Combinatorial Drug Strategy Could Be Key To Treating Alzheimer’s

Alzheimer’s disease is a notoriously difficult condition to treat. The complete lack of any disease modifying treatments being licensed since the disease was first diagnosed over 100 years ago exemplifies this difficulty.

There are multiple reasons for this failure and is a contentious issue among some researchers.

4 Major Pathologies

Alzheimer’s disease is a complex condition, with multiple genetic and environmental factors contributing to onset of disease and multiple cellular and molecular pathways pushing pathogenesis. The 4 major pathologies are:

  • neurovascular dysfunction and associated mitochondrial dysfunction
  • amyloid and tau protein deposits
  • excessive oxidative stress
  • inflammatory damage from reactive glial cells

Therapeutic treatments and drugs placed in clinical trials have focussed on only one of the pathogenic mechanisms of Alzheimer’s disease (amyloid and tau protein deposits). This has enabled the other factors which contribute towards to the disease to flourish unhindered by therapy, and may be the reason why all clinical trials have been unsuccessful for the disease so far.

5-Drug Treatment

James Weinstein from Marshall University School of Medicine has proposed a combination of medications as a means to treat the multifactorial pathology present in Alzheimer’s disease. The treatment would combine 4 drugs and a vitamin to treat the four different major pathologies of Alzheimer’s disease.

All of the drugs proposed are currently used for various conditions and have been used in preliminary tests for Alzheimer’s disease with minimal side-effects arising from the treatments.

The drugs proposed were selected due to their ability to improve blood flow to the brain (trental), reduce neuronal protein depositions (nilotinib), reduce the production of reactive oxygen species (methylene blue), and inhibit reactive gliosis and pro-inflammatory cytokines (nicergoline). In addition to this, Weinstein proposes the prescription of vitamin B6, to further protect against damaging oxidative stress and harmful modifications to proteins.

Potential Small Trial Cohorts

Weinstein further postulates that a combinatory therapy which treats all major pathological hallmarks of Alzheimer’s disease is likely to cause a termination of dementia related progression. This has also led to his suggestion that a clinical trial for such a combinatory medical regime would only require a small cohort of patients (15 people) to establish a significant effect from the treatment.

This is in stark contrast to other clinical studies which commonly require thousands of patients to establish a statistically significant effect and thereby validate the treatment and study as truly effective.

Taking Down A Multi-Faceted Disease

The concept of targeting multiple facets of a disease is not particularly new – numerous anti-microbial and chemotherapeutic therapies utilise combination treatments to maximise patient outcome. For use in Alzheimer’s disease, on the other hand, is a relatively novel concept, and yet to be fully tested.

Whether the therapeutic regime proposed by Weinstein in this paper will be proved to be affective or not to treat Alzheimer’s disease may not be so important. The shift of view in therapeutic targets in this neurodegenerative disease to the targeting of more than one protein or process may lead to drugs which reach clinical trials with an enhanced chance to succeed, rather than asking a drug to do the job of a combinatory panel of drugs.

James D.Weinstein
A unique and promising combination of medications for the treatment of Alzheimer’s disease
Medical Hypotheses; November 2017. Volume 109 , 53 – 55 doi.org/10.1016/j.mehy.2017.09.021

Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester.