Pilot Study of Immunomodulatory Versus Antiinflammatory Therapy in Alzheimer's Disease

Objectives. The protocol is focused on the immune and inflammatory reactions in Alzheimer's disease (AD) and the possibility that blocking the inflammatory response may alter the course of the illness. The specific plan is to evaluate the biologic and clinical effects of two doses of cyclophosphamide (CY) immunotherapy in AD patients compared to the clinically available cyclooxygenase-2 inhibitor (COX-2), rofecoxib. The study will test the hypotheses that CY: 1) Is safe and tolerable in AD patients in meaningful clinical doses, 2) Can modify central nervous system inflammation and immune responses in AD, 3) Inhibits neurodegeneration in AD brains as indicated by peripheral biomarkers of AD pathology, and 4) Is different quantitatively or qualitatively in its effect on immune markers than placebo or other clinically-available anti-inflammatory drugs such as the COX-2 inhibitor, rofecoxib.

Rationale. Inflammation and immunologic responses appear to contribute significantly to neurodegeneration in (AD). In a pathological process termed gliosis, the brain's resident immune cells (microglia and astroglia) undergo chronic activation and possible proliferation, promoting neuronal injury and death by several means. Activated microglia and astroglia produce compounds that are directly cytotoxic to neurons, and they express molecules that greatly amplify immune and inflammatory processes in the brain. Excessive glial activation and proliferation are thought to be pivotal events hastening the demise of synapses and neurons in AD. Conversely, the growing understanding of immune and inflammatory pathology in AD has provided new opportunities for designing disease-altering treatments for AD. Preliminary clinical trials of anti-inflammatory drugs in AD patients, epidemiologic studies of anti-inflammatory drug use, and experimental models linking neurodegeneration with neuroimmune/neuroinflammatory processes suggest strongly that medications such as nonsteroidal-anti-inflammatory drugs (NSAIDs) and immunomodulatory agents may have an important role in altering the course of AD. CY is a potent anti-inflammatory and immunomodulatory drug that acts primarily by inhibiting proliferation of immune cells. Moreover, as immune cell proliferation appears to be an important aspect of AD pathophysiology and disease progression, an exploratory, dose-finding trial of a cytotoxic/cytostatic drug such as CY is appropriate, especially since CY is already widely used for the treatment of other immune-mediated illnesses. Furthermore, a preliminary European trial of CY in AD patients has already demonstrated an improvement in cognitive function that correlated highly with the degree of immunomodulation achieved.

Design. Study subjects will include 60 male and female patients with mild-moderate AD. In a randomized, placebo-controlled trial, two doses of CY or rofecoxib will be compared over a 6-month period. While the primary outcome measures will be safety and immunologic data, cognitive and other behavioral measures will also be collected. The biological outcome measures will include measures of brain volume (assessed by magnetic resonance imaging) and cerebrospinal fluid biomarkers of neurodegeneration, neuroinflammation, and neuroimmune activation. In addition, peripheral lymphocyte subsets and peripheral markers of inflammation will be assessed. This design is meant to provide dose-finding data to help design a more definitive efficacy trial with CY if the safety/tolerability parameters are acceptable in this pilot study.