Bumetanide for Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia, affecting up to 70% of all people with dementia.¹ In the early stages, symptoms can be subtle, and often dismissed by people as lapses in memory, or just having trouble with finding the right words for everyday objects.¹ The symptoms and rate of neurodegeneration will vary depending on the individual, but ultimately leads to complete dependence and finally death, usually from another illness (e.g. pneumonia).¹

The accumulation of beta-amyloid plaques and tau tangles is still considered some of the main features of Alzheimer’s disease.² Changes to the brain may begin a decade before symptoms appear,² resulting in destruction of cholinergic neurons, leading to a fall in acetylcholine concentrations.³ Ultimately, healthy neurons stop functioning, lose connections with other neurons, and die.

As more and more neurons die, the brain begins to shrink, such that there is widespread damage and significant shrinkage in brain tissue in severe Alzheimer’s disease.² This damage appears to start in the hippocampus and the entorhinal cortex, which are essential for forming memories.²

The mechanism for Alzheimer’s disease development is not entirely understood, but recent work is shedding more insight into factors which might contribute (e.g. the role of diabetes and insulin in brain health,⁴ and brain cells with processing fats or lipids).⁵

The apolipoprotein E gene (APOE4) is one of the most significant risk factors for late-onset Alzheimer’s disease, but inheriting this gene does not mean one will definitely develop the disease.^5,6

The APOE protein helps carry cholesterol and other types of fat in the bloodstream, but the exact reason for why and how this gene increases the risk of Alzheimer’s disease is not entirely defined.⁵ Approximately 25% of the population are heterozygous carriers (i.e. one copy of APOE4) which incurs a 3-4 fold risk of developing Alzheimer’s disease, while 2-3% of the population carry both copies of APOE4, which carries a 12-14-fold risk.^5,6

The management options for Alzheimer’s disease are still limited, and no intervention prevents or changes the pathology.^1,3 Current treatment (anticholinesterases and memantine), provide temporary improvements in cognitive functioning and/or reduce the rate of cognitive and functional decline, at best. Anticholinesterases (e.g. donepezil, galantamine or rivastigmine) appear comparable in efficacy, and reduce the breakdown of acetylcholine to counteract the fall in acetylcholine concentrations following destruction of cholinergic neurons.³ Since Alzheimer’s disease is also thought to be associated with glutamate-induced neuronal degradation, particularly overactivation of the N-methyl-D-aspartate (NMDA) receptors, memantine (an NMDA antagonist) is also used.³

Unfortunately, the clinical usefulness of existing pharmacological agents and effect on quality of life remains uncertain.³ The optimal duration of treatment with is also unclear, with ongoing use guided by risk of side effects versus benefits, which, if any, usually appear within 3-6 months of starting treatment.³

Perhaps the silver lining is with precision medicines, and the opportunity to target therapy for those with specific APOE genotypes, as it is known that people with different genotypes will respond differently to treatment.⁶ Recent work in cancer using computational drug-repurposing algorithms looked at existing medicines which could reverse or ‘flip’ differentially expressed genes in diseased states back to normal levels, with the thought that these medicines would then be effective against the disease.⁶

This work was re-used as an imprecise database to look at APOE genotype-dependent transcriptomic signatures of Alzheimer’s disease, and bumetanide was identified as the top medicine for APOE4-related Alzheimer’s disease.

The follow up animal studies were also promising, with bumetanide rescuing ‘electrophysiological, pathological or cognitive deficits’ in APOE4 knock-in mice with and without beta-amyloid accumulation, and reversing transcriptomic signatures of Alzheimer’s disease.⁶ Finally, data from two electronic health records with a combined total of over 7 million people across the United States identified 3,751 people prescribed bumetanide who were over 65 years of age. When these people were compared against a ‘control’ group who were not exposed to bumetanide, and stratified against other risk factors (e.g. age, gender, hypertension), there was a significantly lower prevalence of Alzheimer’s disease, in the order of a 40-70% decrease.⁶

Bumetanide is commonly known as a loop diuretic, and works by inhibiting sodium and chloride reabsorption in the ascending loop of Henle.⁷ The ‘neuroprotective’ effect is in part thought to be via bumetanide’s action at the Na–K–2Cl cotransporter (NKCC1) which is behind the blood brain barrier.⁸ A comparison of the neuronal pathways in the mouse Alzheimer’s disease model, when compared with humans, found three overlapping pathways, suggesting the benefits of bumetanide were related to the these pathways: GABAergic synapses, circadian entrainment and morphine addiction.⁶

Much more work is needed before bumetanide can be considered clinically for Alzheimer’s disease, including strategies to overcome the blood brain barrier to access the CNS,⁸ and looking at the benefits specifically in people with APOE4 genotyping.

While still early days, these types of drug repurposing algorithms, using databases created from cell types more precisely matched with the condition under investigation, could reduce costs and accelerate the time between when a molecule is discovered, to its use clinically as a medicine. In this instance, building databases created from cell types relevant to neurological conditions may potentially uncover targets more promising than bumetanide.

References

1. Dementia Australia. Alzheimer’s disease | Dementia: Dementia Australia Ltd; 2020. At: www.dementia.org.au/about-dementia/types-of-dementia/alzheimers-disease
2. NIH National Institute on Aging. Alzheimer’s Disease Fact Sheet US: US Department of Health and Human Services; 2021 [updated 2021. At: www.nia.nih.gov/health/alzheimers-disease-fact-sheet
3. Australian Medicines Handbook. Australian Medicines Handbook – Alzheimer’s disease: Australian Medicines Handbook Pty Ltd; 2022.
4. The Lancet. Diabetes and brain health: Elsevier Inc; 2020. At: www.thelancet.com/series/diabetes-brain-health#:~:text=A%20joint%20Series%20between%20The,people%20at%20risk%20of%20cognitive
5. NIH National Institute on Aging. Study reveals how APOE4 gene may increase risk for dementia US: US Department of Health and Human Services; 2021 [updated 2021]. At: www.nia.nih.gov/news/study-reveals-how-apoe4-gene-may-increase-risk-dementia
6. Taubes A, Nova P, Zalocusky K, et al. Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease. Nature Aging 2021;1:932–47.
7. Australian Medicines Handbook. Australian Medicines Handbook – Bumetanide: Australian Medicines Handbook Pty Ltd; 2022.
8. Löscherab W, K K. CNS pharmacology of NKCC1 inhibitors. Neuropharmacology 2022;205(2022).

DR ESTHER LAU BPharm (Hons), PhD, GCResComm, GradCertAcadPrac, AACPA, MPS is Acting Head of Discipline and a Senior Lecturer in the Discipline of Pharmacy at the Queensland University of Technology (QUT).

PROFESSOR LISA NISSEN BPharm, PhD, FPS, FHKAPh, FSHP is the Head, School of Clinical Sciences, at QUT.