Late-onset epilepsy rises sharply after symptomatic Alzheimer’s emerges in adults with Down syndrome and is associated with faster cognitive decline and more than double the risk of death.
New-onset seizures may be an important clinical warning sign of Alzheimer’s disease progression in adults with Down syndrome, according to researchers.
In what they say was the largest longitudinal study yet to examine the relationship, the multicentre study of 4804 adults found the cumulative incidence of epilepsy climbed from 9.5% at the time of Alzheimer’s disease diagnosis to 56.9% nine years later.
Late-onset myoclonic epilepsy in Down syndrome (LOMEDS) was also associated with faster cognitive deterioration and a more than twofold increase in mortality.
Results have been published this month in The Lancet. The researchers said epilepsy emerged particularly strongly around the onset of symptomatic Alzheimer’s disease, with generalised myoclonic and tonic-clonic seizures the predominant presentations.
The findings could have important implications for surveillance of adults with Down syndrome, who have an exceptionally high risk of Alzheimer’s disease, they said.
“In this large, longitudinal, multicentre study of adults with Down syndrome, we showed that epilepsy is a frequent and clinically significant condition emerging around the onset of symptomatic Alzheimer’s disease,” the researchers wrote.
“The incidence of seizures increases steeply following symptomatic Alzheimer’s disease diagnosis, with cumulative risk around 60% within a decade.
“Importantly, LOMEDS (predefined as the peak of epilepsy coinciding with symptomatic Alzheimer’s disease) is not only common but also prognostically relevant, being associated with increased mortality and accelerated cognitive decline.
“These findings position epilepsy as a major component of the clinical trajectory of Down syndrome-associated Alzheimer’s disease, extending previous observations from smaller series and emphasising the interplay between neurodegeneration and network hyperexcitability in the Down syndrome population.”
APP gene triplication on chromosome 21 is associated with near-universal Alzheimer’s neuropathology by age 40 and a lifetime dementia risk greater than 90%, the researchers noted.
Previous studies have suggested epilepsy became much more common in older adults with Down syndrome, particularly those with symptomatic Alzheimer’s disease, but these were generally small and cross-sectional, they said.
The timing of epilepsy in relation to Alzheimer’s symptoms, and its implications for cognition and survival, remained uncertain.
The new study pooled seven international clinical cohorts and followed adults aged 18 years and older between 2012 and 2025. Alzheimer’s disease staging was established by clinical consensus, while epilepsy was defined according to International League Against Epilepsy criteria.
Of the 4804 participants, 3238 were cognitively stable, 267 had uncertain or non-neurodegenerative cognitive decline, 321 had prodromal Alzheimer’s disease and 978 had Alzheimer’s disease dementia. Mean follow-up was 3.4 years.
Active epilepsy affected about 15% of the cohort overall, but prevalence rose steeply with age, from 39.4 per 1000 among people aged 18-24 years to 389.6 per 1000 among those aged 60 years and older.
The increase was largely driven by symptomatic Alzheimer’s disease: among participants aged 60 years and older, prevalence was 459.3 per 1000 in those with symptomatic disease compared with 121.2 per 1000 among asymptomatic participants.
Importantly, chronological age itself did not appear to be the key determinant once Alzheimer’s disease had developed.
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Each additional year since Alzheimer’s disease diagnosis was associated with a 33% increase in the odds of LOMEDS (adjusted OR 1.33, 95% CI 1.22-1.45). Severe-to-profound intellectual disability (OR 2.14, 95% CI 1.25-3.70) and APOE ε4 carriage (OR 1.61, 95% CI 1.04-2.49) were also independently associated with increased risk.
Once Alzheimer’s disease was established, the likelihood of developing LOMEDS depended on disease stage (time since Alzheimer’s disease diagnosis) and was independent of age itself, the researchers said.”
LOMEDS also appeared to mark a substantially poorer prognosis. It was associated with a mortality hazard ratio of 2.10 (95% CI 1.57-2.82), while cognitive deterioration after seizure onset occurred at roughly twice the rate seen in people with symptomatic Alzheimer’s disease without epilepsy.
There was an intriguing treatment signal. Participants who received antiseizure medication after myoclonic seizures were less likely to progress to generalised tonic-clonic seizures than untreated participants.
But the researchers stressed that the observational study could not establish that treatment caused the difference, and said randomised trials were needed to determine whether early antiseizure therapy could alter the trajectory of Down syndrome-associated Alzheimer’s disease.
They said routine EEG may not provide an easy solution for identifying those at risk. Interictal epileptiform discharges performed poorly as a classifier of epilepsy, with an area under the curve of 0.57, while background slowing had an AUC of 0.60.
In an accompanying Lancet comment, Dr Zinayida Schlachetzki and Professor Michael Rafii, of the University of Southern California, said the findings provided “timely and compelling evidence” of a marked increase in first-time seizures after Alzheimer’s disease diagnosis in people with Down syndrome, linked with accelerated cognitive decline and increased mortality.
They said LOMEDS could be both an expression of underlying Alzheimer’s pathology and “an accelerator of disease progression” and warned that the condition was likely to be under-recognised and often untreated in its earlier stages.
They said the findings made early identification particularly important, noting that people who did not receive antiseizure medication following their first myoclonic event frequently went on to develop generalised tonic-clonic seizures.
However, there are currently no recommendations specifying which antiseizure medications should be used for LOMEDS, they said, and trials were needed to determine whether treating myoclonus can prevent subsequent tonic-clonic seizures or slow Alzheimer’s-related cognitive deterioration.
They also pointed to important limitations. The study population was predominantly White European, potentially limiting generalisability, while the predominance of cognitively stable participants and possible dropout of symptomatic participants could have introduced selection bias.
Nevertheless, Dr Schlachetzki and Professor Rafii said this was the first large longitudinal study to comprehensively characterise the onset, progression and prognosis of epilepsy in relation to symptomatic Down syndrome-associated Alzheimer’s disease.
“This is the first large longitudinal study to enable a comprehensive characterisation of epilepsy onset, progression, and prognosis in relation to symptomatic Down syndrome-associated Alzheimer’s disease,” the commentators concluded.
“The findings may inform the design of future prospective trials by supporting the selection of relevant endpoints and defining windows for surveillance and intervention.
“Further studies are needed to elucidate the relationship between LOMEDS and biomarkers of Alzheimer’s disease pathology, and to assess whether early antiepileptic treatment or pre-emptive reduction of neuronal hyperexcitability before seizure onset can improve outcomes in LOMEDS and Alzheimer’s disease.
“From a clinical standpoint, these results support systematic seizure surveillance in adults with Down syndrome – particularly those at increased risk – to enable comprehensive medical care and improve clinical outcomes.”
