a specific type of sleep brain activity, which in turn impairs the brain's ability to consolidate memories over time. These findings point to sleep spindle activity as a potential early biomarker and mechanistic link between Alzheimer's-related brain changes and memory problems, and they highlight that accelerated long-term forgetting — distinct from the short-term memory loss typically associated with Alzheimer's — may be one of the very first signs of the disease.
You J, Bender A, Berezuk C, Noriega-Makarskyy D, Baena A, Munera D, et al.. (2026). Long-term forgetting, sleep, and tau in autosomal-dominant Alzheimer's disease.. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.71235