Editorial: Cytokine Inhibition for Treatment of Alzheimer's Disease

In this month's Neurology & Neurosurgery eSection of Medscape General Medicine, Tobinick and colleagues[1] present an open-label trial of a tumor necrosis factor (TNF)-alpha inhibitor (etanercept) for the treatment of Alzheimer's disease (AD). They administered 25-50 mg of etanercept by extrathecal injection into a cervical spine interspinous space weekly for 6 months to 15 participants at stages of AD varying from mild to severe. They report significant improvements in several cognitive and functional assessments, including the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and Severe Impairment Battery (SIB). The improvements began at 1 month and were sustained for the 6-months duration of the trial. The authors highlight the response of one participant with advanced dementia who demonstrated significant functional improvement. Although the treatment is relatively invasive, it was well tolerated by the participants without evidence of any study-related adverse events. One participant died, but the clinical picture did not appear study-related.

Increasing amounts of evidence indicate that inflammatory processes are involved in the neurotoxicity of AD.[2,3] A central event in these processes appears to be the activation of microglia by a variety of factors, including beta amyloid and proinflammatory cytokines.[4] Activated microglia in turn release proinflammatory cytokines, such as interleukin (IL)-1-beta, IL-6, and TNF-alpha, that may lead to neuronal death and dysfunction by a variety of mechanisms, including (1) enhancement of glutamate-induced excitotoxicity[5]; (2) inhibition of long-term potentiation, which limits functional plasticity after neuronal injury[6,7]; and (3) inhibition of hippocampal neurogenesis.[8] Within this group of functionally interrelated cytokines, TNF-alpha is particularly prominent as a potential intermediary in AD. Recent studies have reported elevated TNF-alpha levels in the cerebrospinal fluid (CSF) and serum of AD patients,[9–11] and found that a single nucleotide polymorphism in the TNF-alpha gene is associated with earlier onset of AD.[12] These findings make neuroinflammation a tempting target for neuroprotective therapies. Therapeutic strategies that affect microglial activation or proinflammatory cytokine release or effect could complement anti-amyloid therapies that are already in development.

Interest in developing novel anti-inflammatory strategies for AD treatment has grown considerably, and this article is the first positive report of such a strategy. Many longitudinal studies have suggested that nonsteroidal anti-inflammatory drugs may protect against the development of AD,[13] but a controlled trial of rofecoxib reported no protective effect.[14] Novel agents in preclinical development include inhibitors of microglial activation[15] and dextromorphans, such as naloxone.[16] One should approach these strategies with some caution, however. Although microglial activation is clearly and consistently associated with senile plaques and the presence of beta amyloid in AD, there is evidence that these activated microglia may serve to clear beta amyloid from plaques and thus be homeostatic (helpful) rather than neurotoxic (harmful).[17] In fact, the presence of activated microglia may be necessary for the clearance of beta amyoid by passive immunization in AD.[18]

For these reasons, manipulation of proinflammatory cytokine levels is a tempting therapeutic target. Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF-alpha cellular receptor linked to the Fc portion of human immunoglobulin (Ig)G1. Etanercept specifically binds to TNF-alpha, rendering it biologically ineffective. The agent has been approved by the US Food and Drug Administration (FDA) for treating rheumatoid arthritis,[19] and is attracting interest as a treatment for immune-mediated conditions, such as psoriasis.[20] It is administered subcutaneously for these conditions and has a relatively benign safety profile, although its use is cautioned in patients with known immunologic conditions, such as multiple sclerosis, or latent infections, such as tuberculosis. Infliximab is a humanized mouse monoclonal antibody that similarly blocks the biological actions of TNF-alpha and may have potential as an AD treatment.

The data presented by Tobinick and colleagues[1] offer promise for future treatments of AD, but must be regarded as highly preliminary. This was an open-label trial of an invasive therapy, and the results may be purely related to a placebo effect; as such, a randomized controlled trial is warranted. The mechanism of administration and action is still quite speculative: It is not known to what extent etanercept penetrates the blood-brain barrier, what levels are achieved in CSF, and what effect it is having on CSF TNF-alpha levels. CSF levels of etanercept may not be necessary for biological effect, however, because binding TNF-alpha peripherally may act as a “sink” for brain TNF-alpha. Additional studies of AD biomarkers in future trials of etanercept could clarify these issues.

Etanercept and other cytokine-inactivating therapies for AD offer novel mechanisms for future AD therapies with the advantage of using currently FDA-approved agents with reasonably known safety profiles. It is not every day (or every year) that one sees such promising AD treatment data as presented in this article, and further studies are clearly warranted.