Alzheimer's Disease - how could gene and cell therapy help?

Alzheimer’s disease is the most common cause of dementia. It is a complex disease that affects nerve cells in many parts of the brain, making effective treatment very challenging. Can gene and cell therapy techniques help us tackle this challenge in the future?

What do we know?

Alzheimer’s disease (AD) is the leading cause of dementia. People affected by AD commonly experience memory loss, confusion and mood swings.

The cause of AD is still unknown. It is thought to be the result of two proteins, called ‘amyloid beta’ and ‘tau’, which are found in deteriorating areas of an AD brain.

Clumps of amyloid beta proteins form plaques that may prevent neurons from sending signals properly.

Tau protein is important for normal cell function, but researchers think that when tau gets gnarled up into ‘tau tangles’ it prevents neurons from getting nutrition.

In common AD, amyloid beta and tau still play a role but it is thought that other processes such as your immune response also contribute to disease.

There is currently no cure for AD.

What are researchers working on?

No stem cell treatments are currently approved for AD. Positive effects have been seen with neural stem cell transplants given to mice with a disease similar to AD, but researchers are still studying what these stem cells are doing and how they might help repair the brain.

Researchers are using induced pluripotent stem cells to grow nerve cells (neurons) and microglia (immune cells) that have the same genetic background as people affected by AD so they can study the disease. These cells represent a tool to look for new drugs that can reduce amyloid, tau, and other disease hallmarks, as well as finding disease signposts that can help diagnose patients with AD earlier.

What are the challenges?

There are many different neurons throughout the brain that are destroyed by AD, making each case unique and very difficult to treat.

Successful regenerative medicine treatments will need to distribute cells to damaged areas throughout the brain, make the correct types of neurons and other brain cells, correctly ‘wire’ new neurons into existing neuron networks, and, above all, be safe (e.g. not cause cancer or other complications).

Some researchers argue that using new neurons made with stem cells to study Alzheimer’s disease will not accurately represent aged brain cells. Other researchers think this approach could be the best way to understand the earliest stages of AD.

If stem cell treatments are eventually developed for AD, these treatments do not stop the cause of AD, meaning treatments may not last and people could suffer relapses.

About Alzheimer's Disease

Illustrations of plaques and tangle in a brain with AD — **Plaques and tangles:** An illustration of the formation of protein tangles and plaques, and their interaction with neurons as Alzheimer's develops

Alzheimer’s disease (AD) is the most common cause of dementia.  The first signs of Alzheimer’s often include lapses in memory or struggling to find the right words. Over time, symptoms such as confusion, mood swings or memory loss develop and become increasingly severe. 

The cause of the disease is still unclear, but researchers have found that people affected by AD have an abnormal build-up of certain proteins in the brain. One of these proteins, called amyloid beta, clumps together to form ‘plaques’. Another, known as tau, gets twisted into protein ‘tangles’. Scientists are still exploring whether these plaques and tangles in the brain lead to the symptoms of AD, or are a by-product of the disease. One theory is that plaques prevent nerve cells inside the brain from communicating properly. Tangles may make it difficult for the cells to get the nutrients they need. Whatever the exact processes involved, it is clear that as AD progresses, nerve cells, also called neurons, are lost. For this reason, AD is known as a neurodegenerative disease.

Estimates suggest that up to around 1.5% of people aged 65-69 and around 25-30% of 90-year-olds have AD. Although the exact cause is not known, a number of risk factors have been linked to the disease. The biggest of these is aging. Women are more likely to be affected than men. Genetics (i.e. family history) plays an important role in AD; this is pointing researchers to new avenues such as the immune system in disease onset and progression More factors are constantly being determined, such as a link to obesity.

How is Alzheimer's Disease treated now?

There is currently no cure for AD. Drugs are available that can help with some of the symptoms temporarily - for example, by improving memory or the ability to manage everyday tasks. Most of these drugs belong to a class called cholinesterase inhibitors (e.g. Aricept, Exelon, Reminyl). They can help prevent the breakdown of a natural substance in the brain called acetylcholine, which carries signals between neurons. However, there are no drugs that delay or halt the loss of neurons.

Over the last two decades extensive research and drug development efforts have identified potential new drugs for clearing the build-up of amyloid protein in the brain. Unfortunately, large clinical trials with these substances have failed. This has raised new questions about how the disease is understood, and how it is studied in the laboratory. Research to date has mainly been carried out on mice with Alzheimer’s-like conditions, known as mouse ‘models’ of the disease.

Stem cells may play a role in providing new disease models that enable researchers to study the disease in human cells, and eventually to develop new treatments. Understanding which genes are associated with AD could also help scientists to develop models to investigate the effects of these genes.

Drawing of a healthy neuron (nerve cell of the brain) Drawing of a neuron affected by Alzheimer's disease

Illustrations of neurons. Left: A healthy neuron. Right: A neuron affected by Alzheimer's Disease

Can stem cells be used to treat Alzheimer's Disease?

No stem cell treatments for AD are yet available.

AD affects many different types of neurons in many parts of the brain. This poses a complex problem for repairing the brain. Research shows that neural stem cells (a type of stem cell found in the brain) can form new neurons. However, transplanting these into the brain of a person with AD to make new, healthy neurons is not straightforward. Furthermore, transplanting new cells into a brain with AD won’t fix the underlying problem which is causing neurons to die. If successful, they might only offer temporary help before more neurons are lost. Even so, treatments using neural stem cells could offer a great deal of help to patients. Even if individuals with AD only get a short delay of the disease, it could have a huge impact on the the patient, communities and the economy. For example, a treatment that gives a 5-year delay in the onset or rate of progression of the condition might reduce both the number of AD cases and economic burden of AD by one-third.

Getting neural stem cells to work as a treatment will be challenging. Even if they were readily available and could be transplanted safely, they would have to achieve several difficult tasks before any therapeutic benefits might be seen. They would have to:

travel into the multiple areas of the brain where damage has occurred
produce the many different types of neurons needed to replace the damaged or lost cells (and produce the right number and proportions of the cells, without making too many new cells)
do this in a way that enables the new neurons to integrate effectively into the brain, making connections to replace the lost parts of a complex network

Despite these significant challenges, scientists have been actively engaged in research on stem cell transplants in mice and studies have shown some benefits. This is still in the early stages of research and there are still many questions to be answered. Much more work is needed before the findings could be applied to developing a therapy for human patients.

Another possible approach to stem cell therapies might be to use certain types of stem cells to deliver proteins called neurotrophins to the brain. In the healthy brain, neurotrophins support the growth and survival of neurons, but in people with AD, neurotrophin production is low. Neural stem cells produce neurotrophins, and so a transplant of these cells might offer a solution this problem. To test this theory, scientists bred mice with the key symptoms and characteristics of AD (such as memory impairment). They injected neural stem cells into the brains of the mice, and subsequently observed some improvement in memory. Further studies are now taking place to understand this effect. The approach has not yet been tested in human patients.

Stem cells can also benefit patients with AD outside of a clinical setting.By using stem cells derived from people with AD to grow large numbers of brain cells in the lab, scientists can create a ‘model’ of the disease to study and to investigate new drugs.

Stem cells and Alzheimer's Disease

Induced pluripotent stem cells (iPSCs)

Researchers are using a type of stem cell called induced pluripotent stem cells (iPSCs)  to study AD. These lab-grown stem cells are made by ‘reprogramming’ other cell types easily taken from patients, such as skin cells. The resulting iPS cells can produce all the different types of cells in the body. This means they could act as a source of cells that are otherwise difficult to obtain, such as the neurons found in the brain.

Scientists are using iPSC technology to grow neurons in the lab to study AD. Researchers use iPSC-derived neurons created from the cells of people with ADto study any abnormalities that might promote the progression of Alzheimer’s disease. This includes studying differences in how these neurons produce, move and release the amyloid beta protein (which forms plaques), and tau protein (which forms the tangles in patients’ brains).

Neurons derived from iPSCs give scientists a valuable opportunity to study neurons similar to the neurons in the brains of people with AD in the laboratory, offering a level of detail that would otherwise not be possible. This allows researchers to gain a much better understanding of how and why protein plaques are formed at the very start of the disease, and what causes neurons to die. It lets researchers experiment with new drugs and therapeutic approaches, and provides a tool to hunt for signposts that can help diagnose AD earlier, increasing the chance of success for new treatments.

Organoids

One of the newest advances in neuroscience is the use of iPSCs to grow brain ‘organoids’. Rather than growing neurons on a flat petri dish, brain organoids are grown in conditions that allow neural stem cells to grow into cell clusters in 3 dimensions (3D). These clusters of cells have a greater variety of cell types than 2D cell cultures, and create complex cell structures that resemble some aspects of human brain tissue. For example, brain organoids create layers of neurons, just like the layers of neurons in the brain. These layers can’t be formed when cells are grown on flat dishes.

The benefit of brain organoids is that they provide brain tissue for studying brain development, function, repair and diseases. Getting living samples of human brain tissue is difficult and can carry ethical issues. Brain organoids allow researchers to grow brain tissue for experiments. Making organoids from iPSCs also allows researchers to study the difference between brain cells with different genetic backgrounds; such as organoids from healthy individuals compared organoids from those from people with AD. Researchers examine various ways that cells in these organoids behave, such as how cells migrate, form complex structures and interact with one another. Currently, scientists are attempting to determine if amyloid beta is more likely to form plaques in organoids than flat experimental systems. If so, brain organoids could become an extremely useful tool in AD research, treatment and drug discovery.

Fluorescently labelled cells in a brain organoid — Micrograph image showing fluorescently labelled cells in a brain organoid. Brain organoids create layers of cells to form complex 3D structures similar to those found in human brains

The immune system and Alzheimer's Disease

Another area that researchers are examining is the role of the immune system in AD. Recent studies of the genes of people with AD suggest that a hyperactive immune system could lead to brain inflammation and damage to neurons. Researchers recently have been able to use iPSCs from people with AD to grow microglia, the brain’s immune cells. Researchers want to know how these cells interact with amyloid beta, and if these cells might trigger the start of AD in people.

Research using iPSCs holds great promise in other ways too. AD is a disease that varies greatly from one person to another. Studying AD using iPSCs from different people has the potential to reveal why there is such variation in AD. It may also indicate what treatments would work best for different individuals and may even be used to develop bespoke treatments, known as ‘personalised medicine’.

Genetics and Alzheimer's Disease

Unlike some conditions, AD is not caused by a single gene. It is influenced by several different genes, as well as environmental factors. Researchers have identified several genes associated with AD and with early-onset AD (which presents before the age of 60). Scientists are working to understand the mechanism of action of these genes. They hope to use this information to develop more effective therapies, and perhaps preventative interventions.

One early-stage clinical trial assessed the effects of using gene therapy to stop the production of the tau protein. (This is called gene silencing.) This trial confirmed that the technique is safe for use in humans, and that it has a biological effect. Further clinical studies with larger numbers or patients are needed in order to determine the effectiveness of the therapy, as well as longer-term studies to investigate the effect this has on the symptoms and progression of the disease.

Researchers are also investigating whether gene editing techniques could be used to promote the production of different neurotrophic factors. These could protect neurons from a damaging environment, and encouraging cell survival, growth, and repair.

The most advanced gene therapy approaches for AD are still in very early clinical trials, and it will take many years of research to confirm whether they are safe and effective for use.

Treatment today and in the future

Although some companies may claim to offer stem cell treatments for AD, many of these are outside the approved and carefully controlled process of clinical trials. There are Phase I and Phase II clinical trials (i.e. trials to assess safety and the effectiveness of a treatment) in countries around the world. Many of these trials are using MSCs for AD. Caution is advised until the results of these trials are published, as there are serious questions about the scientific rationale and the safety for many studies.

It should be noted that websites that list current clinical trials, like clinicaltrials.gov, do NOT evaluate if the trial is scientifically sound, or if a reputable institution is carrying it out. Currently, no proven, safe and effective cell therapy or gene therapy is available in the EU. However, scientists are already using stem cell technology to carry out rigorous studies on the causes and effects of AD, and expect their findings will play an important role in finding new drugs and perhaps also cell- or gene-based therapies in the future.

Find out more

Agradecimentos e Direitos de Autor

This factsheet was created by Mahendra De Silva in 2014.

Reviewed and updated by Fred H. Gage, Laura Phipps, Pietro Tiraboschi, Håkan Toresson and Selina Wray in 2014.

Reviewed and updated by Selina Wray in 2016.

Edited by Ryan Lewis in 2018.

Reviewed and updated by Charlie Arber in 2018.

Reviewed and updated by Dr. Rebecca Sims, Senior Research Fellow, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University.

Animated image created by 7mike5000 from Inside the Brain: Unraveling the Mystery of Alzheimer's Disease by the National Institute on Aging. High magnification image of nerve cells called astrocytes by Nephron. Micrograph image showing fluorescently labelled cells in a brain organoid supplied by Charlie Arber, UCL Institute of Neurology. All remaining images courtesy of the National Institute on Aging/National Institutes of Health.

New tools for disease research: reprogrammed cells in disease modelling

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