Why haven’t we cured Alzheimer’s disease?

By Alexandra Grba

As our global population ages, the occurence of neurodegenerative disease is predicted to rise dramatically. Advances in medicine mean that our bodies are being taken care of more efficiently than ever before, allowing us to grow very old while our brains deteriorate.  Currently, over 50 million people worldwide suffer from dementia; a condition that refers to a loss of cognitive functioning (National Institute on Aging, 2021). Alzheimer’s disease is the most common form of dementia and cases of this debilitating disease are expected to triple by 2050 (WHO, 2021). This will not only cause immeasurable human suffering, but also an inordinate strain on resources and health care. Our limited understanding about how dementia develops, clinical trial failures and lack of funding means that there are no cures to treat or slow neurodegenerative diseases at present.

Alzheimer’s disease is the most common neurodegenerative disease, affecting millions of people each year. Around 1% of Alzheimer’s cases are genetic, and in these instances the disease is associated with an early onset and symptoms first appearing in middle age. The majority of cases, however, are related to ageing. Alzheimer’s is characterised by a progressive neurodegeneration, with symptoms worsening over time. The ability to think, remember and make decisions is severely impaired, alongside poor motor coordination, the onset of mental illness and disrupted sleep (Alzheimer’s Research UK, 2021). Imaging of the brain in Alzheimer’s patients has revealed that the disease is associated with a loss of cortical brain volume, enlarged ventricles, widened sulci and thinned gyri (Harris, de Rooij & Kuhl, 2018).  In addition, Alzheimer’s disease is known to be caused in part by neuronal death. This is particularly problematic considering that neurons are permanently postmitotic, and therefore cannot divide or become replenished. At a cellular level, the disease is characterised by so-called amyloid plaques and neurofibrillary tangles, formed by the pathological molecules Amyloid-beta and phosphorylated tau respectively (Harris, de Rooij & Kuhl, 2018). 

Treating Alzheimer’s disease is particularly problematic as it develops for up to 20 years undetected before noticeable symptoms first appear (Holtzman, Mandelkow & Selkoe, 2012). This means that significant damage to the brain and neurons has occurred before diagnosis, which is difficult or potentially impossible to reverse or even treat. As a result, potential therapies must be used at a very early stage, before the manifestation of clinical symptoms. Blood tests for disease markers such as phosphorylated tau are currently available to diagnose Alzheimer’s early, however permanent treatment is yet unavailable. Acetylcholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist, memantine, are the only drugs available for the treatment of Alzheimer’s, however their effects are moderate and transient and do not offer a real solution to disease treatment (Holtzman, Mandelkow & Selkoe, 2012).

Glutamatergic and cholinergic signalling in the brain is implicated in learning and memory, and it is thought that defects in these signalling pathways contribute to Alzheimer’s disease (Parsons et al., 2013). The synaptic NMDA receptor is activated and opened by glutamate, allowing calcium ions to flow to the postsynaptic neuron and activate a signalling cascade which results in synaptic plasticity, the activity-dependant alteration of synaptic strength, resulting in learning and memory. Under normal conditions, magnesium ions block NMDA receptor channels, and transiently unblock upon membrane depolarisation after the glutamate signal. In Alzheimer’s, NMDA receptors are thought to be constitutively stimulated, leading to constant calcium ion influx in the postsynaptic neuron (Danysz & Parsons, 2003). This creates ‘background noise’ from which normal glutamatergic signalling cannot be deciphered, and could also lead to neurodegeneration through excitotoxicity (Danysz & Parsons, 2003). There is evidence that amyloid-beta inhibits the astroglial glutamate transporter (Nyakas et al., 2011) and reduces glutamate reuptake, increasing levels of glutamate around the synaptic cleft. 

The amyloid-beta protein has also been implicated in reducing release, synthesis and transport of acetylcholine. Preclinical studies involving cholinergic antagonists resulted in impaired memory in animals, implicating cholinergic signalling in Alzheimer’s disease (Parsons et al., 2013). In addition, biopsies of the neocortex have revealed that choline uptake, choline acetyltransferase activity and resulting acetylcholine production are depressed in patients with Alzheimer’s, implicating a loss of presynaptic cholinergic nerve endings as a key factor in causing Alzheimer’s disease (Sims et al., 1983). It is thought that cholinergic neuron degeneration leads to reduced acetylcholine levels and weakened signalling, leading to cognitive and memory deficits (Parsons et al., 2013).

The two classes of drug currently available for Alzheimer’s treatment are the aforementioned NMDA receptor antagonist memantine, and acetylcholinesterase inhibitors donepezil, galantamine and rivastigmine. Memantine binds in the NMDA receptor ion channel (Chen et al., 1992) with a higher affinity than the magnesium ions, meaning that, during prolonged stimulation in the pathological state, it does not dissociate as the magnesium ions would. It does dissociate, however, during normal signalling, when high concentrations of glutamate are transiently present for normal neurotransmission (Parsons et al., 2013). As a result, the physiological signals can be deciphered from the ‘background noise’ and normal signalling may proceed. On the other hand, acetylcholinesterase inhibitors serve to inhibit the breakdown of acetylcholine, boosting cholinergic activity lost in Alzheimer’s disease (Parsons et al., 2013).

While dementia is globally more prevalent than cancer, there has been significantly less funding for research into these diseases. For comparison, there are only around 5000 researchers in the U.K. for dementia and 25,000 for cancer. In addition, there have only been a few thousand clinical trials for dementia since the year 2000 and over 25,000 for cancer (Dementia Statistics Hub, 2021). These figures represent the alarming lack of action with regard to curing dementia and is reflected by the lack of suitable drugs on the market to slow or prevent the progression of these neurodegenerative diseases. Drugs such as acetylcholinesterase inhibitors and memantine have not been found effective in the long term and only offer transient relief, illustrating how more research into understanding the pathology of Alzheimer’s disease is critical. Recently, a link between innate immunity and Alzheimer’s disease (Shi et al., 2019) has indicated that brain immune cells such as microglia could be a potential drug target in disease treatment. Such advances show there is much progress to be made with research into Alzheimer’s disease, and a renewed effort is required in order to respond to this increasingly prevalent health concern.

References :

Alzheimer’s Research UK. (2021) Alzheimer’s Research UK – the UK’s leading Alzheimer’s research charity. Available from: http://www.alzheimersresearchuk.org/ [Accessed 3 March 2021].

Chen, H., Pellegrini, J., Aggarwal, S., Lei, S., Warach, S., Jensen, F. and Lipton, S. (1992) Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. The Journal of Neuroscience, 12(11), 4427-4436. Available from: doi: 10.1523/JNEUROSCI.12-11-04427.1992

Danysz, W. and Parsons, C. (2003) The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. International Journal of Geriatric Psychiatry, 18(S1), S23-S32. Available from: doi: 10.1002/gps.938

Dementia Statistics Hub. (2021) Dementia Statistics Hub | Alzheimer’s Research UK. [online] Available at: <https://www.dementiastatistics.org&gt; [Accessed 3 March 2021].

Harris, T., de Rooij, R. and Kuhl, E. (2018) The Shrinking Brain: Cerebral Atrophy Following Traumatic Brain Injury. Annals of Biomedical Engineering, 47(9), 1941-1959.

Available from:doi: 10.1007/s10439-018-02148-2

Holtzman, D., Mandelkow, E. and Selkoe, D. (2012) Alzheimer Disease in 2020. Cold Spring Harbor Perspectives in Medicine, 2(11), a011585-a011585.Available from: doi: 10.1101/cshperspect.a011585.

National Institute on Aging. (2021) What Is Dementia? Symptoms, Types, and Diagnosis. [online] Available from: https://www.nia.nih.gov/health/what-dementia-symptoms-types-and-diagnosis [Accessed 3 March 2021].

Nyakas, C., Granic, I., Halmy, L., Banerjee, P. and Luiten, P. (2011) The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behavioural Brain Research, 221(2), 594-603. Available from:doi: 10.1016/j.bbr.2010.05.033

Parsons, C., Danysz, W., Dekundy, A. and Pulte, I. (2013) Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer’s Disease. Neurotoxicity Research, 24(3), 358-369. Available from: doi: 10.1007/s12640-013-9398-z

Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P.M., Remolina Serrano, J., Hoyle, R., Holtzman, D.M. (2019) Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 216 (11), 2546–2561. Available from: doi.org/10.1084/jem.20190980 

Sims, N., Bowen, D., Allen, S., Smith, C., Neary, D., Thomas, D. and Davison, A. (1983) Presynaptic Cholinergic Dysfunction in Patients with Dementia. Journal of Neurochemistry, 40(2), 503-509. Available from: doi:10.1111/j.1471-4159.1983.tb11311.x

Who.int. (2021) Dementia cases set to triple by 2050 but still largely ignored. Available from: 

https://www.who.int/mediacentre/news/releases/2012/dementia_20120411/en/&nbsp;   [Accessed 16 February 2021] 

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