ELUCID: Late-Onset Unexplained Epilepsy as a Risk Factor for Cognitive Impairment and Dementia — A Multi-Center Prospective Longitudinal Study (Protocol and Data Resource)

Abstract

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, yet the mechanisms underlying progression 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 high risk for these outcomes, establishing 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. Participants undergo a baseline evaluation that includes a detailed clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood biomarkers, and are followed at 6-month intervals for up to 5 years to record cognitive and neurological changes. The primary outcomes of interest are the development of mild cognitive impairment (MCI) and/or dementia. The study aims to establish LoUE disease subtypes based on biomarkers, cognitive trajectories, and imaging features; to identify risk factors and mechanisms associated with cognitive decline in LoUE; 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.

This bdsp.io project is the umbrella (parent) resource for the ELUCID study. It describes the study and the multimodal data being collected. De-identified data — brain MRI, overnight EEG, cognitive/neuropsychological data, and blood-based biomarkers — together with derived features and the code for individual analyses will be added here, and released as companion child projects, as they become available.

Background

Late-onset unexplained epilepsy (LoUE) — epilepsy beginning after age 55 with no clear etiology — accounts for up to 25% of all new epilepsy cases and afflicts roughly 50,000 new patients in the U.S. each year. Its public-health impact is growing: older adults are the fastest-growing demographic in the U.S., and the incidence of epilepsy in older adults is rising even as the incidence of stroke, dementia, and traumatic brain injury (common identifiable causes of late-onset epilepsy) has declined. Much of this growing incidence therefore remains unexplained and falls within the category of LoUE.

While current clinical management of LoUE focuses primarily on preventing seizures, excess morbidity and mortality in LoUE relate more to dementia and stroke than to seizures. LoUE is highly pharmacosensitive — over 80% of individuals achieve seizure-freedom on medication alone and seizures account for <1% of deaths — yet individuals with LoUE have a 2–3-fold increased risk of dementia, a 2–3-fold increased risk of stroke, and a 3-fold increased risk of mortality compared with similar people without epilepsy. LoUE may thus mark a critical window for early intervention to prevent subsequent dementia or stroke.

A major shortcoming of the current clinical approach to LoUE is that LoUE is treated as a homogeneous condition, when substantial clinical heterogeneity and multiple underlying pathologies are likely. There is an urgent need for a precision-medicine approach in which disease subtyping informs an individual's risk of dementia (or stroke) and guides targeted therapy. ELUCID is designed to build the clinically annotated, multimodal biorepository needed to define these subtypes and to develop practical risk-stratification tools.

Aims. (1) Establish an unbiased framework for identifying mechanisms of dementia in LoUE; (2) identify clinical features and biomarkers associated with the development of cognitive decline and dementia in LoUE; and (3) develop practical clinical tools to forecast an individual's risk of developing MCI and/or dementia after presentation with LoUE.

Methods

Study design

ELUCID (Epilepsy of Late-onset Unknown etiology as a risk factor for Cognitive Impairment and Dementia) is a 10-center, prospective, longitudinal observational study that will enroll 600 participants with LoUE. The original 7 study sites are: Massachusetts General Hospital, Boston, MA (coordinating site); Beth Israel Deaconess Medical Center, Boston, MA; Brigham and Women's Hospital, Boston, MA; Icahn School of Medicine at Mount Sinai, New York, NY; Johns Hopkins Medicine, Baltimore, MD; University of Alabama at Birmingham, Birmingham, AL; and University of Texas Southwestern, Dallas, TX. In 2026, 3 additional study sites were added: Stanford University, Palo Alto, CA; University of California Los Angeles, Los Angeles, CA; and University of Virginia, Charlottesville, VA.

Population and eligibility

Participants are aged ≥55 at the time of their first seizure, which occurred within 3 years of enrollment, with no identifiable etiology. Individuals with a prior diagnosis of dementia or intellectual disability, an identifiable seizure etiology (e.g., cortical stroke, hemorrhage, severe TBI, tumor), provoked seizures, prior brain surgery, or a structural neocortical epileptogenic lesion on MRI are excluded. Dementia is formally screened out during a telephone interview (subjective cognitive-decline questions → TICS → informant QDRS).

Baseline assessment and modalities

• Clinical history & questionnaires — seizure and dementia risk factors, autoimmune/medical/psychiatric history, STOP-BANG, FRAIL scale, lifestyle and social-determinants measures, captured in a central REDCap database.
• Neuropsychological testing — a battery administered at baseline and annually to track cognitive trajectories.
• 3T brain MRI — Siemens Prisma protocol closely aligned to ADNI-3 Basic (Sagittal 3D Accelerated MPRAGE; Sagittal 3D FLAIR; Accelerated High-Resolution Hippocampus; Axial T2*; and, when possible, Axial DTI, Axial 3D pASL, and 10-min resting-state fMRI). FreeSurfer cortical/subcortical morphometry and automated white-matter-hyperintensity segmentation are derived centrally.
• Overnight scalp EEG — at-home recording set up by registered technologists using the 10–20 system with T1/T2 electrodes and single-lead EKG, on a 24-channel Lifelines device sampled at 200 Hz. EEGs are read for slowing and epileptiform abnormalities; automated spike detection and sleep macro-/micro-architectural features are extracted.
• Fasting blood draw & biorepository — plasma, serum, buffy coat, and whole blood processed to BioSEND standards. DNA yields APOE genotype and LRRK2 G2019S status. Blood biomarkers: neuropathology (Aβ42, Aβ40, p-tau217, NfL, GFAP); inflammatory markers (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A, TNF-α); vascular-health markers (bFGF, Flt1, PlGF, VEGF, VEGF-C, VEGF-D); and general/vascular labs (creatinine, fasting lipids, HbA1c).

Follow-up and outcomes

After baseline, visits occur every 6 months, alternating phone and in-person, for up to 5 years. An interval-history questionnaire captures seizure frequency/severity, medications, and interim medical, psychiatric, and functional changes. Primary outcomes are the development of MCI and dementia (adjudicated by NIA-AA criteria at consensus meetings); secondary outcomes are ischemic/hemorrhagic stroke, TIA, myocardial infarction, serious cardiac arrhythmia, and mortality. A target enrollment of 600 provides ≥80% power to detect the study's primary associations.

Data Description

Placeholder / umbrella project — data added as it becomes available. This is the parent bdsp.io resource for the ELUCID study. At present it describes the study design and the multimodal data being collected prospectively; de-identified data are being added incrementally, beginning with the overnight scalp EEG recordings (see Data organization and access, below). As collection, quality control, and de-identification are completed, data and derived features will be added here and released through companion child projects, each carrying its own DOI and analysis code.

Data expected to be released (de-identified) over the life of the study:

• Brain MRI — 3T ADNI-3-aligned structural and (where acquired) diffusion, ASL, and resting-state sequences, plus FreeSurfer morphometry and white-matter-hyperintensity volumes.
• Overnight scalp EEG — 24-channel home recordings (200 Hz), with expert annotations and automated spike / sleep-architecture features.
• Cognitive / neuropsychological data — baseline and annual test batteries and derived composite measures.
• Blood-based biomarkers — neuropathology, inflammatory, and vascular panels; APOE and LRRK2 genotypes; banked plasma/DNA metadata (samples managed by BioSEND).
• Clinical & outcome data — de-identified questionnaire, comorbidity, medication, and adjudicated MCI/dementia and secondary-outcome data.

Per the study's data-availability commitment, all de-identified study data will be made publicly available on completion of the study. Check the version history and the linked companion projects for the current set of released data.

Data organization and access. De-identified ELUCID data are hosted in the credentialed-access bdsp-opendata-repository repository and released to approved users through the Request access link on this page; interact with the data using the AWS CLI or SDK against the access point you are issued (see the bdsp.io data-access tutorial).

The initial release comprises the overnight scalp EEG recordings, organized according to the Brain Imaging Data Structure (BIDS) standard for EEG, under the prefix:

s3://bdsp-opendata-repository/EEG/bids/ELUCID/

As a BIDS dataset it includes the standard sidecar metadata — dataset_description.json, participants.tsv, and per-recording .json/.tsv sidecars describing subjects, sessions, and acquisition parameters. The dataset is being populated now and will grow over time as collection, quality control, and de-identification proceed; additional modalities (brain MRI, cognitive/neuropsychological data, and blood-based biomarkers) and further EEG recordings will be added and released as versioned companion child projects. As we analyze the data we will add derived features and expert annotations (for example, EEG spike and sleep-stage annotations and MRI-derived morphometry) alongside the corresponding raw data.

Because collection is ongoing, the exact set of folders and files will expand across versions; consult dataset_description.json and this project's version history for the current contents.

Usage Notes

This umbrella project is the citable landing page for the ELUCID study and the anchor for its future data releases. Data are being added incrementally — beginning with the overnight scalp EEG recordings, in BIDS format — and accessed by credentialed users via the Request access link on this page. The page will be versioned as data and companion child projects are added. To cite the study protocol, please use the reference listed under “How to cite this project” below.

Researchers interested in the ELUCID biorepository or in collaboration should contact the corresponding author. As de-identified modalities (MRI, EEG, cognitive, and blood-biomarker data) are released, this page will link to each companion project and its DOI, and usage notes for accessing and analyzing that data will be added here.

Release Notes

Version 1.0.0 — initial publication of the ELUCID umbrella project. Establishes the study landing page and describes the multimodal data being collected. No data files are included in this version; de-identified data and companion analysis projects will be added in subsequent versions as they become available.

Ethics

ELUCID has obtained IRB approval (no. 2023P001566, August 2023), with the Mass General Brigham IRB serving as the single IRB of record for all 10 study sites. Written informed consent is obtained from every participant prior to enrollment. All de-identified study data will be made publicly available on completion of the study.

Acknowledgements

This work was supported by the National Institutes of Health / National Institute of Neurological Disorders and Stroke (R01 NS130119). Blood collection, processing, and long-term sample management are coordinated through BioSEND, an NIH-sponsored biorepository service. The authors thank the ELUCID study participants, their study partners, and the research coordinators and technologists at all ELUCID study sites.

Conflicts of Interest

Dr. Lam has served as a paid consultant for Neurona Therapeutics, Acadia Pharmaceuticals, and UCB, and has received research support from Sage Therapeutics and Neurona Therapeutics. Dr. Westover is a co-founder of, scientific advisor and consultant to, and has a personal equity interest in Beacon Biosignals. The remaining authors have no conflicts of interest to disclose.

References

1. Lam AD, Johnson EL, Sarkis RA, Blank LJ, Gaston TE, Shafi MM, Zepeda R, Pellerin KR, Jette N, Greve DN, Chibnik LB, Amariglio RE, Marshall GA, Westover MB. Late-onset unexplained epilepsy as a risk factor for cognitive impairment and dementia: Protocol for a multi-center prospective longitudinal observational study (ELUCID). Epilepsia Open. 2026 Feb;11(1):363-375. doi: 10.1002/epi4.70184. Epub 2025 Nov 29. PMID: 41317246; PMCID: PMC12903818.