Alzheimer’s disease conventional treatment

Several overlapping mechanisms have been proposed to explain the underlying pathology of AD, and both current and potential future treatments are based on modification of these pathways.

 

 

Figure 1. Possible therapeutic targets: A) secretase enzyme inhibitors;B)N-methyl-D-aspartate (NMDA) receptors modulators – memantine; C) anti-inflammatory treatments, including non-steroidal anti-inflammatory drugs (NSAIDs); D) immunotherapy: immunization and monoclonal antibodies (anti-amyloid therapy); E) anti-tau therapy; F) anti-cholinesterase inhibitors – donepezil, rivastigmine, galantamine.

Unfortunately to date no drug was able to prevent development nor progression of AD. The conventional treatment consists of drugs aimed at control the symptoms.

  1. Approved drug treatment for cognitive symptoms:

    • Cholinesterase inhibitors (donepezil, rivastigmine and galantamine) – Acetylcholine is a neurotransmitter with important role in memory and learning. It was already demonstrated that AD patients have a cholinergic deficit and that cholinergic depletion is a late feature of the neurodegenerative cascade. Cholinesterase inhibitors (ChEIs) block the cholinesterase enzyme. This enzyme breaks down acetylcholine at the synaptic cleft. The inhibition of cholinesterase, increases the amount of acetylcholine in neuron’s surrounding, potentiating cholinergic transmission.
    • N-methyl-D-aspartate (NMDA) receptor blocker – (Memantine): Glutamate is a powerful excitatory neurotransmitter. An overexposure to glutamate, or the overstimulation of its N-methyl-D-aspartate (NMDA) receptor, is called excitotoxicity and plays an important role in the progressive neuronal loss of AD. Memantine blocks the NMDA receptor and, thus, may be neuroprotective by preventing neuron loss, as well as improving symptoms by helping to restore function of damaged neurons.

These two classes of drugs are the most used despite the frustrating results in scientific studies and also in clinical practice. A well-designed systematic review by the McMaster University Evidence-Based Practice Center evaluated 92 publications representing 59 studies of pharmacological agents for dementias.

The authors concluded: “Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia”.

A new Cochrane revision evaluating the efficacy of memantine in patients already taking ChEIs, showed that there is a small clinical benefit of memantine in people with moderate-to-severe AD, but no benefit in people with mild AD. “A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months of treatment”.

Most of clinical trials on ChEIs were of short (3 or 6 months) duration. As these results were considered sufficient for regulatory approval of the ChEIs, there was little incentive for pharmaceutical firms to do longer studies. However, long term use of ChEIs is common in clinical practice. We can find in the literature some independent reports that show information on adverse effects of cholinesterase inhibitors when these agents are used on a long-term basis. Such effects include anorexia, urinary incontinency, weight loss, syncope, bradycardia, falls, hip fractures, and increased need for a cardiac pacemaker.

Another problem to keep in mind is the “prescribing cascade”, where the first agent causes an adverse drug effect (e.g., urinary incontinence) that is treated by the prescription of a second medication to deal with the drug-induced problem. The concurrent prescription of pro-cholinergic and anticholinergic agents, which could blunt each other’s therapeutic effects leading to a pharmacological stalemate, is a particular concern with this specific combination of drugs.

  1. Drug treatment for agitation, psychosis, depression

Many different drugs are used to control psychiatric symptoms including antipsychotic, antidepressants, benzodiazepines and anticonvulsants. Once more they do not change the course of the disease, or try to abolish its cause, but are aimed to control the symptoms. A few examples of most used drugs:

  • Carbamazepine, Valproate
  • Diazepam, Clonazepam
  • Citalopram, Fluoxetine
  • Quetiapine, Risperidone, Olanzapine

  1. Potential future drug treatment:

    • Anti-amyloid therapy: Aβ production cascade depends on the cleavage of the amyloid-β protein precursor (AβPP) by enzymes called β- and γ-secretase. Inhibition or modulation of these secretases is a potential strategy for inhibiting Aβ production and thus prevent cognitive decline. Both inhibitor and modulators of γ-secretase showed promise results in mice and these results were reproduced in healthy human volunteers. Unfortunately, toxicity of the drug has prevented it from progressing to later stage clinical trials. β-secretase inhibitors (BACE) may also reduce Aβ, however, difficulties to find a drug that pass the blood–brain barrier have limited its progress. These difficulties are now being overcome, and orally available small molecule BACE1 inhibitors have been shown to reduce Aβ in animal models and is under study in humans.
    • Immunization Anti-Aβ: Anti-Aβ antibodies have shown great promise in pre-clinical studies, however, their usefulness in the clinical has not been demonstrate due to detrimental immune responses after active immunization.
    • Monoclonal antibody: to prevent over-activation of microglia, and to reduce dangerous immune response, a humanized anti-Aβ monoclonal antibody was developed that was shown to prevent amyloid aggregation and prevent Aβ cytotoxicity in neurons and mixed cortical cell cultures but did not demonstrate any treatment effect on either cognitive or functional outcomes. New monoclonal antibodies are under study and constitute a potential drug treatment in the future.
    • Tau-target therapy: The tau protein is a structural protein that helps stabilize the microtubules of neurons; however, hyperphosphorylation and aggregation may occur, forming filaments within neurons that condense into neurofibrillary tangles that are associated with neurodegeneration. Modulation of the pathological tau protein species may be a viable disease intervention and is a potential treatment under research.Until recently, several high-profile clinical trials of pharmacological agents targeted at modifying the amyloid cascade have been undertaken, with largely disappointing results. Some of these studies have been discontinued because of no improvement in cognition in the study group and worsening cognition at higher doses compared to controls. Incidence of side effects (including skin cancer) was also higher in the study group.

Until recently, several high-profile clinical trials of pharmacological agents targeted at modifying the amyloid cascade have been undertaken, with largely disappointing results. Some of these studies have been discontinued because of no improvement in cognition in the study group and worsening cognition at higher doses compared to controls. Incidence of side effects (including skin cancer) was also higher in the study group.

Studies of potentially disease-modifying therapy up to now have generally been undertaken in patients with clinically detectable, established disease, while it is already documented that the pathological changes associated with dementia begin several years before the emergence of the clinical syndrome. In this case, studies should be aimed to act in this pre-clinical stage, before the neurodegenerative process has been established. It is clear that PREVENTION is the most safe and effective way to fight AD.

References:

  1. Briggs R, Kennely SP, O’Nail D; Drug treatment in Alzheimer’s disease. Clinical Medicine 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922703/
  2. Hane FT, Robinson M et al; Recent Progress in Alzheimer’s disease research, part 3: diagnosis and treatment.J Alzheimers Dis 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389048/
  3. Hogan DB; Long-term efficacy and toxicity of cholinesterase inhibitors in the treatment of Alzheimer’s disease. Can J Psychiatry 2014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304580/
  4. Raina P, Santaguida P, Ismalia A et al; Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008. https://www.ncbi.nlm.nih.gov/pubmed/18316756
  5. McShane R, Westby MJ, Roberts E et al; Memantine for dementia. Cochrane Database Syst Rev 2019 https://www.ncbi.nlm.nih.gov/pubmed/30891742
  6. Rabins PV, Rovner BW, Rummans T et al; Guideline Watch (October 2014): Practice Guideline For The Treatment Of Patients With Alzheimer’s Disease And Other Dementias. org. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/alzheimerwatch.pdf
  7. May PC, Dean RA, Lowe SL et al; Robust central reduction of amyloid-ß in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci 2011. https://www.ncbi.nlm.nih.gov/pubmed/22090477/
  8. Vassar R;BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther 2014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304279/
  9. Shahpasand K, Shamloo AS, et al; “Tau immunotherapy: Hopes and hindrances”.Hum Vaccin Immunother 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806642/