This study will examine the effect of the drugs lithium and divalproex (Depakote) on tau
proteins, a type of protein in the brain and spinal fluid that are altered in patients with
Alzheimer's disease. Both drugs are approved by the Food and Drug Administration to treat
mood disorders, and both have been shown in animal studies to decrease the amount of altered
tau protein. This study will determine whether lithium alone or in combination with
divalproex reduces the altered tau protein in the spinal fluid of patients with Alzheimer's
Patients with Alzheimer's disease who are between 40 and 90 years of age may be eligible for
this study. Candidates are screened with a medical history and physical examination,
neurologic and neuropsychological evaluation, blood and urine tests, electrocardiogram
(EKG), and, if needed, a magnetic resonance imaging (MRI) scan of the brain.
Participants undergo the following tests and procedures:
- Drug treatment: Patients take study drugs for 6 weeks.
- Weekly clinic visits: Patients come to the clinic once a week for a physical
examination, blood and urine tests, a review of drug side effects, and to receive the
next week's supply of medications.
- Lumbar puncture (spinal tap): Patients have a lumbar puncture at study weeks 2, 4, and
6 to measure various brain chemicals and tau proteins in the cerebrospinal fluid (CSF),
which bathes the brain and spinal cord. For this test, a local anesthetic is given and
a needle is inserted in the space between the bones in the lower back where the CSF
circulates below the spinal cord. A small amount of fluid is collected through the
- Follow-up visit: Two weeks after completing the study medication, patients return to
the clinic for a final evaluation, including a physical examination and blood and urine
The overall objective of this study is to examine the acute effects of lithium alone and/or
in combination with divalproex on surrogate measures of neuroprotective activity in patients
with Alzheimer's disease. It is hypothesized that at safe and tolerable doses these drugs
will inhibit glycogen synthase kinase-3 activity and reduce the phosphorylated tau epitopes
threonine-181 and threonine-231 implicated in the pathogenesis of this disorder. In this
proof-of-principle study, efficacy on reducing tau phosphorylated epitopes will be assessed
through cerebrospinal fluid (CSF) measurements. Safety will be monitored by means of
frequent clinical evaluations and laboratory tests.
Patient is between the ages of 40 and 90 (inclusive).
Patient will have a diagnosis of AD; the study will be confined to patients who are able
to provide consent (pass a capacity assessment).
The modified Hachinski Ischemia Score must be less than 4.
Brain MRI performed within 15 months of enrollment must be compatible with the diagnosis
Patient and/or caregiver are willing to adhere to protocol requirements as evidenced by
written, informed consent.
Patients meeting any of the following exclusion criteria during screening or during the
study will not be enrolled or will be immediately excluded from the study, as appropriate:
Patient has a history of any medical condition that can reasonably be expected to subject
the patient to unwarranted risk.
Patient has clinically significant laboratory abnormalities that would preclude
administration of lithium and divalproex.
Patient is taking a prohibited concomitant medication. The following medications are
forbidden for at least one month prior to the treatment phase (unless otherwise noted) and
during the course of the study:
Any investigational drugs;
Anti-depressants (eligibility will be considered as long as dosage remains stable
throughout the study);
Anticonvulsants and other mood stabilizing drugs;
Treatment that may provoke lithium toxicity due to reduced renal clearance, including
metronidazole, spectinomycin, tetracycline;
Treatment that may substantially increase steady-state plasma lithium levels resulting in
lithium toxicity, including angiotensin-converting enzyme inhibitors, NSAIDS, diuretics;
Treatment that may increase the risk of neurotoxicity, including calcium channel blocking
Drugs that may increase urinary lithium excretion resulting in lower serum lithium
concentrations, such as acetazolamide, urea, xanthine preparations, alkalinizing agents
such as sodium bicarbonate, theophylline;
Drugs that interact with lithium, including methyldopa;
Neuroleptics (eligibility will be considered as long as dosage remains stable throughout
the study). If patient is on existing atypical neuroleptic drugs, these will be continued
at the same dose. Patients will not start a new prescription for atypical antipsychotics
during the study;
Drugs that may prolong the effects of lithium, including neuromuscular blocking agents;
Patient has not been using an adequate contraceptive method for the last 30 days or
unwilling to continue contraception throughout the study, or is not at least one year
post-menopausal (if female).
Patient is pregnant or breastfeeding.
Patient has participated in a clinical study with an investigational drug within the last
Patient has a condition (such as active drug or alcohol abuse) that, in the opinion of the
investigators, would interfere with compliance or safety.
Patient has known hypersensitivity to lithium or divalproex.
Patient's inability to swallow tablets or to comply with medication schedule.
Patient has no adequate caregiver.
Patient and/or caregiver are unwilling to sign an informed consent or to comply with
Patient is unwilling to have lumbar puncture.