Dementia has Many Causative Factors! The Latest Theories Revealed

Dementia is now commonly viewed as a disease that has many contributing factors. These involve complex cascades of physiological processes that we do not yet fully understand. Put simply, it is not a singular disease, but an agglomeration of pathologies that lead to a loss of cognitive function.

Just to remind everyone that this will be my last piece until after Christmas. As I mentioned last week, this week’s article is on the causes of dementia.

Dementia is an extremely complex disease and in recognition of this, both national and international initiatives have been developed. The Global Alzheimer’s Association Interactive Network (GAAIN) was launched in 2019 by the European Union’s Innovative Medicines Initiative.

This allows researchers to access huge, shared data sets while sharing their own data by joining a global network of Alzheimer’s disease centres. In January 2021 the Davos Alzheimer’s Collaborative (DAC) was also launched to help address the global dementia crisis.

Meanwhile in the UK the Prime Minister’s ‘Challenge on Dementia 2020’ set out more than 50 specific commitments that together will hopefully make England the world leader in dementia care, research and awareness. This was set up by David Cameron in February 2015 and its legacy continues today in the strange political universe that we now enjoy.

The pandemic and the ability of Boris Johnson to defy any political gravity has been other-worldly. Anecdotes about ‘Peppa Pig World’ add a sense of surrealism to our political landscape. Then there is the distraction of those in government failing to adhere to their own social distancing guidelines.

Assuming Matt Hancock’s wandering hands were free to explore his own in-tray, before he was replaced by Sajid Javid, he might have found some paperwork relating to ‘Challenge on Dementia 2020’. This was probably covered in wine stains from the infamous Christmas Parties which led to the resignation of a tearful Allegra Stratton (even stranger was the fact that Rishi Sunak was best man at her wedding in 2011). The party that took place at Downing Street during Christmas 2020 has not gone unnoticed on social media platforms.

In honour of the scandal a Facebook event has been set up for a mass party at the gates of Downing Street this coming Christmas. More than a million people have been invited to an event outside Number 10 on Christmas Eve.

Apparently, at the time of writing, more than 415,000 people said they are attending, while almost 585,000 people are ‘interested’ in attending the ‘Christmas rave’. It is being organised by DJ John Mancini, with people urged to ‘bring who you like’ and ‘bring your own nibbles and drink’. Who would want to be Boris Johnson! It is great to have a bit of fun but back to more serious matters.

Traditional Opinions on Dementia

In the UK, the number of people with dementia is estimated at 850,000. There are also roughly 540,000 carers of people with dementia just in England alone (BREXIT has also led to a huge deficit of experienced carers). It is estimated that one in three people will care for a person with dementia in their lifetime. Half of these people will be employed.

It is estimated that some 66,000 people have already cut their working hours to care for a family member, whilst 50,000 people have left work altogether. There is a considerable economic cost associated with the disease estimated at £23 billion a year, which is predicted to triple by 2040. This is more than the cost of cancer, heart disease and stroke.

We mentioned last week that one of the hallmarks of AD is amyloid-β protein which aggregates in between neurons to eventually form large plaques. Beta-amyloid is chemically ‘sticky’ and it appears to accumulate into amyloid plaques which we then view as a hallmark of AD. According to the amyloid hypothesis, these stages of amyloid-β protein aggregation disrupt cell-to-cell communication and activate immune cells. These immune cells trigger inflammation. Ultimately, the brain cells are destroyed.

This hypothesis of amyloid-β protein has dominated Alzheimer’s research for 25 years because it was an obvious target. Since plaques in the brain are a hallmark of the disease, it seemed likely this was the culprit. It can be compared to cholesterol deposition as an indicator of cardiovascular disease. Unfortunately, as with heart disease, once people have symptoms the damage has already been done and the presence of amyloid-β protein or cholesterol is irrelevant.  

Serious doubts began to emerge as various amyloid-β protein targeting drugs successively failed to make any impact on clinical symptoms of dementia. These failures reinvigorated doubts over the 25-year-old theory that amyloid-β protein was crucial in AD. Many researchers now consider that it is time to explore other avenues. As I mentioned last week, it has come as no surprise that the latest drug to combat amyloid-β protein called Aducanumab, just recently approved by the FDA, has been met with considerable controversy.

Another hallmark of AD is the aggregation of Tau proteins which help build a key cellular structure called a microtubule. Microtubules are microscopic hollow tubes that form cellular scaffolding, they are important in giving a cell its shape.

They also act as an inner transport network enabling essential materials to move within a cell. In AD, because of abnormal chemical changes, small fragments of Tau aggregate together. These tangles block the transportation network inside the cell, eventually affect cell communication and cause cell death. There are no drugs that are successful in preventing a build-up of Tau protein. This is made more complicated because Tau protein aggregates occur inside neurons, making it tricky to access. To make matters worse there are even various different forms of Tau.

Changing Perspectives on dementia

In general AD is now commonly viewed as a disease that has many contributing factors. These involve complex cascades of cellular and molecular processes that we do not yet fully understand. Put simply, it is not a singular disease, but an agglomeration of pathologies that lead to a loss of cognitive function.

It is perhaps unfortunate that having a narrow focus specifically on amyloid-β protein may have served to limit progress. In comparison treatment programmes for cardiovascular disease involve a comprehensive array of medications, surgeries and lifestyle factors like diet and exercise. The same approach should be used for AD.

I have recently written two articles about the connection between dementia and a western diet. There is a definite link between a poor diet, obesity and dementia. However, a recent study published in the ‘Nature’ journal on December 8th, 2021, demonstrates that exercise also has an important role to play in dementia.  Physical exercise is generally beneficial to our health, and it has been shown to reduce cognitive ageing and neurodegeneration.

In this latest study blood plasma was collected from mice that were given access to a running wheel. Apparently, these busy little mice were running up to six miles a night. When the plasma from the fit mice was infused into a group of sedentary mice (who did not have access to a running wheel) their cognitive powers were remarkably increased. The study identified a protein called ‘clusterin’ that was present in the plasma extracted from the fit mice.

Further research showed that this binds to receptors of blood vessels in the brain and helps mitigate inflammation. The study proved that exercise has anti-inflammatory benefits. This implies that patients with cognitive impairment who participate in structured exercise could improve their cognitive abilities (the protein clusterin is also present in us).

There are also many other factors involved in determining the likelihood of dementia. There are genetic mutations that can lead to increased susceptibility. These genes will increase the likelihood of developing the disease but do not specifically guarantee it will occur. Studies have found several genes that increase the risk of Alzheimer’s. APOE-e4 is the first risk gene identified and remains the gene with the strongest impact on risk. It is estimated that 40-65% of people diagnosed with Alzheimer’s have the APOE-e4 gene.

APOE-e4 is one of three common forms of the APOE gene; the others are APOE-e2 and APOE-e3. We all inherit a copy of some form of APOE from each parent. Those who inherit one copy of APOE-e4 from their mother or father have an increased risk of developing Alzheimer’s. Those who inherit two copies from their mother and father have an even higher risk, but not a certainty. In addition to raising risk, APOE-e4 may tend to make symptoms appear at a younger age than usual. Combined with our genetic inheritance there are also a range of pathologies that influence our likelihood of developing dementia.  

It is now recognised that there is also connection between midlife hypertension and Alzheimer’s. Hypertension will lead to vascular damage in our central nervous system, and this will increase the likelihood of developing dementia. There is also a correlation with Type 2 Diabetes.

Some studies suggest that there is an increased susceptibility to dementia because insulin has an important role in helping to maintain our neural synapses and in the regulation of our vascular functions. There is also evidence that oxidative stress can have an impact. Oxidative stress is an imbalance between harmful and damaging reactive free radicals and antioxidants in your body. Free radicals are a natural by-product of our metabolism.

They are what is known as oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. Free radicals can cause large chain chemical reactions in your body because they react so easily with other molecules. These reactions are called oxidation.

Research has also implied that even infections can have a role in determining whether we get dementia. Although there have been conflicting findings over the years, evidence is building that certain viruses and bacteria increase risk. It has been demonstrated that gum disease can increase the risk of AD by about 70%.

The bacteria Porphyromonas gingivalis and its toxic enzymes has been found in the brains of people suffering from AD. As of yet there is no direct link between dental hygiene and Alzheimer’s risk, but it is probably a good idea to brush, floss and see your dentist regularly. It has also been shown that an infection by Herpes Zoster can trigger amyloid-β protein aggregation.

Some studies have also linked sleep problems with AD. This is possibly because while we sleep potentially harmful proteins are removed and flushed away. Research suggests a night without sleep leads to higher levels of amyloid-β protein, Tau accumulation and brain inflammation. There is also growing evidence that blows to the head can increase the risk of developing dementia.

A study published this year demonstrated a higher incidence of neurodegeneration in former male professional football players.  In this study, risk of neurodegenerative disease was higher among former professional soccer players with longer careers and among those in non-goalkeeper positions. The study recommended strategies to reduce head impact exposure may be advisable to reduce negative outcomes in this population.

Research suggests that Alzheimer’s disease has many contributing factors that involve physiological processes that we don’t yet understand and any number of pathological factors.