What is Alzheimer’s disease?

Imagine trying to remember important events from your past or struggling to recognise your loved ones - that’s the reality for many people living with Alzheimer’s disease. It is one of the most common causes of dementia, accounting for 60-70% of diagnosed cases worldwide.¹

Alzheimer's disease is a neurodegenerative condition, meaning that it causes gradual and progressive loss of function of the brain's nerve cells (neurons) in the central nervous system over time. This process can cause problems with memory, thinking, and behaviour, making everyday tasks challenging.¹

Alzheimer’s disease can classified into two types:

• Late-onset Alzheimer's disease: this type is the most common form of Alzheimer's disease that typically affects people over the age of 65. It develops gradually and occurs as a result of ageing, genetics, and environmental factors¹ 
• Early-onset familial Alzheimer’s disease: this type of Alzheimer's affects individuals under the age of 65, sometimes even as young as 40s or 50s. It is caused by genetics and tends to progress more rapidly than late-onset Alzheimer's disease¹ 

Neuropathology of Alzheimer’s disease

In Alzheimer's disease, the brain undergoes structural and functional changes that affect how it works, leading to the symptoms that are seen in the disease. These changes can be underpinned by two neuropathologies: the abnormal build-up of amyloid-beta and tau protein in the brain.^1,2

Amyloid-beta 

In a healthy brain, amyloid-beta is a type of protein that is involved in various functions, including maintaining brain health and supporting communication between neurons.² Amyloid-beta is usually cleared away efficiently and does not form clumps in the brain. In Alzheimer's disease, these amyloid-beta proteins become sticky and start to clump together outside neurons known as plaques. Plaques can make it harder for neurons to function properly, leading to problems with memory, thinking, and reasoning.² 

Neurofibrillary tangles

Tau proteins are important for maintaining the structure and function of a neuron's microtubules, which act like a road or pathway, ensuring that neurons can transport nutrients, molecules, and other substances to other neurons when needed. This helps the neuron to function and communicate effectively. In Alzheimer's disease, tau proteins become abnormal and start to clump together, forming tangles inside neurons called neurofibrillary tangles. These tangles can make it difficult for neurons to transport essential nutrients and communicate with other neurons. As a result, these neurons become damaged and eventually die, contributing to the overall cognitive decline in brain function that is typically seen in Alzheimer’s disease.³ 

Progression of Alzheimer’s disease 

Alzheimer’s disease can begin years before the symptoms are present and tend to progress through three different phases:⁴

• Preclinical phase: this marks the earliest stage of the disease, characterised by neuropathological changes in the brain. The abnormal build-up of amyloid-beta plaques and neurofibrillary tangles can begin 10-20 years before the onset of symptoms. This phase can last for several years or even decades before people start to show symptoms of Alzheimer's disease
• Prodromal phase: some people may experience mild cognitive impairment, such as forgetfulness, difficulty finding words, trouble with problem-solving or decision-making. However, these symptoms do not interfere with daily life and are not severe enough to be classified as dementia 
• Alzheimer’s dementia phase: this stage is characterised by severe cognitive, behavioural, and functional decline which interferes with their ability to perform daily activities independently. This phase represents the progression of the prodromal phase to severe impairment 

What are comorbidities? 

Comorbidity refers to the presence of one or more health conditions that can occur alongside a primary health condition at the same time in a patient. Conditions that are described as being comorbid are often chronic and long-term and are associated with poorer clinical outcomes of the main health condition. These conditions may occur independently of each other or may influence each other’s course, treatment, and outcomes.⁵ 

The relationship between comorbidities and Alzheimer’s disease

Along with various neurodegenerative disorders including Alzheimer’s disease, are associated comorbidities which can occur alongside and exacerbate the symptoms of Alzheimer's. These comorbidities may occur before symptoms become noticeable and are believed to emerge during the preclinical phase of Alzheimer’s disease when neuropathological changes are already happening in the brain.⁶ For example, conditions like cardiovascular diseases and diabetes can develop years before cognitive symptoms appear. Also, having Alzheimer's disease may increase the risk of developing certain health conditions.⁵ This may be because they impact the function of the brain by promoting chronic inflammation, and a prolonged immune response releasing pro-inflammatory molecules such as cytokines and chemokines. This chronic inflammation can result in tissue and organ damage, and prevent the body's ability to clear amyloid-beta plaques and neurofibrillary tangles.^5,6

Common comorbidities associated with Alzheimer’s disease

Dealing with Alzheimer’s is tough enough on its own, but when other health issues arise, it can make things even more challenging for the affected person.

Cardiovascular diseases

Cardiovascular diseases such as hypertension (high blood pressure), high cholesterol, obesity, and coronary artery disease have been associated with the development of Alzheimer's disease years later.^5,7 Both Alzheimer's and cardiovascular diseases are progressive conditions that can develop years before symptoms manifest. Also, cardiovascular diseases may develop earlier than Alzheimer’s disease.⁸ Not only do cardiovascular risk factors increase the risk of developing Alzheimer's disease but are commonly experienced in those who have the condition.⁷ 

The relationship between cardiovascular conditions and the development of Alzheimer’s disease is not fully understood. It is believed to occur due to chronic inflammation throughout the body, including the brain.⁸ Inflammation is a natural response by the immune system to injury or infection, but when it becomes chronic, it can damage tissues and contribute to the development of various conditions, including Alzheimer’s disease.⁸

Diabetes mellitus 

Type 2 diabetes can increase the risk of developing and co-occurring with Alzheimer’s disease. Alzheimer’s disease and type 2 diabetes are age-related conditions and tend to develop over a period of time.^5,9,10 This is because the same risk factors of cardiovascular diseases can increase the risk of developing type 2 diabetes and Alzheimer’s disease. Even after managing cardiovascular-related conditions, people with type 2 diabetes can experience tissue loss (atrophy) and white matter damage (leukoaraiosis) in the brain, which are associated with the cognitive decline seen in Alzheimer's.⁹

Insulin and insulin resistance play a role in the connection between type 2 diabetes and Alzheimer’s disease. Insulin is a hormone (chemical) that helps to lower blood sugar levels and is also important for brain health as it supports the growth and function of neurons. Insulin is transported to the brain, particularly to areas involved in memory and learning. High levels of insulin in the blood, even in people without diabetes, are linked to poorer cognitive function.⁹

Type 2 diabetes is a lifelong condition, chronic high levels of insulin can disrupt neuronal health and may contribute to the development of Alzheimer's disease over time.⁹ 

Depression

Depression is one of the most frequent psychiatric disorders and occurs in nearly 50% of people with Alzheimer’s disease and exacerbates the progression of the disease.¹⁰ Both Alzheimer’s and depression share overlapping symptoms, including loss of appetite, sleep disturbances, fatigue, and impaired concentration.^5,11 It remains unclear whether depression is a risk factor for developing or an early symptom of Alzheimer's. 

It has been suggested that changes in the level of neurotransmitters (e.g., serotonin, dopamine, noradrenaline, acetylcholine, and glutamate) and loss of neurons in specific regions that are linked to memory and thinking are present in both depression and Alzheimer’s disease, causing the development of depressive symptoms and increasing the risk of Alzheimer's.⁹

Sleep disorders

Sleep disturbances, such as insomnia, sleep apnoea, and restless leg syndrome are common in people with Alzheimer’s disease and can appear in the preclinical or prodromal phase of the disease.¹² Poor sleep quality can worsen cognitive functions which are already affected by people with Alzheimer’s disease, making the symptoms more pronounced. 

Those with Alzheimer’s disease can experience reduced deep sleep, also known as slow-wave sleep. Slow-wave sleep is one of the third stages of sleep and is characterised by deep relaxation, decreased heart rate, and slowed breathing. Slow-wave sleep is essential for physical rest and recovery, as well as for memory consolidation and overall brain health. Reduction of slow-wave sleep can lead to various sleep disturbances, such as frequent awakenings during the night. Reduced slow-wave sleep in Alzheimer’s disease can put the brain and body under significant stress. Not only can it impair cognitive function but also contributes to chronic inflammation of the brain and accelerates the progression of Alzheimer's.¹² 

Osteoporosis

Osteoporosis is a condition characterised by weak and brittle bones, which not only increases the risk of developing Alzheimer’s disease but is also frequently reported in individuals already diagnosed with the disease.^14,15 Also, having Alzheimer's disease increases the risk of osteoporosis.¹⁴ This is because people with Alzheimer's often have disrupted sleep, less physical activity, and don't get enough sunlight, which can lead to a lack of Vitamin D and weaker bones.^14,15

The relationship between osteoporosis and Alzheimer’s disease can be explained by the abnormal build-up of amyloid-beta protein in both the brain and the bones. In normal bone function, there is a continuous process called bone remodelling, where old bone tissue is broken down and replaced by new bone tissue.¹⁵ In Alzheimer's disease, the build-up of amyloid-beta protein can disrupt the balance between new bone formation and the breakdown of old bone tissue, contributing to osteoporosis.^14,15 Also, chronic inflammation, hormonal changes, physical inactivity, and limited exposure to sunlight can exacerbate symptoms of cognitive decline in Alzheimer's disease.^14,15  

Summary 

Alzheimer’s disease is a neurodegenerative condition that leads to problems with memory, thinking, and reasoning. Comorbidities like cardiovascular disease, diabetes, and others can often occur independently or at the same time. They tend to appear before the onset of Alzheimer's disease during the preclinical or prodromal phase. Comorbidities can exacerbate the symptoms and progression of Alzheimer’s leading to chronic inflammation, and making it harder for the body to clear amyloid-beta plaques and neurofibrillary tangles.