Alzheimer’s Disease (AD) is now the most common of all the neurodegenerative diseases in the elderly (Dubois et al., 2010). It is affecting increasingly more people as we age and the numbers are set to continue rising as the population gets older. Not only is there a financial burden on global healthcare systems, it is a disease which has powerful emotional impacts on people caring for those with this type of dementia and for all families afflicted by the condition (Querfurth & LaFerla, 2010).
A Brief History Of Alzheimer’s Disease
The condition was first identified by Aloysius ‘Alois’ Alzheimer who was a German psychiatrist who lived in the late 19th Century until his death in 1913. He noticed particular types of patient who developed progressively worsening symptoms of behaviour. One such patient was Auguste Deter who was a special case study for characterising the external manifestations of the disease.
The condition is now labelled a syndrome and is the most common type of dementia in the developed world. It is estimated there are 46 million people living with this dementia. It is a progressive disease and is unfortunately irreversible.
The syndrome is characterised by loss of brain function where memory, thinking and reasoning, intellectual and cognitive skills gradually disappear. In all cases there is a change in personality and overall behaviour which is extremely distressing not only for the sufferer but also for those living with a person who has the condition.
At the moment the exact causes of Alzheimer’s are not understood but there are a number of risk factors associated with its development.
Alzheimer’s disease also has a related set of dementias termed ADRD.
Incidence Of the Disease
Roughly 3 per cent of men and women between the ages of 65 and 74 suffer with AD. About half those over the age of 85 and older may have the condition in its early stages. Nearly 3.6 million people around the world are diagnosed with it.
In the USA, there are over 50 million Americans aged over 65 years of age with AD and that is likely to more than double by 2060 according to the US Census Bureau when reported in 2018. It is the second leading cause of death in Australia according to news articles from 2021.
Pathogenesis
One physiological change to patients occurs in the state of their brain. There is an appearance of high levels of abnormal proteins which aggregate together to form ‘plaque’ and ‘tangles’. The plaques are peculiar in themselves. They are groups of proteins which form Aβ oligomers. These plaques appear to build up around synapses. One theory is that these sticky clumps then physically interfere with the synaptic based receptors which disrupts nerve transmission. One of the consequences is that the circuitry involved in memory creation and retention is disrupted severely. Another aspect is that the plaques also trigger immune -inflammation responses. as with an infection, immune cells are triggered to destroy those cells containing the plaque or those cells that have been modified in some way. In so doing, neural and brain cells are destroyed in the process. These seem to literally block the brain.
Risk Factors
Over the years of study a number of risk factors have become associated with development of the disease. There is no single cause for the disease. Some risk factors though may be more influential than others. It could be a mix of genetic, environmental and lifestyle factors. The whole development may take years and be a combination of numerous factors.
- Age, especially over 65 years of age.
- High blood pressure or hypertension
- Head injury
- Coronary heart disease
- Diabetes
- High cholesterol levels
- Possible genetic element as with a family history of the condition
- Down’s syndrome
- Some form of cognitive impairment
- Smoking and alcohol use
- High levels of plasma homocysteine
- Excessive sugar consumption
Age
Alzheimer’s disease is most common in people over the age of 65. It affects an estimated 1 in 14 people over the age of 65 and 1 in 6 people over the age of 80. There are however a significant number of people affected between the ages of 40 and 65. This is known as early- or young-onset Alzheimer’s disease.
Stages Of Alzheimer’s Disease
Stage 1 (Normal)…mentally healthy person
Stage 2: Normal aged forgetfulness
Some people over the age of 65 experience subjective complaints of cognitive and functional difficulties.
Stage 3: Mild cognitive impairment
The ability to do various activities is impaired. Very often job performance might decline if they are still working.
Stage 4: Moderate Alzheimer’s Disease
An inability to manage complex activities associated with life such as finances, cooking meals for example. Usually one of the clearest signs of the onset of the disease.
Stage 5: Moderate Alzheimer’s Disease
An inability to choose what clothing to wear for weather conditions and for other daily circumstances.
Stage 6: Moderately severe Alzheimer’s Disease
An inability to perform most of life’s activities.
Stage 7: Severe Alzheimer’s Disease
The sufferer requires continuous assistance with the basic activities needed for life and indeed survival.
Latest thoughts on the cause of the disease
Recent studies from the Curtin Health Innovation Research Institute (CHIRI), Curtin University in Australia have highlighted a possible cause for the disease. With the finding comes the possibility of new preventive approaches and treatments (Lam et al., 2021).
The study published in PLOS Biology using mouse models suggests that fat-carrying proteins called lipoproteins are also transporting toxic proteins such as beta-amyloid from the blood into the brain.
Drugs & Treatment For Alzheimer’s Disease
At the biochemical level, it is known that an oxidized LDL receptor 1 and the angiotensin 1 converting enzyme are linked to the way in which brain cells bind a protein called Apolipoprotein 4 (APOE4). This protein reduces the build up of harmful proteins which are called plaques.
There are a number of drugs available which slow down the progression of the disease. Pharmacological intervention includes the use of acetylcholinesterase inhibitors. These prevent the breakdown of acetylcholine which is a chemical messenger essential for memory and learning. Common drugs include Galantamine (Razadyne ex. Reimnyl)), Donepezil (Aricept) and Rivastigmine (Exelon) (Mehta et al., 2012). The commonly used drug Tacrine has now been withdrawn from the market by the USA’s Food And Drug Administration (FDA) because it is associated with liver damage.
Memantine
Other drugs which have effectiveness against severe forms of Alzheimer’s include those which are N-methyl d-aspartate (NDMA) receptor antagonists. One particular drug known as Memantine not only blocks this receptor for NDMA but also inhibits its overstimulation by glutamate which is a potent neurotransmitter.
Memantine is taken orally as a tablet or solution. Its benefits on patients are variable but it can improve cognitive function in some patients. The drug binds to the NMDA (N-methyl-D-aspartate) receptor preventing glutamate from overactivating the NMDA receptor. Overactive NMDA receptors are linked to excessive amounts of calcium passing into the neurones. Excessive amounts of calcium in such neurones are damaging to it and eventually cause death of the neurone. Unfortunately memantine does not reverse the neurodegeneration, but simply alleviates it.
The latest therapies are starting to exploit nano-based technologies as an alternative route to conventional drug delivery approaches (Altinoglu & Adali, 2020). These have been tested with natural bioactives and there is considerable interest in curcumin which is isolated from turmeric, in huperzine A, beta-asarone, folic acid and extract of Gingko biloba.
There are also some interesting lifestyle choices that can be made too. Clearly improvements in exercise and overall activity would suffice. Drinking coffee is claimed to be a possible way of ameliorating the effects of cognitive decline and this may be related to both the functions of caffeine and the polyphenols contained in the coffee.
The phenomenon may be related to impairment in enzyme functions creating structural proteins in the brain. Glycation is an important biochemical reaction which possibly means certain proteins are affected. There is a link with excessive sugar consumption but this might have as much to do with diabetes than any other effect.
To find out more about the subject view the Alzheimer’s Research UK web-site.
References
Altinoglu, G., Adali, T. (2020) Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems. Curr Drug Targets. 21(7) pp. 628-646. doi: 10.2174/1389450120666191118123151. PMID: 31744447.
Dubois, B., Feldman, H.H., Jacova, C., et al. (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 9(11) pp. 1118–1127
Lam, V., et al. (2021) Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype. PLOS Biology. doi.org/10.1371/journal.pbio.3001358.
Mehta, M., Adem, A., Sabbagh, M. (2012) New acetylcholinesterase inhibitors for Alzheimer’s disease. Int. J. Alzheimers Dis. 2012:728983.
Querfurth, H.W., LaFerla, F.M. (2010) Alzheimer’s disease. N. Engl. J Med. 362(4) pp. 329–344.
Leave a Reply