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Monday 19 January 2015

Alzheimer's disease - the causes and consequences

Alzheimer’s disease is the most common form of dementia and affects almost half a million people in the UK alone - and the number is rising[1]. Typical symptoms of Alzheimer’s include lapses in memory, mood swings, and difficulties performing everyday activities[1], but the exact symptoms a patient will display are unique to the individual. The only thing that is consistent between all Alzheimer’s patients is the debilitating effects this disease has on the patient and their quality of life. Many patients suffer from extreme memory loss, losing the ability to recognise friends and loved ones. Some patients even lose the ability to feed themselves and rely on carers and family members for basic life skills that we take for granted.

Despite being identified in the early 20th century, we are still not exactly certain why some of us will develop Alzheimer’s while others will not. Our brains are complex organs that provide us with memories, personalities and make each individual unique; any disease that affects this vital organ can lead to drastic changes in someone’s life. Alzheimer’s is no different; it’s a progressive disease meaning the damage to the brain worsens over time, leading to more pronounced symptoms and deterioration in a patient’s condition[1].

Photograph of Auguste Deter, the first patient to be diagnosed with Alzheimer's Disease
Auguste Deter was the first person to be diagnosed with Alzheimer’s disease, in 1901. She died in 1906, aged 55. Photograph by unknown photographer, 1902. (Public domain)

There are many aspects of Alzheimer’s that makes finding a cause, and indeed a cure, more difficult. For example, Alzheimer’s is unique to each individual patient depending on which part of the brain is affected. There are many different types of dementia, of which Alzheimers is only one, and differentiating between them is difficult because the symptoms are similar and can be very vague in the early stages, and similar to other conditions such as depression. We’re currently able to diagnose Alzheimer’s with 90% accuracy; it’s impossible to achieve 100% without dissecting the brain itself [2], although other diagnosis methods are rapidly catching up!

When we are able to examine the brain, one issue immediately becomes obvious. A person with Alzheimer’s possesses many “plaques” and “tangles” within the brain[3], a fact noticed by Aloysius Alzheimer, from whom the disease derives its name[4]. Plaques and tangles are caused by the buildup of tau and beta-amyloid proteins in the brain. While these proteins do exist in the healthy brain, in patients with Alzheimer's abnormal processes make them clump together[5]. These abnormal protein behaviours are thought to contribute to the many symptoms of Alzheimer’s, but what isn’t known is whether this is causing the Alzheimer’s or occurs as a consequence of the disease. Interestingly, individuals have been found who have all the neurological changes associated with Alzheimer’s without ever displaying any symptoms of the disease[3]. This adds to the mystery of the “plaques” and “tangles” and what their actual role in Alzheimer’s might be.

Image illustrating the effects of Tau molecules on neurons courtesy NIA
The “plaques” and “tangles” found in the brains of Alzheimer’s patients are caused by two proteins behaving abnormally; beta-amyloid is thought to usually be involved in neuronal development, but in many Alzheimer’s patients the protein is not processed properly. The incorrect processing leads to a build-up of large amounts of beta-amyloid as the protein loses its solubility. The higher concentrations lead to this protein creating large aggregates known as “plaques”. “Tangles” are instead caused by the protein “tau”, which in Alzheimer’s patients has too many phosphate groups added to the protein, this makes tau clump together within the nerve cells.[5] Image credit: National Institute on Aging (public domain)

In a minor number of Alzheimer’s patients, specific mutations in the DNA code lead to this abnormal behaviour of tau and beta-amyloid [6]. Cases can be also be attributed to mutations in a protein called APOE, however the mutation only increases the risk of an individual developing Alzheimer’s and does not guarantee the onset of the disease[7]. However, these make up the minority of Alzheimer’s cases; in the majority of patients the onset of disease does not appear to correlate to an incorrect DNA code. It would appear therefore that there is more going on with Alzheimer’s disease than first meets the eye and that in the majority of cases perhaps Alzheimer’s is not specifically caused by a mutation in an individual’s DNA.

More recently, scientific studies have been focusing on another potential cause of Alzheimer’s; changes in a person’s epigenetics[8]. Epigenetics is best thought of as an additional layer of information to a person’s DNA, but this information is not present in the DNA code itself. For an example of how the epigenetic code can work, read the two following sentences:

I am not shouting at you.


There is no difference in the characters or letters or words in these sentences yet most people will read the second sentence as if I am shouting the words to you from across a room. This is very similar to how epigenetics works; no changes to the actual DNA code are made, but adding or removing chemical groups attached to the DNA changes how it is read. Such groups are called epigenetic marks. Some groups allow the DNA to be read more easily but other marks compress the DNA making it less easy to access, which effectively silences genes. Ultimately, this results in a change of the expression of the genes where these groups are present or absent. The chemical groups added to DNA make up the epigenetic code (or epigenome) and provide a link between our environments and how our genes are expressed. For example, scientists have shown that smoking, diet and activity levels all affect our epigenome[9][10]. The epigenome is also affected by age, and can vary enormously between individuals and even between identical twins[11]. The majority of epigenetics is not passed on to offspring, however in some cases the epigenetic code can be inherited.

Infographic of epigenetic mechanisms
An epigenetic mark is the term given to groups that contribute to epigenetics, including methyl groups, acetyl groups, ubiquitin, phosphate and other biochemical groups. Most of them target the histone proteins, while methyl groups attach to the DNA. Image credit: NIH (public domain)

When the epigenome was analysed in detail in Alzheimer’s patients several differences were found with the methylation of the DNA in comparison to individuals without Alzheimer’s. Methylation involves adding a methyl group, which consists of one carbon atom and three hydrogen atoms, to the DNA. Methyl groups can provide a physical obstruction to proteins attempting to read the DNA and also recruit other enzymes to compress it. The methylation of DNA steadily increases with age, silencing more and more genes and making the effects of methylation more difficult to study. However, a group of scientists in America have determined 71 potential methylation sites out of 415,848 sites studied where the methylation between a healthy individual and someone with Alzheimer’s differs. Out of these 71 sites, 12 were further validated as being significant in an independent set of subjects and these changes appeared to occur in the early pre-symptomatic stages of Alzheimer’s disease. Furthermore some of these changes were associated with genes relevant to Alzheimer’s disease[12]. Nevertheless, we encounter a similar problem to “plaques” and tangles”; currently we are not certain whether these changes in a person’s epigenetics are a cause or a consequence of Alzheimer’s.

No definitive cause can currently be attributed to these dramatic changes but researchers are delving ever deeper into the how and why. It may well be there is no singular cause of Alzheimer’s disease and that in fact a combination of all the factors described, including an individual’s lifestyle, contribute to the development of the disease One would hope that with more research we may be able to start answering some of the questions surrounding the causes of this debilitating condition and begin to provide a cure for the thousands of patients worldwide.

Alice Carstairs is beginning the second year of her PhD at the University of York as part of the Biomedical Tissue Research group. Alice’s PhD focusses around the study of adult stem cells and using these to model both healthy and diseased skeletal development. Alice can also be found at Just Beyond the Bench where she blogs about recent findings in both molecular and cell biology and tweets at @AECarstairs.

why don't all references have links?

[1] Alzheimer’s Society, Factsheet: What is Alzheimer’s disease?
[2] NIH Senior Health, Alzheimers Disease - Symptoms and Diagnosis
[3] Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J Neuropathol Exp Neurol. 1996 Oct;55(10):1083–8.
[4] Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer’s disease. The Lancet. 1997 May 24;349(9064):1546–9.
[5] Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurology. 2014 April 71;(4):505-8.
[6] Goedert M and Spillantini M, G. A Century of Alzheimer's Disease. Science. 2006 Nov;314(5800):777-781
[7] Alzheimer's Society: Genetics of dementia
[8] Veerappan CS, Sleiman S, Coppola G. Epigenetics of Alzheimer’s disease and frontotemporal dementia. Neurother J Am Soc Exp Neurother. 2013 Oct;10(4):709–21.
[9] Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet TIG. 2004 Aug;20(8):350–8.
[10] Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003 Mar;33 Suppl:245–54.
[11] Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005 Jul 26;102(30):10604–9.
[12] De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014 Sep;17(9):1156–63.

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