Levetiracetam for Alzheimer's Disease Neuropsychiatric Symptoms Related to Epilepsy Trial (LAPSE)

Patients with Alzheimer's disease (AD) are increasingly recognized to have seizures in addition to cognitive decline. Seizures may contribute to memory problems as well as other symptoms common in AD like agitation, depression, or apathy. These symptoms are collectively called neuro-psychiatric symptoms. Studies of magnetic resonance imaging (MRI) in patients with AD have suggested that injury to certain parts of the brain can cause these neuro-psychiatric symptoms. Based on this evidence, the investigators hypothesize that seizures can also cause neuro-psychiatric symptoms in patients with AD and may be related to the injury seen on MRI.

The current study will follow participants for 1 year and will involve participants with AD who also have neuro-psychiatric symptoms. Participants will be examined with three brain wave studies to assess for seizure-like activity. Participants with seizure-like activity will all receive levetiracetam for 1 year. All participants will have their neuro-psychiatric symptoms, cognitive abilities, quality of life, and AD severity assessed throughout the year. The investigators plan to determine if levetiracetam changes the severity of the participants' neuro-psychiatric symptoms compared to their baseline as well as compared to participants without seizure-like activity. 65 participants will need to be recruited to test the study hypotheses. The study will take place at Walter Reed National Military Medical Center.

Alzheimer's Disease (AD) has long been known to carry an increased risk of seizure, with early estimates suggesting patients with AD have a 10-22% risk at least one unprovoked seizure and an 8- to 10-fold higher seizure rate over the general population. Retrospective data has suggested that the onset of both clinical seizure and abnormal discharge on electroencephalogram (EEG) may cluster around or even precede the onset of cognitive decline. With extended EEG and/or 1-hour magnetoencephalogram (MEG), up to 42% of patients with AD have evidence of subclinical seizure or epileptiform discharges, two-thirds of which were identified only during sleep. Recent evidence has also found a much higher incidence of dyscognitive seizure (47%) and other nonconvulsive semiologies (55%) than previously reported, including jamais vu, déjà vu, sensory phenomenon, speech arrest/aphasia, and amnestic spells.

A particularly problematic aspect of dementia in general and AD in particular is neuropsychiatric symptoms. Neuropsychiatric symptoms increase with duration and severity of dementia, observed in as much as 60-90% of these patients. To some extent, neuropsychiatric symptoms may also be associated with focal dysfunction, particularly of the non-dominant fronto-temporal lobes. Seizure or transient epileptiform discharges, then, might explain some of the neuropsychiatric manifestations associated with AD, especially since the most common areas of discharge are the fronto-temporal lobes in AD. Neuropsychiatric symptoms and their causes are of particular concern in the management of patients with AD given the strain on patients and families and their high association with nursing home placement.

This study will complete up to 3 serial EEGs on each participant, and all participants with epileptiform activity identified on EEG will be started on levetiracetam. All participants will be followed with serial neuro-psychiatric symptom, cognitive, severity, and quality-of-life metrics in order to analyze the effect of levetiracetam on these measures over 1 year.

Eligibility Criteria:
Inclusion Criteria:

* Meet the National Institute of Aging-Alzheimer's Association criteria for probable AD
* Twelve-item Neuropsychiatric Inventory with score 4 or greater
* MMSE \<26
* Stable doses current medications, including acetylcholinesterase inhibitors if applicable, for at least 4 weeks prior to trial entry
* Reliable caregiver willing and available to assist with medication administration, outcome measures
* MRI completed with no evidence of potential seizure focus as outlined in the exclusion criteria

Exclusion Criteria:

* Imaging suggestive of potential seizure focus or alternative cause of dementia
* Previous Epilepsy diagnosis
* Use of anti-epileptic medication for any indication within previous three months
* History of head trauma with loss of consciousness more than 30 minutes
* Alcohol/Substance abuse within 5 years of dementia onset or previous 5 years
* History of Korsakoff's syndrome
* History of encephalitis/meningitis
* Female participant who is pregnant, lactating or planning pregnancy during trial
* Scheduled elective surgery or other procedures requiring general anesthesia during the trial
* Participant with life expectancy of less than 12 months
* Any cancer requiring current chemotherapy
* Known allergy or history of previous adverse reaction to levetiracetam
* Major depression or other significant behavioral disturbance preceding Alzheimer's Disease diagnosis
* Enrollment in another clinical treatment trial
* Laboratory evidence of an alternative cause of dementia or which might preclude treatment, including untreated vitamin B12 deficiency, untreated hypothyroidism, syphilis, positive human immunodeficiency virus testing, end-stage renal disease on dialysis, significant renal impairment (creatinine clearance \<75 ml/minute), or liver function tests \>2x upper limit of normal within the preceding three months