Alzheimer’s Disease

Treatments: Best Practices

The cause of Alzheimer’s disease (AD) is essentially still unknown, although less than 5% of cases can be attributed to genetic mutations that predispose individuals to Alzheimer’s. There is currently no cure for AD, but there are treatments to slow its progression, mprove cognition and quality of life.

Commonly Prescribed Drugs

Donepezil: this drug is an acetylcholinesterase inhibitor (ChEI) marketed under the name Aricept. It acts by inhibiting the enzyme acetylcholinesterase, an enzyme responsible for metabolizing the neurotransmitter acetylcholine. Acetylcholine is vital to thought, memory, decision making and other cognitive processes. Inhibition of acetylcholinesterase causes the concentration of acetylcholine to increase in the brain. This helps improve cognitive ability in a patient with Alzheimer’s.

● Rivastigmine: another ChEI that is marketed under the name Exelon. It acts by the same mechanism as donepezil, although its effects may lessen as the disease progresses as fewer cholinergic neurons remain functionally intact. In addition, in vivo studies have shown that combination with NMDAs such as memantine does not affect its performance as a ChEI.

Galantamine: a ChEI marketed under the name Razadyne. Very similar to both donepezil and rivastigmine and acts by the same mechanism.

Memantine: this drug is in a class called N-methyl-D-aspartase (NMDA) receptor antagonists. Memantine functions by binding to the NMDA receptor and modulating the concentrations of glutamate. This is an important pathway to modulate since glutamate is involved in long-term potentiation, a process vital to learning and memory, as well as preventing calcium buildup, which can lead to cell death. NMDA receptor agonists are commonly coupled with CHEIs (donepezil) as adjuvants. It is sold under the name Namenda.

Research Pipeline

NIC5-15

This investigational drug is being developed by the pharmaceutical company Humanetics in collaboration with Mount Sinai School of Medicine. It acts by preventing the formation of amyloid plaques by inhibiting certain insulin mechanisms and the enzyme gamma secretase. Preventing the formation of plaques seems to be the direction of Alzheimer’s treatment research today. Aβ is a segment of a larger protein called Aβ precursor protein (βPP). Aβ is excised from βPP by two enzymes called beta and gamma secretase. By inhibiting gamma secretase, Aβ cannot form and can thus not aggregate.

LMTX

This drug is a second generation tau protein aggregation inhibitor (TAI) produced by the company TauRx in collaboration with the University of Aberdeen in the UK. Tau protein aggregation, which leads to the formation of neurofibrillary tangles, is a hot target for Alzheimer’s treatment. Normally functioning tau protein stabilizes microtubules in neuronal axons. They act as tracks for growth and branching of axons. The first generation of this drug is called Rember. Both drugs uses the active ingredient methylthioninium chloride and in phase II clinical trials, it has shown to reduce Alzheimer’s progression by 90% in 2 years. LMTX is an improved version of Rember, as it shows increased bioavailability and tolerability. On May 22, 2013 TauRx announced that LMTX will be tested in phase III clinical trials, involving 1,500 patients in 20 countries.

IVIG

Phase III clinical trials for IVIG (intravenous immunoglobulin), a mixture of antibodies and immunoglobulin G completed in May of 2013. It functions by binding to amyloid beta. Although primary endpoint results came out negative, there is still potential for Alzheimer’s treatment. In two subpopulations of participants, those with the ApoE4 risk gene and those moderately affected, showed beneficial effects from IVIG. Results from well established cognitive tests called the Modified Mini-Mental State (3MS) Examination and the Trails B test showed significant improvement in cognitive ability when compared to placebo. In addition, biomarker results showed lower levels of the most neurotoxic Aβ1-42 fragment, lower levels of brain fibrillar amyloid, and no effect on tau protein phosphorylation. These results are significant in that with further research, IVIG could be a very effective treatment for Alzheimer’s, as well as a mode of passive immunization.

Vaccines

CAD106: This vaccine candidate produced by the Swiss company Novartis completed its phase II trial in December of 2012. It is an active immunization designed to trigger the body’s immune defense against harmful beta amyloid. The researchers found that 80% of the patients involved in the trials developed their own protective antibodies against amyloid beta without suffering any side-effects over the duration of the study. Even so, larger trials still need to be conducted to ensure its efficacy.11 According to the most recent quarterly report from Novartis, this drug will not be fully developed until sometime after 2017, which is not far off into the future.

Monophosphoryl Lipid A (MPL): researchers at the University of Laval School of Medicine in Québec, Centre Hospitalier Universitaire de Québec in collaboration with GlaxoSmithKline have high hopes for this compound. MPL is a toll-like receptor agonist that arouses brain immune cell activity to fight production and deposition of amyloid beta. A study conducted in mice showed 80% plaque clearance in 3 months. Not only could this be a treatment for those already affected, it could also be administered as a vaccine for preventative measures. GSK and Canadian researchers hope that these trials will move into humans within the next two years, but it could be less since MPL has already proven to be safe in humans (used as a vaccine adjuvant).

Solanezumab

This investigational drug produced by Eli Lilly and is a humanized monoclonal antibody that binds to the central region of amyloid beta peptides.14 It had failed in a previous phase III clinical trial involving patients with mild and moderate Alzheimers. However reports from the company indicated the drug showed beneficial effects in patients with mild Alzheimer’s. Eli Lilly believes the reason that solanezumab fail the first time was that a quarter of the patients did not have amyloid beta plaques and were suffering from a form of dementia not caused by Alzheimer’s. In this new trial, they will be screening patients for amyloid beta and will focus on patients with mild Alzheimer’s. Solanezumab has been shown previously in phase I and II trials to be safe, causing no serious side effects.

Centers of Excellence

● National Institute of Aging – Alzheimer’s Disease Center, 30 centers in 19 states

○ These centers seem to be at the forefront of Alzheimer’s research.

● Mary S. Easton Center for Alzheimer’s Disease Research – UCLA School of Medicine

● Johns Hopkins School of Medicine – Alzheimer’s Disease Research Center

 

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