Alice D. Lam

Background and ObjectivesLate-onset unexplained epilepsy (LOUE) has been linked to accelerated cognitive decline. However, the role of neurodegenerative proteins and whether they exert their effect...

Adults older than age 55 years have the highest incidence rate and are the fastest-growing population among people with epilepsy. The aim of this study was to characterize the etiologies of new-onset seizures in older adults and to examine how seizure etiology varies across demographic groups. We used data from 7 US epilepsy centers from 2021 to 2025 and compared findings with those of previous population-based studies, providing an updated view and highlighting opportunities for prevention and improved risk stratification. We retrospectively reviewed medical charts of 2,052 patients aged ≥55 years at the time of a first seizure, who were evaluated at 7 epilepsy centers between 2021 and 2025. We categorized seizures by etiology as follows: ischemic stroke, hemorrhagic stroke, tumor, neurodegeneration, provoked seizures, traumatic brain injury, and unknown. We examined differences in etiology by demographic strata (age, sex, race, and primary language) using chi-square tests, Kruskal-Wallis tests, analysis of variance, and Cuzick tests. The most frequent seizure etiologies among older adults were unknown (29.9%), ischemic stroke (15.4%), and provoked seizures (14.9%). Neurodegenerative disease was the etiology for 5.3% of cases overall but increased in prevalence with age, accounting for 18.5% among patients aged 85-89 years. Seizure etiologies also differed by sex and race. Men more commonly had seizures caused by cerebrovascular disease and traumatic brain injury, while women more commonly had seizures due to neurodegenerative disease. Black patients had higher proportions of ischemic stroke and neurodegenerative disease, while unexplained epilepsy was more common among White patients. The causes of late-onset seizures vary based on age, sex, and race. Nearly one-third of cases of epilepsy in older adults remain unexplained despite advances in imaging techniques, underscoring the need for further research on the mechanisms and health implications of late-onset unexplained epilepsy. Improved prevention of cerebrovascular disease and optimized management of provoked seizures may reduce the growing burden of epilepsy in older adults.

Late-onset epilepsy is increasingly recognized as a major and growing neurological condition in older adults, driven by population aging and rising incidence rates, yet approximately one-third of cases remain unexplained (late-onset unexplained epilepsy, LoUE). LoUE is diagnostically challenging, as seizures are often subtle and nonconvulsive, routine EEG has limited sensitivity. Converging evidence from animal models and clinical studies suggests that aging-related reductions in seizure threshold, vascular dysfunction, neurodegenerative processes, and immune dysregulation (“inflammaging”) all contribute to epileptogenesis, often through interacting and cumulative pathways. Clinically, while many patients respond to antiseizure medications, a subset experience refractory disease. Importantly, LoUE should not be viewed as a single entity but rather as a heterogeneous syndrome arising within diverse biological contexts shaped by lifetime exposures, comorbidities, and underlying pathology. Advancing the field will require prospective, multimodal studies integrating neuroimaging, fluid biomarkers, and detailed phenotyping to define mechanistic subtypes and enable a transition toward precision medicine approaches aimed at reducing the burden of seizures and their downstream consequences in older adults.

Epilepsy is a common comorbidity of Alzheimer’s disease (AD) and related dementias (ADRD). Both epilepsy and ADRD affect the mesial temporal structures in volume and morphology. Nonetheless, mesial temporal shape and volume asymmetry remain understudied in persons with dementia and mild cognitive impairment, collectively called persons with cognitive impairment (PWCI) and co-morbid epilepsy. We investigated hippocampal and amygdalar left-to-right shape and volume asymmetry in AD (AD_Epi) and non-AD (nonAD_Epi) with co-morbid epilepsy. This multicentre study included participants from 39 US Alzheimer’s disease centres from 9/2005 to 12/2021. We categorized participants into group 1: PWCI with epilepsy (subclassified into AD_Epi and nonAD_Epi); group 2: PWCI without epilepsy (subclassified into AD_NoEpi and nonAD_NoEpi); and group 3: healthy controls (HC). We used a fixed-ratio, optimal propensity score matching to match group 1 participants to groups 2 and 3. Matching was based on age, sex and type of dementia (AD versus nonAD) for group 2 and age and sex for group 3. We used FreeSurfer for MRI segmentation of hippocampi and amygdalae. For volume asymmetry, we subtracted the right volume from the left and divided it by the total volume of the structure (right + left). For shape asymmetry, we calculated a 512-point shape model using left and flipped right hippocampi and, similarly, a 256-point shape model for amygdalae. Next, we calculated the point-by-point shape asymmetry between left and right hippocampi and amygdalae in a normal direction for each participant. Multivariable linear models were used to compare volume and shape asymmetry among groups after adjusting for age, sex, total intracranial volume and dementia severity. We compared AD_Epi versus AD_NoEpi, nonAD_Epi versus nonAD_NoEpi, AD_Epi versus HC, nonAD_Epi versus HC, AD_NoEpi versus HC and nonAD_NoEpi versus HC. Analyses were adjusted for multiple comparisons. A total of 703 participants were included [391(55.62%) female, average age: 70.78 years]. These included 35 AD_Epi, 28 nonAD_Epi, 183 AD_NoEpi, 137 nonAD_NoEpi and 320 HC. For shape analyses, AD_Epi showed greater left-to-right asymmetry (Left smaller than right) in hippocampal tail compared with HC. Those with nonAD_Epi demonstrated greater left–to-right asymmetry in the hippocampal head compared with both nonAD_NoEpi and HC. AD_NoEpi had an asymmetrically smaller left hippocampal head and right amygdala than HC. We found no group differences in volume asymmetries. Our study found left smaller than right hippocampal head asymmetry in non-Alzheimer’s dementia with epilepsy and left smaller than right hippocampal tail asymmetry in Alzheimer’s disease with epilepsy. These findings suggest that hippocampal shape asymmetry may serve as a neuroimaging correlate of epilepsy in ADRD.

Summary: Bridging clinical and basic research is increasingly recognized as a priority in the epilepsy field, yet opportunities for integration remain limited by the time, space, and financial constraints of scientific meetings. To address this gap, the Research Task Force of the Young Epilepsy Section of the International League Against Epilepsy (ILAE‐YES) organized a free global webinar series designed to promote translational dialogue and provide accessible research education for early‐career clinicians, researchers, and physician‐scientists. Based on a preliminary ILAE‐YES community survey, eight topics of high interest were selected: (1) epigenetics, (2) EEG biomarkers, (3) ictogenesis, (4) thalamo‐cortical network, (5) sudden unexpected death in epilepsy, (6) neurodegeneration and seizures, (7) seizure‐related brain damage, and (8) neuromodulation therapy. From March to June 2025, eight live Zoom webinars were held, each featuring expert speakers representing both basic science and clinical perspectives, with recordings made available as unlisted YouTube videos to ensure on‐demand access. A total of 1199 individuals from 116 countries registered, 63.2% from low‐ and middle‐income countries. Live attendance averaged 50 participants per session, and the mean session duration was 71.6 min, including an average of 16 min of discussion. Post‐session feedback was obtained from 285 respondents; overall satisfaction was high, with 93.3% rating their experience as 4 or 5 on a 5‐point Likert scale. Speaker satisfaction was similarly high (95.4%), and 80.0% reported gaining new research ideas. Although access to YouTube and Google Forms may have limited participation in some regions, the series provided an inclusive and globally accessible platform. These findings demonstrated that free, discussion‐focused online webinars represent a scalable, low‐cost, and reproducible educational model that can effectively promote international engagement and integration between clinical and basic epilepsy research, aligning with the ILAE's global educational mission and complementing WHO IGAP priorities on capacity building and equitable access to knowledge. Plain Language Summary: Bringing together basic science and clinical research is important for improving epilepsy care, but many researchers have limited opportunities to learn across these fields. We organized a free global webinar series that helped early‐career clinicians and researchers learn about epilepsy research by combining scientific talks with clinical perspectives and open discussion. More than 1100 participants from over 100 countries joined, and most reported high satisfaction and gaining new research ideas. These results show that free, discussion‐based online webinars can provide an accessible way to support research education and international learning in epilepsy.

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.

Sleep architecture, including spindles and slow oscillations, is disrupted in Alzheimer disease (AD). How changes in these sleep elements relate to cognitive decline is less clear. Our objectives were to examine changes in sleep macroarchitecture and microarchitecture in early clinical stages of AD compared with older adult controls (CTLs) and to investigate their associations with longitudinal cognitive change. This was both a cross-sectional and longitudinal study performed at Mass General Brigham Hospitals, where participants with early AD or CTLs underwent overnight ambulatory scalp EEG and longitudinal cognitive testing. We compared sleep microarchitectural features extracted from the EEG, including spindle activity, across the brain topography and between groups. We then performed longitudinal analyses using mixed-effects models to test the association of these sleep features with changes in cognition on the Montreal Cognitive Assessment (MoCA), collected annually for up to 7 years. AD (n = 47, mean age 74.1 years, 66% female) and CTL (n = 43, mean age 72.6 years, 56% female) groups spent a similar proportion of sleep time in each stage of sleep. Sleep efficiency, however, was lower in the AD group (mean: CTL 75.1% vs AD 70.9%; p = 0.034). We found a significant reduction in spindle range power (11-16 Hz) in patients with AD compared with CTLs, particularly in the temporal regions (mean normalized power at EEG channels T3/T4: CTL 3.13 ± 1.13 vs AD 2.48 ± 1.01; p = 0.005). In participants with longitudinal MoCA scores (AD = 26, CTL = 25), reduced temporal lobe spindle density (β = 0.61, 95% CI 0.35-0.87; false discovery rate [FDR]-adjusted p < 0.001) and temporal lobe spindle power (β = 0.56, 95% CI 0.22-0.88; FDR-adjusted p = 0.005) were each associated with a faster rate of cognitive decline. Temporal lobe sleep spindle activity is reduced in early clinical stages of AD and is associated with a faster rate of cognitive decline. Our results underscore the importance of including temporal lobe measurements when assessing sleep neurophysiology in AD, which is not standard in polysomnography. Future work examining the relationship between AD biomarkers and reduced spindle activity is needed to elucidate the potential mechanisms underlying these findings.

Background: Late‐onset unexplained epilepsy (LoUE), defined as epilepsy starting after age 55 with no clearly identified cause, has emerged as a significant risk factor for dementia. Individuals presenting with LoUE have no prior history of dementia. Yet, LoUE is associated with a 2‐3x increased risk of developing dementia, and up to 25% of individuals with LoUE develop dementia within 4 years after their first seizure. We have little understanding of the mechanisms that underlie development of dementia in LoUE. Method: The ELUCID Study (Epilepsy of Late‐onset Unknown etiology as a risk factor for Cognitive Impairment and Dementia) is a multi‐center, prospective longitudinal observational study of LoUE, focused on understanding mechanisms and predicting outcomes of mild cognitive impairment and dementia in LoUE. ELUCID will enroll 600 participants with LoUE (and without dementia) across 7 study sites. Participants undergo a baseline evaluation with clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood draw, and are followed longitudinally with interval history every 6 months and annual cognitive testing. The primary outcomes are development of mild cognitive impairment and dementia. Result: To date, 67 ELUCID participants have completed their initial study visit, with mean age of 67.9±7.2 years and 38.8% female. The sample includes 89.6% White, 3% Black, 1.5% Asian, 6% unreported race, and 1.5% Hispanic ethnicity. Mean level of education was 16.9±2.7 years. Vascular risk factors were common, including hypertension (51%), hyperlipidemia (58%), diabetes mellitus (6%), coronary artery disease (9%), and obstructive sleep apnea (28%). A family history of seizures was present in 23.9% of participants, and a family history of dementia in 58%. Cognitive test scores largely fell within normal range, including: MMSE: 28.7±1.5; Logical Memory Delayed: 11.9±3.4; FCSRT Free Recall: 31.6±6.4; Trails B: 94.3±54.4; Digit Symbol Substitution: 41.9±10.1; and Category Fluency (animals): 17.0±4.9. Subjectively, 32.8% of participants felt their memory had worsened compared to 6 months prior. Conclusion: The ELUCID Study is a large longitudinal study of LoUE that will define its relationship to Alzheimer's disease and related dementias. Here we describe the study protocol and provide an early report of the baseline demographic and clinical characteristics of the accruing ELUCID study population.

Objective: Late‐onset unexplained epilepsy (LoUE), defined as epilepsy onset after age 55 without an obvious cause, is an important risk factor for dementia. Studies have shown that 10%–25% of individuals with LoUE develop dementia within 3–4 years following their first seizure. However, the mechanisms underlying progression from LoUE to dementia remain poorly understood. The goals of the ELUCID study are to identify risk factors associated with the development of cognitive decline and dementia in LoUE and to develop tools to identify patients at a high risk for these outcomes and thereby establish a foundation for dementia prevention strategies in this population. Methods and Analysis: ELUCID is a multi‐center prospective longitudinal observational study that will enroll 600 participants aged 55 or older with LoUE across seven U.S. medical centers. Participants will undergo a baseline evaluation that includes a detailed clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood biomarkers. Participants will be followed at 6‐month intervals for up to 5 years, to record cognitive and neurological changes, with the primary outcomes of interest being the development of mild cognitive impairment and/or dementia. This study aims to establish LoUE disease subtypes based on biomarkers, cognitive trajectories, and imaging features and to develop a risk stratification tool for predicting cognitive decline and dementia in patients presenting with LoUE. Ethics and Dissemination: ELUCID has obtained IRB approval (no. 2023P001566, August 2023), with the Mass General Brigham IRB serving as the single IRB of record. All de‐identified study data will be made publicly available on completion of the study. Plain Language Summary: The ELUCID study is a research project involving several medical centers across the U.S. It will focus on older adults who have recently developed seizures without a clear cause. Participants undergo an initial evaluation that includes questions about their medical history, a brain MRI , an overnight scalp EEG (brain wave study), and a blood draw. They will be followed over time with health questionnaires and yearly tests of memory and thinking. The purpose of the study is to learn what factors increase the risk of dementia in this population and to develop tools to predict which individuals are at the highest risk.