Abstract
Lisgaras CP, Giménez S, Carmona-Iragui M, Maure-Blesa L, Blessing E, Fortea J, Osorio RS. Alzheimers Dement. 2025;21(7):e70386. https://doi.org/10.1002/alz.70386 Introduction: Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. Methods: Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10–20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. Results: Fourteen individuals with DS and five age-matched euploid controls were studied, with all DS cases showing HFOs. HFOs emerged before AD dementia and LOMEDS and showed hemispheric lateralization in asymptomatic but not symptomatic AD dementia cases. A trend toward increasing HFO rates with age in DS warrants further confirmation. Discussion: HFOs are promising biomarkers that may predict symptomatic AD dementia in adults with DS.
Commentary
In Alzheimer's disease (AD), there is an elevated incidence of epileptiform activity, 1 which is associated with faster cognitive decline. 2 In addition, individuals with epilepsy are at a higher risk of developing AD. 3 Given the reciprocal link between AD and epilepsy, addressing hyperexcitability and epileptiform activity in patients could constitute a compelling therapeutic avenue for modifying disease progression. Notably, therapeutic efforts to delay the onset of AD or slow down cognitive decline need to be initiated early in disease progression for best efficacy. Early intervention is needed because by the time that mild cognitive impairment (MCI) or AD are clinically diagnosed, the brain has already accumulated decades worth of pathological alterations. Unfortunately, early biomarkers of AD with predictive value have proven elusive, which complicates the study of the earliest changes associated with AD and of the effects of preventive treatments before overt clinical symptoms appear.
Outside of AD caused by familial autosomal dominant mutations (<5% of all AD cases), the risk of developing sporadic AD and the rate of disease progression are influenced by many factors, including age, sex, the presence of risk or protective gene variants, environmental exposures, and lifestyle, among others. While the presence of one or more risk factors stacks the odds, developing AD or not is still not definite. However, there is one demographic that is so prone to developing AD that given enough time, it is almost certain to appear: individuals with Down syndrome (DS). A large proportion of individuals with DS develop epileptiform abnormalities, and most eventually show clinical signs of AD. 4 Histological features of AD-related neuropathology emerge at a young age, likely driven by overproduction of the amyloid precursor protein (APP) as a consequence of an extra copy of the APP gene that resides on chromosome 21, 5 which is triplicated in DS. In this sense, the DS demographic could offer a unique glimpse into the pathophysiology of early-stage AD, well before robust symptoms appear and a diagnosis becomes possible.
High-frequency oscillations (HFOs) in the fast ripple frequency range (>250 Hz), typically associated with epileptogenic tissue, 6 have emerged as electroencephalographic (EEG) biomarkers of hyperexcitability. Interest in HFOs in the fields of epilepsy care and research has grown over the past two decades, in part due to their potential as markers of epileptogenic tissue and predictors of its successful resection, as well as of epilepsy severity and treatment outcomes. 6 Evidence of HFOs in AD began to emerge more recently. In 2023, Lisgaras and Scharfman reported that HFOs similar in duration and spectral properties to the ones found in mouse models of epilepsy could be detected in mouse models of AD and DS. 7 The presence of HFOs in the context of human AD was later documented in patients in a 2025 study by Shandilya et al. 8 Lisgaras et al now show that HFOs appear to be ubiquitous in individuals with DS, whether they are asymptomatic or symptomatic with an MCI or AD diagnosis, and regardless of the presence or absence of epileptiform activity. 9
In this study, Lisgaras et al investigated HFOs on polysomnographic video-EEG recordings from individuals with DS from the Down-Alzheimer Barcelona Neuroimaging Initiative and from matching, cognitively normal euploid subjects selected from the Sant Pau Initiative on Degeneration. Subjects with DS were stratified in three groups: asymptomatic individuals with no cognitive signs of AD, individuals with MCI who did not meet the criteria for a dementia diagnosis, and individuals with AD dementia.9,10 The presence of HFOs in all individuals with DS—and none of the euploid controls—stands out among the findings. However, far from being generalized phenomena spanning the entire cortex, HFOs were detected only in a fraction of EEG channels per subject. HFO rate and the number of channels where they could be detected did not differ according to dementia diagnosis. Notably, the spatial distribution of HFOs in asymptomatic individuals with DS and in symptomatic individuals with MCI or AD differed. In all of the asymptomatic individuals, HFOs were lateralized, preferentially appearing in channels from the right hemisphere, whereas symptomatic individuals tended to show lower asymmetry, suggesting that some aspects of HFOs might change through disease progression. Age may also play a role in the loss of strict lateralization, given that the asymptomatic individuals were younger than symptomatic individuals.
Remarkably, although none of the subjects had a history of epilepsy when the EEG recordings were acquired, epileptiform activity was detected in over half of the participants with DS. Individuals with and without detectable epileptiform activity were found to have similar rates of HFOs, which were also present in a similar proportion of EEG channels. This finding mirrors the recent discovery of HFOs over 250 Hz both in epileptic and in non-epileptic AD patients. 8 The presence of these HFOs in both cohorts supports the authors’ interpretation that they might not be just a widespread feature in DS, but a hallmark of the earliest stages of AD progression. Further research may be necessary to confirm this relationship.
A strength of this work lies in its analysis of more intricate measures beyond the presence/absence and rate of occurrence of HFOs. An example of this is the exploration of interhemispheric and frontotemporal asymmetry in the distribution of HFOs, which brings forth the possibility that the spatial distribution of HFOs could hold predictive value. In this sense, analyzing the characteristics of HFOs across the sleep–wake states could provide new perspectives. Previous research showed that HFOs can be detected in awake AD patients. 8 Lisgaras et al now provide evidence of their presence—and abundance, occurring at a rate of several per minute—during NREM sleep in individuals with DS. 9 This abundance could point towards NREM sleep as the ideal sleep–wake state for the quantification of HFOs in clinical settings, and the authors chose to carry out all analyses during this state. In contrast, Lisgaras and Scharfman previously found that HFOs also occur during wakefulness and REM sleep in AD and DS mouse models, albeit at a reduced rate. 7 Since the generation, maintenance, and function of sleep–wake states involve vastly different combinations of neurotransmitters and neuromodulators, activity patterns, and brain nuclei, further investigating HFOs during wakefulness and REM sleep, perhaps longitudinally, and tapping into creative measures such as the proportional distribution of HFOs in these states through aging and AD progression could yield surprising insights.
The DS demographic is a vulnerable sector of the population in which epilepsy and AD have exceptionally high incidences. Individuals with DS would benefit greatly from the development of new prevention strategies and disease-modifying therapies, particularly ones that could be initiated fairly early in life, which would require a biomarker with predictive value. Some aspect of the intrinsic properties, rate, spatial distribution, or temporal dynamics of HFOs might hold a key to identifying this early window of opportunity, and perhaps even to distinguishing responders from non-responders upon treatment. 8
The work by Lisgaras et al supports the existence of a tight link between HFOs and AD and highlights the need for further investigation. If HFOs are confirmed to indeed precede the development of epileptiform activity and AD dementia, their value as biomarkers could be extraordinary.
