Modulation of microglia as a potential therapy for Alzheimer’s disease

In an ever-growing, ageing population, neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease are becoming more and more prevalent. Years of research have uncovered many key players in the origin and progression of these diseases, though an effective therapy is still much sought after.

Neurodegenerative diseases have many pathologies and causes that are specific to each type. Alzheimer’s disease is characterized by the accumulation of toxic proteins called Amyloid beta and a reduction in the connections between neurons (called synapses) in the brain. One common aspect present in all neurodegenerative diseases is neuroinflammation, an immune response mediated largely by cells in the brain called microglia. Microglia make up 5-20% of brain cells and play a significant role in disease and injury. They help to ‘clean up’ in the brain removing dead cells and debris to keep the brain functioning healthily. When the brain is under stress or experiences injury, the microglia are activated and release pro inflammatory mediators called cytokines, such as IL-6 and TNF-a, as a protective mechanism. In a healthy brain, the release of these molecules produces local inflammation that signals back to the microglia that they are needed to clear and repair the injury. In chronic neuroinflammation, the constant activation of microglia leads to sustained release of toxic cytokines and an excessive, pathogenic inflammation ensues. Such chronic inflammation of the nervous tissue triggered by persistent injury or toxic protein build up in the brain is detrimental and eventually results in the microglia damaging the neurons.

In Alzheimer’s disease, it was believed that microglia were initially activated as a defensive response, to fight against and remove the toxic build up of Amyloid beta. It is now hypothesized that as the microglia become chronically activated, they not only act on toxic proteins but start to indiscriminately destroy synapses in the brain. It is at this point that microglia activation may become a damaging pathogenic response, leading to the exacerbation and development of Alzheimer’s disease. Excessive microglia activity on synapses is likely to play a crucial role in the loss of cognition and memory.

An alternate theory proposes a ‘yin and yang’ role of microglia in Alzheimer’s disease. This suggests early on in disease states, microglia are helpful and are positively recruited to sites of toxic Amyloid Beta build up. However as the disease progresses the microglia become overwhelmed, and signal this through excessive release of toxic pro-inflammatory cytokines. One study using brain scanners describes a ‘twin peak’ of microglia activation in patients suffering from Alzheimer’s Disease – an early protective peak and a later pro-inflammatory peak (Wood, H. 2017).

Aligned with the ‘yin and yang’ theory, microglia can exist in one of two phenotypes; a pro-inflammatory form, associated with neurotoxicity (M1) and an anti-inflammatory form associated with neuroprotection (M2) (Song, G.J. and Suk, K. 2017). M1 phenotypes produce toxic pro-inflammatory mediators such as TNF-a and IL-6, which activate the cells to deal with infection or injury. After an initial first response of the M1 microglia, M2 phenotypes produce anti-inflammatory cytokines such as IL-10, which lead to brain repair. Chronic exposure to the pro-inflammatory toxic amyloid beta plaques maintains the activation of M1 microglia, which eventually contributes to neuron and synapse damage, leading to neuronal degeneration. Identifying the mechanisms that modulate the M1/M2 phenotypes could help uncover how local CNS inflammation can lead to the devastating effects of neuronal degeneration. Additionally, finding ways to control and reduce this chronic microglia activation and inflammation in Alzheimer’s’ disease could have huge therapeutic benefit. Several pharmacological interventions to modulate the microglial phenotypes have been investigated, however all have had limited efficacy when tested in clinical trials. A better understanding of the mechanisms involved in microglia activation and polarization is needed to go forward.

Possible therapeutic interventions

One avenue currently being explored involves a class of drug called Histone Deacetylase inhibitors (HDACi). Histone deacetylase’s are enzymes that remove acetyl groups from lysine amino acids in proteins and are involved in regulating gene expression within our cells. Research has shown HDAC’s are implicated in inflammatory responses (Kannan, V. 2013), interacting with the microglia in our brains. It is clear that inhibitors of HDAC suppress this microglia-activated immune response and push microglia towards the protective M2 phenotype (Waang, G. 2015), but exactly how they do so is not known.

It was assumed HDAC inhibitors achieve this by increasing gene expression within microglia. However recently published research by neuroscientists at the University of Leeds (Wood, I. 2017) has shown that HDAC inhibitors can still inhibit microglia activation even when the synthesis of new proteins is stopped, suggesting that their ability to increase gene expression is not important for their effect in microglia. Studying where in the cell that the HDACs exert their effects is the first step in identifying the important target protein, and will ultimately lead to uncovering the mechanisms by which they work to push microglia towards the M2 phenotype, hence reducing the inflammatory response.

One problem with using HDAC inhibitors as a therapeutic intervention is that they act in a very broad non-specific fashion, affecting many cell processes. Uncovering how HDAC inhibitors work to reduce M1 microglia activation would allow an opportunity to develop more targeted and specific therapeutic interventions for Alzheimer’s disease with reduced potential for deleterious side effects. Chronic neuroinflammation is a common pathology shared with other neurodegenerative disorders, and thus finding ways to control and reduce microglia activation using HDAC inhibitors will not only be crucial in Alzheimer’s disease, but will be beneficial more widely.

Author: Rachel Coneys

Edited by: Molly Campbell


Wood, H., 2017. Alzheimer disease: Twin peaks of microglial activation observed in Alzheimer disease. Nat Rev Neurol. 13(3):p129

Wood, I., Grigg, R., and Durham, B., 2017. Inhibition of histone deacetylase 1 or 2 reduces microglia activation through a gene expression independent mechanism. Found online at:

Song, G.J., and Suk, K., 2017. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. Front Aging Neurosci. 15;9:p139

Kannan, V., Brouwer, N., Hanisch, U.K., Regen, T., Eggen, B.J., and Boddeke, H.W., 2013. Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res. 91(9):p1133-42

Wang, G., Shi, Y., Jiang, X., Leak, R. K., Hu, X., Wu, Y., and Chen, J., 2015. HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. Proceedings of the National Academy of Sciences, 112(9), 2853-2853.



The Ice Bucket Challenge – How Did It Contribute to Scientific Research?

The Ice That Got the Gene

Remember the ice bucket challenge? Of summer 2014? Where what seemed like a lot of people all of a sudden had the urge to chuck ice cold water over themselves and film it? Well it turned out this wasn’t just another new crazy internet fad. The ice bucket challenge was started by Nancy Frates from the UK after her son was diagnosed with the condition ALS (amyotrophic lateral sclerosis); it was to gain awareness of the progressive neurodegenerative disease and raise money to fund new research. There were over 17million people who uploaded videos of their challenge onto social media sites including many celebrities such as Bill Gates and Mark Zuckerberg. A staggering £87.7M was raised for ALS, funding 6 new research projects! This has led to the scientific discovery of new genes associated with both the hereditary and sporadic causes of the disease that will lead to new therapeutic targets for potential drugs.

Project MinE

Project MinE largely funded by the ice bucket challenge is the largest ever study of inherited ALS. More than 80 researchers from over 11 different countries conducted searches for risk genes in ALS affected families. Bernard Muller and Robert Jan Suit, entrepreneurs from the Netherlands, were both diagnosed with ALS in 2010 and 2011. They made a decision to turn their business skills to finding a solution and so founded Project MinE. The project started with thousands of untested blood samples from ALS patients that were sat gathering dust in a Netherlands lab. Project MinE was chosen to be the recipient of the funds raised by the ice bucket challenge which enabled them to fund their project and commence the analysis of the blood samples. The researchers used arrays of common single nucleotide polymorphisms (SNPs) to genotype 15,156 ALS patients and 26,224 healthy controls from many different countries totalling more than 18 million SNPs tested. Some 1,861 had whole genome sequencing, which involves reading every single one of the six billion letters in the human genome (A, G, C, T).

What is a Single Nucleotide Polymorphism?

A nucleotide is a single building block of DNA. There are 4 building blocks of DNA: adenine (A), guanine (G), cytosine (C), thymine (T). A single nucleotide polymorphism is the most common form of variation in the genetic code and involves the change of one nucleotide. For example, in a certain segment of DNA a SNP may replace adenine with cytosine. These changes occur once in every 300 nucleotides throughout the genome averaging around 10 million SNPs. These nucleotide changes can affect a genes function, but most have no effect on a person’s health or development. SNPs can be used by scientists to discover information within the genome such as being a biological marker allowing scientists to locate genes associated with disease. They can be used to track disease inheritance, predict a person’s response to certain drugs, and susceptibility to toxins.




New Risk Gene

A new risk gene now associated with and believed to be in amongst the most common genes to contribute to ALS is the NEK1 gene. This gene encodes for the… wait for it, it’s a bit of a mouthful: serine/threonine kinase NIMA (never in mitosis gene A)- related kinase. The NEK1 gene has many diverse functions within a cell such as mitosis (production of identical daughter cells from cell division), microtubule stability, internal transportation of proteins, formation of primary cilia that sense mechanical and chemical stimuli, regulation of the permeability of the mitochondrial membrane, and assists with DNA repair. Disruption of these cellular functions is linked to the onset of ALS. The role of NEK1 in ALS is not fully understood yet; according to Dr Lucie Bruijn from the ALS Association, they are unsure whether it is the NEK1 gene itself that is connected to ALS development or mutations within the gene, with another possibility being a link between this gene combined with mutations in another gene. Including the NEK1 gene there is a total of 7 genes recently found in association with ALS which are TBK1, CCNF, GLE1, MATR3, TUBA4A, CHCHD10. This discovery has provided researchers with a new target for therapy development and a new avenue of research to look down to gain a better understanding of what causes the disease. So to all of you who participated – bravo!

Author: Laura Ellis

Editor: Molly Campbell


Bettencourt, C. and Houlden, H. (2015). Exome sequencing uncovers hidden pathways in familial and sporadic ALS. Nature Neuroscience, 18(5), pp.611-613.

Cirulli, E., Lasseigne, B., Petrovski, S., Sapp, P., Dion, P., Leblond, C., Couthouis, J., Lu, Y., Wang, Q., Krueger, B., Ren, Z., Keebler, J., Han, Y., Levy, S., Boone, B., Wimbish, J., Waite, L., Jones, A., Carulli, J., Day-Williams, A., Staropoli, J., Xin, W., Chesi, A., Raphael, A., McKenna-Yasek, D., Cady, J., Vianney de Jong, J., Kenna, K., Smith, B., Topp, S., Miller, J., Gkazi, A., Al-Chalabi, A., van den Berg, L., Veldink, J., Silani, V., Ticozzi, N., Shaw, C., Baloh, R., Appel, S., Simpson, E., Lagier-Tourenne, C., Pulst, S., Gibson, S., Trojanowski, J., Elman, L., McCluskey, L., Grossman, M., Shneider, N., Chung, W., Ravits, J., Glass, J., Sims, K., Van Deerlin, V., Maniatis, T., Hayes, S., Ordureau, A., Swarup, S., Landers, J., Baas, F., Allen, A., Bedlack, R., Harper, J., Gitler, A., Rouleau, G., Brown, R., Harms, M., Cooper, G., Harris, T., Myers, R. and Goldstein, D. (2015). Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 347(6229), pp.1436-1441. (2016). Homepage – ALS Association. [online] Available at: [Accessed 19 Sep. 2016].

Sporadic Glutamate and Motor Neuron Disease.

Categorization and Sporadic Glutamate Cause of Motor Neurons Disease

This article will follow on from the previous motor neurone article on the familial causes, here the focus will be on the categorization and the glutamate sporadic origin of the disease.

How is MND categorised?

Diseases of the motor neurones are classified dependant on where the degeneration occurs; this is either the upper motor neurons, the lower motor neurons or both; or whether the disease is sporadic or familial (hereditary).

Upper motor neurons, also known as corticospinal neurons, originate in the motor region of the cerebral cortex (precentral gyrus) of the frontal lobe. These neurons project from here to the brain stem where they synapse with lower motor neurons to deliver nerve signals. Glutamate is released from corticospinal neurons. Lower motor neurons, also known as anterior horn cells are found in the in the anterior grey column (ventral horn) of the spinal cord, and cranial nuclei within the brain stem. These neurons give control of movement to arms, legs, face, chest, tongue and throat, and act as a link between upper motor neurons and muscle fibres.

Amyotrophic lateral sclerosis (ALS) affects both upper and lower motor neurons, Primary lateral Sclerosis affects just upper motor neurons, Muscular atrophy affects just the lower, and Progressive Bulbar Palsy affects the lowest motor neurons of the brain stem.

Sporadic Glutamate

Glutamate is the most abundant excitatory neurotransmitter. A neurotransmitter is a type of messenger that transports information from one nerve to the next. When glutamate is synaptically released from the neuron it binds to ionotropic and metabotropic receptors causing depolarisation (activation) of the adjacent cell. The activity of glutamate is terminated by specific glutamate reuptake transporters located on surrounding astrocytes and neurons, these glutamate up-takers are known as EAAT 1-5 (excitatory amino acid transporter).

Figure 1: Shows the synthesis and lysis pathway of glutamate.

(Singuer Associates, Inc. 2001)



There is evidence to suggest some people with MND have become more sensitive to glutamate (Foran, E. 2009). Glutamate is a powerful excitatory neurotransmitter therefore abnormally high concentrations can cause over excitation of a neuron, known as excitotoxicity. Excitotoxicity can also be caused by dysregulated activity of glutamate receptors; they may themselves become overly sensitive to glutamate meaning they are activated by a lower than normal concentration. Prolongation of excitotoxicity leads to the death of the neurons. Alternatively ineffective or dysfunctional glutamate re-uptake transporters leads to a build-up of glutamate around the synapse; again causing over excitation and cell death. The reduced number of neurons due to degeneration means signals from the motor cortex can no longer effectively travel to muscles causing the symptoms of motor neurone disease.

One receptor found to be particularly important is the EEAT2 (Tanaka, et al. 1997). It was demonstrated by Rothstein and team (1996) that the removal of this receptor in knockout mice produced an increased extracellular level of glutamate along with increased progressive paralysis and neurodegeneration in rats; suggesting that the EEAT2 glutamate re-uptake transporter is essential for maintaining normal levels of glutamate.

Riluzole Treatment

Riluzole is the only FDA-approved drug based treatment for amyotrophic lateral sclerosis (ALS) form of MND which can prolong survival by an average of 3 months found in two large clinical trials performed by Bensimon and Lacomblez (1996). Riluzole is an antiglutamatergic drug which regulates the release of glutamate and postsynaptic receptor activation and inhibits voltage-sensitive channels from opening (Andreadou, E. 2008). Plasma levels of glutamate and other excitatory neurotransmitters are reduced with this treatment as well as extracellular glutamate levels decreased by the upregulation of the EEAT up-takers (Fumagalli, E. 2008).

Other sporadic causes

There are other sporadic causes of MND such as within the mitochondria, aggregates and RNA processing, and cell transport disruption. A new gene has now also been associated with MND called the NEK1 due to money raised by the Ice Bucket Challenge started in 2014. The same challenge lead to 6 new research projects being funded for research into ALS which will be my next NeuroBlog post!

Author: Laura Ellis

Editor: Molly Campbell


Andreadou, E., Kapaki, E., Kokotis, P., Paraskevas, G., Katsaros, N., Libitaki, G., Zis, V., Sfagos, C. and Vassilopoulos, D. (2008). Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: The effect of riluzole treatment. Clinical Neurology and Neurosurgery, 110(3), pp.222-226.

Foran, E. and Trotti, D. (2009). Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis. Antioxidants & Redox Signaling, 11(7), pp.1587-1602.

Fumagalli, E., Funicello, M., Rauen, T., Gobbi, M. and Mennini, T. (2008). Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology, 578(2-3), pp.171-176.

Lacomblez, L., Bensimon, G., Meininger, V., Leigh, P. and Guillet, P. (1996). Dose-ranging study of riluzole in amyotrophic lateral sclerosis. The Lancet, 347(9013), pp.1425-1431.

Rothstein, J., Dykes-Hoberg, M., Pardo, C., Bristol, L., Jin, L., Kuncl, R., Kanai, Y., Hediger, M., Wang, Y., Schielke, J. and Welty, D. (1996). Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate. Neuron, 16(3), pp.675-686.

Tanaka, K. (1997). Epilepsy and Exacerbation of Brain Injury in Mice Lacking the Glutamate Transporter GLT-1. Science, 276(5319), pp.1699-1702.


Motor Neurone Disease

Familial forms of Motor neurone disease (MND)

Motor neurone disease is a progressive neurodegenerative disorder that attacks nerves of the brain and spinal cord which gradually inhibits nerve signals from reaching the muscles. This leads to muscle weakness and visible muscle atrophy. As the disease progresses actions such as walking, gripping, swallowing and breathing become increasingly difficult, and eventually impossible. In this article I will be discussing the hereditary forms of MND known as familial motor neurone disease and the symptoms related.

Symptoms of MND

Symptoms of motor neurone disease usually develop slowly and subtly over time and typically fall into 3 stages, the initial stage, advanced stage and the end stage. In two-thirds of cases first symptoms occur in the arm or leg known as limb-onset disease. This can be categorised by a weakened grip or tripping up due to muscle weakness; this can often be accompanied by fasciculation’s (muscle twitching) or muscle cramps. Bulbar-onset disease occurs in around a quarter of cases, this affects the muscles of the throat required for swallowing and speech. Advanced symptoms can display visible muscle atrophy due to the wearing away of muscle from inactivity. Limb function gradually becomes worse due to severe weakness leading to a person becoming unable to move. Joint aches and pain develop due to spasticity; this is a condition where the muscles become stiff and rigid. Breathing becomes progressively difficult as the nerves that control the respiratory muscles become more damaged which can leave a person short of breath after simple day to day tasks. End stage symptoms takes the disease into its final stages. A person will suffer increasing body paralysis and significant shortness of breath to which then non-invasive breathing assistance isn’t enough to compensate for the loss of normal lung function. Sufferers of MND usually become drowsy before falling into a deep sleep where they usually die peacefully.


Mentally aware

As MND affects only motor neurones a person’s cognitive function is not lost, meaning they are aware of their condition and symptoms. Although in around 15% of cases people with MND may also suffer with frontotemporal dementia; symptoms include difficulty with planning, concentration and use of language. Some people have additional symptoms that are not directly caused by MND but relate to the reality of living with the disease. These may include anxiety, depression and insomnia.


What causes MND?

According to the MND association around 5-10% of cases are caused by hereditary genetic factors known as familial motor neurone disease. Although a person may have a genetic mutation, this alone does not cause the disease but does increase the likelihood of development. There are four major genetic mutations associated with MND. A genetic mutation occurs when the instructions carried within the gene become scrambled in some way which may lead to the body’s processes not functioning accordingly.

One third of the 5-10% have a mutation in the C9ORF72 gene found on chromosome 9. Normal transcription of this gene encodes for a protein found in many tissues including the brain, although its function is unknown. The protein is found in the presynaptic terminals of neurons and in the fluid that surrounds the nucleus. The gene contains a region of 6 DNA nucleotides (the building blocks of DNA) of four guanines and two cytosines and can be repeated several times or just once. When this nucleotide sequence is repeated too many times, in a mutation called a hexanucleotide, it can cause the amyotrophic lateral sclerosis (ALS) form of MND (DeJesus-Hernandez M 2011). It’s not known for certain how many repeats cause MND but it is believed to be over 30. The hexanucleotide mutation has been found to reduce the amount of protein produced by the C9ORF72 gene, which may alter and interfere with the cells’ function; although it is unclear how this protein causes the disease. Mutations in this gene are also responsible for frontotemporal dementia (FTD) although again it is still unclear why some develop MND, FTD or both (Chio, A. et al 2012).

Another gene known to cause MND is the SOD1 gene located on chromosome 21. This gene, under normal function, encodes for an enzyme called superoxide dismutase (SOD) which is abundant in many cells throughout the body. The role of superoxide dismutase is responsible for the breakdown of toxic charged oxygen molecules, called superoxide molecules, by its binding to copper and zinc. The production of these molecules is a by-product of normal functioning cells, although a build-up of them internally can cause the cell damage (Rakhit R. 2006). There are at least 170 mutations of the SOD1 gene known to cause MND. One particular mutation is the changing of an amino acid alanine to valine which causes the enzyme SOD to gain new, but harmful, properties. Researchers are unclear as to why the cells that are affected in MND are sensitive to the SOD1 mutation but it is believed to be due the increased level of toxic free radicals or the formation of aggregates (clumps) of misfolded SOD that cause cell death (Shaw, B. 2007).

The gene TARDBP located on chromosome 1 is responsible for the production of a protein called transactive response DNA binding protein 43 kDa (TDP-43). This protein is found in most tissues and is responsible in regulating transcription (the first step in the production of new proteins) by binding to DNA and mRNA. TDP-43 cuts and rearranges the amino acid building blocks of proteins in different ways leading to the formation of different versions of certain proteins in a process known as alternative splicing. There are around 50 mutations in this gene known to cause MND which affect the region of the TDP-43 that is responsible for the alternative splicing process. The mutations are thought to cause the proteins to misfold and aggregate within motor neurons. Again it is unclear the reasons why motor neurons die and to whether a build-up of aggregated TDP-43 is the cause of death or a by-product of the dying cell (Buratti, E. 2008). The onset of frontotemporal dementia is also associated with mutations in this gene.

Found on chromosome 16, the FUS gene is also responsible in assisting transcription processes by producing a protein called Fused in Sarcoma (FUS). The FUS assists messenger RNA out of the nucleus to be further processed into a mature protein and also helps repair mistakes in DNA. There are around 50 mutations in this gene that can cause MND by interfering with the transport of mRNA which is likely to cause aggregates of FUS within neurons. People who have the FUS gene mutation tend to develop the disease at an earlier age and have a decreased life expectancy. Like the previous 3 genes, mutations in this gene may also cause frontotemporal dementia (Hewitt, C. 2010).


There is currently no cure for motor neuron disease. Extensive research is underway to discover further details about what causes the disease and to find potential life changing medications. The only drug available that has shown to extend survival by two to three months on average is Riluzole which slows the progressive damage to cells by reduction to glutamate sensitivity. Other treatments include physiotherapy to ease cramps, Baclofen medication to ease muscle stiffness, Amitriptyline or botulin injections to stop saliva drooling, and percutaneous endoscopic gastrostomy tube for food intake when dysphagia (swallowing) becomes too difficult. None of these treatments cure MND but may to help improve quality of life.






Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Chio, A. et al 2012


Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. DeJesus-Hernandez M et al 2011


Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis. Rakhit R1Chakrabartty A. 2006


How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein? Shaw BF1Valentine JS.


Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Buratti E1Baralle FE.


Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Hewitt C1Kirby JHighley JRHartley JAHibberd RHollinger HCWilliams TLInce PGMcDermott CJShaw PJ.


Author: Laura Ellis

Editor: Rosemary Porter

Alzheimer’s Disease – What Do We Know?

Risk factors for Alzheimer’s; what we can do to prevent the disease.
In today’s population, Alzheimer’s disease (AD) is becoming more and more prevalent. This is because it is a disease associated with ageing; as we live longer, the incidence of Alzheimer’s becomes greater. It is therefore becoming increasingly important for us to learn more about the disease so that one day we can find a cure. What is Alzheimer’s and how can we reduce the risk?

What is Alzheimer’s?
Alzheimer’s is a neurodegenerative disease resulting from neuronal cell death in the brain. Alzheimer’s is characterised by a large number of amyloid plaques in the brain that surround neurones, and this can result in vascular damage. The main component of these damaging plaques is amyloid-β protein, and it is the deposition of this protein that leads to neurofibrillary tangles and cells loss. Many people know someone with this disease, however there is currently no cure and the disease kills more people than breast cancer and prostate cancer combined. There’s a variety of symptoms that you can spot in a person with Alzheimer’s. Note that it is advisable that anyone with the below symptoms should visit a doctor. A typical symptom is a gradually worsening ability to remember new information, which occurs as a result of the death of neurones which are involved in memory. Other symptoms include challenges in solving problems, problems with words, misplacing things, confusion and mood changes.


Figure 1: Image showing the loss of brain mass that occurs as a result of Alzheimer’s. Note that the ventricles (spaces within the brain) are larger in the pathological condition case. Image sourced from

What are the risk factors for Alzheimer’s?
Unfortunately there are many risk factors for this neurodegenerative disease that we cannot change. The greatest risk factor for Alzheimer’s is age; as an individual gets older, their chance of developing Alzheimer’s increases. This was found in a study on the age-specific incidence of Alzheimer’s in a community (Liesi et al., 1995). They found that the incidence of Alzheimer’s disease was 14 times high among persons older than 85 years compared with those between 65 and 69 years of age. Another risk factor is family history; the more family members a person has with Alzheimer’s, the greater their risk of developing the disease. This is because there are genes known to be involved in Alzheimer’s. A study into the genetic background of Alzheimer’s (A.Rocchi et al., 2003) identified three genes responsible for the rare early-onset (where symptoms are typically seen before the age of 60) form of the disease. These are the amyloid precursor protein (APP) gene, the presenilin 1 (PSEN1) gene and the presenilin 2 (PSEN2) gene. These are called deterministic genes, meaning that anyone who inherits them will develop the disorder. However this rare, familial form of AD accounts for only 5% of all cases. The remaining 95% are mostly late-onset cases, of which the cause is a complex one involving environmental factors as well as genetic ones. A gene called apolipoprotein E (APOE-e4) has been found to be associated with sporadic late-onset AD cases, as well as being the only gene with a confirmed role in AD. Scientists estimate that APOE-e4 may be a factor in up to 25% of Alzheimer’s cases. If a person inherits this form of APOE, they have an increased wisk of developing the disease. Genetic testing for the above genes is available, however not routinely recommended by doctors.

There are various risk factors for Alzheimer’s based on a person’s medical history. Conditions that affect the cardiovascular system, such as diabetes, high blood cholesterol and strokes are implicated in developing Alzheimer’s disease: if an older person has had a stroke, it doubles their risk of dementia. Although the link isn’t clear yet to scientists, people who have had depression later in life are significantly more likely to develop dementia. In addition, a link between Alzheimer’s and Down’s syndrome has also been observed.

What are lifestyle factors that we can change in order to reduce the risk?
Recent research is beginning to tell us more about risk factors that we could influence through lifestyle choices, and effective control of other health conditions. One known risk which we can prevent is head trauma. It has been suggested that deposits that form in the brain as a result of a head injury lead to dementia. A study which investigated this risk factor was conducted by A. Borenstein Graves et al, (1989). They explored a case study of 130 matched pairs, matched by age and sex. They found that a history of head injury resulting in loss of consciousness or that caused the subject to seek medical care was recorded in 24% of the cases and 8.5% of the controls, leading to an odds ratio of 3.5. Ischemic heart disease is implicated in vascular dementia. Your brain requires oxygen, and as each heartbeat pumps approximately 25% of your blood to your head, if this is not saturated with oxygen then the brain is also deprived. You can manage this risk by monitoring your blood pressure and cholesterol levels, and speaking to your doctor about how to reduce the risk of cardiovascular disease. Weight management is another factor important in preventing Alzheimer’s. Managing your diet can reduce the risk of high blood pressure and heart disease which, as mentioned above, increases the risk of dementia. Reducing the consumption of saturated fat is one way we can reduce the narrowing of the arteries, thus reducing the risk of developing vascular dementia.

Another dietary element that we can manage is the consumption of vitamin D; low levels are associated with an increased risk of dementia. Vitamin D can be obtained from eggs and oily fish. You should avoid cigarettes as it has an extremely harmful effect all over the body, including blood vessels in the brain. Research suggests that light to moderate amounts of alcohol may protect the brain against Alzheimer’s. However drinking above the recommended amounts of alcohol can significantly increase the risk of Alzheimer’s. In addition, ongoing research into the effect of social activity has suggested that people who are more socially active have a reduced risk of developing the disease. Puzzles that challenge the brain are considered as increasing the brain’s ability to compensate for damage that Alzheimer’s may incur, and so are encouraged to prevent disease onset. A study into the 7 main risk factors for Alzheimer’s, namely diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity, found that up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) could be attributable to these factors (Barnes, D. et al., 2011). The study suggested that a 10–25% reduction in all seven risk factors could prevent as many as 1–3 million AD cases worldwide.


How can we help Alzheimer’s suffers?
We can help fund the amazing research that is supported by Alzheimer’s Research UK by donating to the cause via the following link: . If you’d like to learn more about Alzheimer’s, you can click on the following link . Look out for volunteer groups in your area to help the ageing community. You can also help by educating friends and family about Alzheimer’s so that they know how to recognise the symptoms and are more aware of the causes.


American Psychiatric association. 1994. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).  4th Revised edition. American Psychiatric Press Inc.

Hebert, L., Scherr, P., Beckett, L., Albert, M., Pilgrim, D., Chown, M.,Funkenstein, H., and Evans, D. 1995. Age-Specific Incidence of Alzheimer’s Disease in a Community Population. JAMA. 273(17), pp. 1354-1359.

Rocchi, A., Pellegrini, S., Siciliano, G., Murri, L. 2003. Causative and susceptibility genes for Alzheimer’s disease: a review. Brain Research Bulletin. 61(1), pp. 1-24.

Borenstein Graves, A., White, E., Koepsell, T., Reifler, B., Van Belle, G., Larson, E., and Raskind, M. 1990. The Association Between Head Trauma and Alzheimer’s Disease. American Journal of Epidemiology. 131(3), pp. 491-501).

Barnes, D., and Yaffe, K. 2011. The Projected Risk Factor Reduction On Alzheimer’s Disease Prevalence. The Lancet Neurology. 10(9), pp. 819-828.

Author: Jess Stonehouse 

Editor: Molly Campbell