Decoding Alzheimer’s Disease: From Diagnosis to Solutions

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Most people have heard of Alzheimer’s disease before – whether we knew a family member that had it or we witnessed its portrayal in pop culture, such as in the movie, ‘The Notebook’. Despite a familiarity with the disease, some may wonder how Alzheimer’s affects brain function and what factors may lead someone to develop the disease.

Over one in nine people over the age of 65 gets Alzheimer’s, making it a relatively common neurological disorder. There are many cellular and molecular changes that happen as the disease begins and progresses, and understanding these changes has led to recent breakthroughs in drug research to combat the disease. 

What is Alzheimer’s disease and how is it diagnosed?

Alzheimer’s is a neurological disorder that progressively gets worse overtime and involves the loss of brain tissue. It’s a particularly devastating disorder because it damages important brain structures that essentially comprise parts of our personality and make us who we are. 

While memory loss is a normal part of aging, patients diagnosed with Alzheimer’s present with severe memory issues and have difficulty making decisions and even performing basic daily tasks (1). This happens because one of the earliest brain regions damaged by the disease is the hippocampus, which is a part of the brain responsible for making and storing memories.

Later in the disease, the damage spreads to the cerebral cortex, which is part of the brain responsible for critical thinking, language, and social behavior. The widespread tissue loss across several important brain structures explains why patients in later stages of this disease often end up needing care by medical professionals. 

There are over 100 different diseases that cause dementia, so how do you determine whether someone has Alzheimer’s instead of some other type of dementia? Unlike other types of dementia, Alzheimer’s involves the build-up of two unique protein aggregates in the brain: amyloid-beta plaques and tau tangles. Both amyloid and tau proteins normally serve helpful functions in the brain, but when a person begins developing Alzheimer’s, then toxic aggregates of these proteins start to build up in the brain and wreak havoc on brain function.

The build-up of amyloid and tau aggregates in the brain can be visualized in living people by undergoing a PET scan using tracers that bind to these proteins (2). The combination of PET scan results, memory tests, and family history can help diagnose Alzheimer’s disease.

What genetic, demographic, or environmental factors lead to Alzheimer’s?

Alzheimer’s disease can actually be subcategorized into two types: early-onset and late-onset. Individuals with early-onset Alzheimer’s typically develop the disease in their 40s and 50s, whereas those with late-onset develop the disease after 65 years of age (3). Importantly, early and late onset Alzheimer’s have unique genetic factors that lead to their development. 

Patients with early-onset Alzheimer’s typically have harmful changes in genes linked to the production or processing of amyloid protein. These gene mutations often lead the body to produce excessive amounts of amyloid protein and lead to the build up of toxic amyloid aggregates. The gene changes that lead to early-onset Alzheimer’s are inheritable, so individuals that have a parent diagnosed with the disease are at an increased risk to get it.

Patients with late-onset Alzheimer’s do not have the same gene changes as those with early-onset. Instead of having changes in genes related to amyloid protein, those with late-onset typically have gene changes related to the gene, APOE. The APOE gene has three different versions in humans, and depending on which version you have, you may be at increased or decreased risk for Alzheimer’s. Individuals with the APOE4 version of the gene have higher risk of developing Alzheimer’s, while those with the APOE3 version have average risk and those with the APOE2 version have decreased risk (4). 

Beyond these genetic factors linked to Alzheimer’s, there are also certain demographics that are more vulnerable to getting the disease. Almost ⅔ of patients are women, and black individuals are twice as likely to develop the disease than white individuals. It is unclear why these demographic groups are more vulnerable to developing the disease, but ongoing research efforts aim to answer this question. While the research on environmental factors linked to Alzheimer’s are less conclusive than genetic studies, it appears that factors such as air pollution and exposure to pesticides and heavy metals (5). 

How does Alzheimer’s affect our brain and its functions?

There are many harmful changes that happen in the brain during Alzheimer’s disease. One of the earliest changes that happens to the brain is the build-up of toxic amyloid protein aggregates. These amyloid aggregates build up in the brain several years before symptoms of Alzheimer’s can even be detected. As the disease progresses and patients start to experience some memory issues, toxic aggregates of tau protein can be found in the brain. Both of these protein aggregates have also been shown to widely spread throughout the brain.

As both of these toxic proteins accumulate in the brain, they lead to many changes that cause our brain to dysfunction. These toxic amyloid and tau aggregates lead to the damage and death of neurons, which are the basic working units in the brain. Neurons send and receive signals to help convey information throughout the body and coordinate all our behaviors. The death of neurons, and ultimately loss of brain tissue, limits the function of the brain and leads to the memory loss and cognitive issues experienced in the later stages of Alzheimer’s disease. 

Recent research has found that Alzheimer’s also leads to inflammation in the brain. Many inflammatory molecules are released in the brain during the disease. These molecules act as signals to alert resident immune cells in the brain, called microglia, that there is inflammation that needs to be attended to (6). The microglia respond to these signals by becoming activated and surveying the brain for cell debris to consume.

It is thought that the activation of microglia may be intended to help in the early stages of the disease, since microglia may help with consuming and breaking down amyloid aggregates. However, when microglia stay activated for a prolonged period of time, they start to consume things they aren’t supposed to, such as neurons. In this sense, the activation of the brain’s immune system may be contributing to the death of neurons.

What are the treatment options for Alzheimer’s?

For several decades, the best treatment options for Alzheimer’s helped manage symptoms of the disease but failed to address the underlying biology responsible for the disease. This included the use of cholinesterase inhibitors, which is a medicine designed to boost the communication between neurons. These drugs improve some of the behavioral symptoms of the disease, such as depression and agitation, but do not have any effect on disease progression, since the death of neurons still occurs. 

Excitingly, in the past few years there have been breakthroughs in drug research to combat Alzheimer’s disease. Therapies aimed towards combating the underlying biology to the disease have targeted the toxic amyloid protein that accumulates in the brain (7). These therapies use an antibody that is specifically designed to attach to amyloid protein and help remove it from the brain.

There are several companies developing anti-amyloid therapies and at various stages of running clinical trials to determine their effectiveness. Two different anti-amyloid drugs, lecanemab and donanemab, were recently tested in human clinical trials and showed a ~4-6-month delay in disease progression. Although this delay in progression may seem minor to some, it gives a glimmer of hope to those suffering from the disease and provides their family members more time to enjoy their company. This breakthrough also shows that treatments targeting the underlying biology of these disease can have meaningful and effective outcomes to slow it down. 

Looking ahead, it is clear that further research will allow us to better understand Alzheimer’s disease and help us develop even more targeted therapies. Other therapies being tested in clinical trials include the development of antibodies to target tau protein aggregates and anti-inflammatories to help reduce inflammation in the brain (8). It will be exciting to see if these new therapies can be even more effective at combating the underlying biology of the disease and help delay disease progression even more dramatically. 

Conclusion

Alzheimer’s disease is a relatively common and devastating neurological disease. This complex disease can affect many different aspects of someone’s behavior and personality and there are several genetic and environmental factors that can contribute to its development. The buildup of toxic amyloid and tau protein aggregates and death of neurons leads to widespread dysfunction in the brain. Recent therapies targeting amyloid protein provide promising drug options for delaying the disease, and continued efforts to develop more effective therapies could one day provide even better therapeutic options for Alzheimer’s patients.  

References:

1. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447
2. Marcus, C., et. al., Brain PET in the Diagnosis of Alzheimer’s Disease. Clin. Nucl. Med. (2015); 39:e413-e426
3. Reitz, C., et. al., Late-onset vs. nonmendelian early-onset Alzheimer disease. Neurol Genet. (2020); 6:e512
4. Koutsodendris, N., et. al., Apolipoprotein E and Alzheimer’s disease: findings, hypotheses, and potential mechanisms. Annu. Rev. Pathol. (2022); 17:73-99
5. Killin, L., et. alEnvironmental risk factors for dementia: a systemic review. BMC Geriatr. (2016); 16:175
6. Long, H., et. al., The role of microglia in Alzheimer’s disease from the perspective of immune inflammation and iron metabolism. Front. Aging Neurosci. (2022); 14:888989
7. Ramanan, V., et. al., Amyloid therapies for Alzheimer’s disease: finally, good news for patients. Mol. Neurodegener. (2023); 18:42
8. Cummings, J., et. al., Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement. (2023); 9:e12385