Alzheimer’s is a chronic, progressive neurodegenerative disease that affects at least 50 million people worldwide. The number of people living with Alzheimer’s has increased dramatically since 1990 due to aging and population growth and is projected to exceed 152 million cases by 2050.1
The burden on care partners and health care systems devoted to care of the elderly is also expected to increase rapidly.2 In 2020, family members and friends provided nearly $257 billion in unpaid care to those living with Alzheimer’s and other dementias.3
Scientists have conducted a vast amount of research on Alzheimer’s over the past few decades and made considerable progress in understanding the disease. However, much work remains to find effective treatments that slow or stop the disease.
Research conducted to date has shown that multiple factors may contribute to the pathology of Alzheimer’s but most efforts have focused on two proteins – amyloid and tau.4,5,6,7,8,9,10,11 At Genentech, we are investigating treatment approaches that target these proteins, which we hope will delay cognitive and functional decline and potentially slow disease progression.
When it comes to how Alzheimer’s manifests in the brain, many factors are at play. Let’s dive into the background needed to understand the disease and the research underway across the field.
Helpful Definitions
Science, like the brain, is complex. To make it easier, we’ve defined some of the commonly used words in this story.
Neurodegeneration in Alzheimer’s
The brain is arguably the most incredible organ in the entire body. It gives people the ability to move, think, feel, communicate and create and preserve memories. Your brain is what makes you who you are, and it does this through billions of nerve cells, called neurons, that are always communicating with each other.
Over the course of a lifetime, people can lose neurons from traumatic injury, environmental toxins, cardiovascular disorders, infectious agents or genetic diseases.12 The loss of neurons can impact a person’s ability to function.13
The word “neurodegeneration” describes any disease that causes neurons to weaken and eventually die. All neurodegenerative diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and Alzheimer’s, are caused by the weakening and death of neurons, but each disease has distinct causes and effects, or “pathologies,” in the brain.14
THE DISCOVERY OF ALZHEIMER’S
In 1906 Alzheimer’s disease was discovered by a researcher named Dr. Alois Alzheimer, who was the first to detail the causes and effects of the disease in the brain.4, 15 After the death of a woman who showed signs of memory loss, language problems, aggression and confusion, Dr. Alzheimer found abnormal clumps of protein in her brain tissue.5 Today, these clumps are known as amyloid plaques and neurofibrillary tangles, which are hallmarks of Alzheimer’s.3
The progression and symptoms of Alzheimer’s
Alzheimer’s begins long before a person shows any symptoms caused by neurodegeneration and progresses along a continuum. The first stage is preclinical (no overt symptoms), then mild cognitive impairment due to Alzheimer’s disease (more subtle cognitive changes than someone with dementia, with minimal impact on daily activities), and then mild, moderate and severe forms of Alzheimer’s dementia (where people start to experience a significant change in their mental abilities and behavior). These changes stretch over a period of 15 to 25 years.16
| Alzheimer’s Stage | Examples of Common Symptoms3,17 |
|---|---|
| Preclinical | None18 |
| Mild cognitive impairment due to Alzheimer’s disease | |
| Mild Alzheimer’s disease dementia | |
| Moderate Alzheimer’s disease dementia | |
| Severe Alzheimer’s disease dementia |
Major areas of research in Alzheimer’s
Alzheimer’s is a complex disease in which several biological processes going awry resulting in neurodegeneration.3,4
A biomarker is any biological factor that relates to the risk and/or presence of a disease. For example, high levels of “bad” cholesterol is a biomarker that predicts heart disease.6,20 Similarly, high levels of amyloid and tau in the brain may place a person at increased risk for Alzheimer’s.3 Several biomarkers are commonly used in Alzheimer’s research.
The various biomarkers thought to play a role in the progression of Alzheimer’s include the following.
Amyloid beta
As described before, amyloid is one of the two main proteins thought to be associated with the neurodegeneration that causes Alzheimer’s.21,22
Amyloid helps the brain recover from injury and protects against bacteria, viruses and tumors.11 However, when errors occur in the production of amyloid, it can stick to itself and form long chains called “oligomers.” These oligomers can combine with one another and form larger structures (or clumps) called amyloid plaques.10,11
Normally, oligomers and plaques are cleared from the brain, but as people age, the body is less able to stop them from building up.23
Alzheimer’s research done to date supports investigating the effectiveness of removing amyloid from the brain, which is known as the “amyloid hypothesis.” This hypothesis is supported by known familial mutations in autosomal dominant Alzheimer’s – or Alzheimer’s caused by underlying genetics – which lead to increased levels of amyloid in the brain.24,25
Tau
Tau is the other main protein thought to be associated with the neurodegeneration that causes Alzheimer’s.26
Tau acts as a key component of a neuron’s cytoskeleton (a “skeleton” made of proteins), which, much like the bones in our bodies, gives neurons their shape and helps them carry out their jobs.13
Tau is very sensitive to changes in the brain. Changes such as amyloid build-up can cause tau to become damaged and a neuron’s cytoskeleton to fall apart. Much like a broken bone makes it hard for a person to move, a neuron cannot function well without a healthy cytoskeleton.13
Also, like amyloid, tau can stick to itself to form tau oligomers, which can spread throughout the brain. Tau oligomers can also build up to form neurofibrillary tangles. These tangles gather inside of neurons, disrupting how they communicate and causing them to die.13
Decades of data have shown that it is increasingly important to understand the effectiveness of slowing or stopping the process of tau spread in the brain.
Neuroinflammation
Inflammation is the process that causes your skin to swell around a cut and a fever to occur when you have an infection. While these can be unpleasant, they are necessary for our body to protect against infections and heal injuries.
Neuroinflammation is a similar process that helps our brain heal after infections or trauma. While short-term neuroinflammation can be helpful, neuroinflammation happening over a long period of time can do more harm than good.27
Because amyloid and tau build up in the brain over many years, neuroinflammation is constantly taking place in an attempt to correct the damage they cause to neurons.14
APOE Gene
Proteins are involved in every aspect of life, from the digestion of food to the growth and repair of our bodies. Genes are pieces of our DNA that carry instructions needed for our cells to make different proteins. We inherit our genes from our parents, and they can come in different forms, which are called alleles. Based on which alleles a person inherits, they may have a lower or higher chance of developing various diseases.28
While many genes are thought to play some role in Alzheimer’s, research has shown that one gene in particular, called apolipoprotein (APOE), has a strong influence on whether a person will develop the disease.29 APOE typically determines how our cells use fats as energy. This gene is associated with other health conditions, including cardiovascular disease and stroke, as it codes for a protein that transports cholesterol in the blood.30 APOE has many alleles but the most common are called ε2, ε3 and ε4. Research suggests that a person’s risk of developing Alzheimer’s can be affected by which APOE alleles they inherit from their parents:15
- APOE ε2 – indicates the lowest risk of developing Alzheimer’s
- APOE ε3 – indicates moderate risk of developing Alzheimer’s
- APOE ε4 – indicates the highest risk of developing Alzheimer’s30
The exact role that APOE plays in the development and progression of Alzheimer’s is not clear, but it is associated with the production and elimination of amyloid beta in the brain. APOE is also emerging as a potential biomarker – or a measurable indicator of what’s happening in the body – that may be used in Alzheimer’s in the future to aid in diagnosis, screening and monitoring disease progression, and a person’s treatment response.31,32,33
ALZHEIMER’S TODAY AND THE FUTURE OF ALZHEIMER’S DISEASE RESEARCH
The knowledge of how Alzheimer’s disease develops and progresses has greatly increased over the last few decades, and researchers are continuing to learn more every day. With over two decades of scientific research in Alzheimer’s, Genentech has made new discoveries and persisted when faced with clinical disappointments. We have listened to the community, learned from our setbacks and built on each success.
Our commitment to Alzheimer’s disease is grounded in our broader commitment to neuroscience – and there is no greater scientific or social challenge in neuroscience than that posed by Alzheimer’s. We are committed to pushing the boundaries of scientific understanding in neuroscience, to help drive earlier detection and diagnosis, develop breakthrough medicines, and ensure broad and equitable access to new therapies. Our hope is to create a tomorrow where neurological disorders no longer limit human potential – to preserve what makes us who we are.