The science of Alzheimer’s disease explained

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.

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 ageingand 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

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 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.

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 behaviour). These changes stretch over a period of 15 to 25 years.16

Alzheimer’s Stage
Alzheimer’s Stage
Preclinical
Mild cognitive impairment due to Alzheimer’s disease
Mild Alzheimer’s disease dementia
Moderate Alzheimer’s disease dementia
Severe Alzheimer’s disease dementia
Examples of Common Symptoms
Examples of Common Symptoms 3,5
None 18
  • Forgetting recent information like appointments or conversations
  • Difficulty judging the sequence of steps in a complex task 19
  • Forgetting material that was just read
  • Difficulty finding the right words 20
  • Losing/misplacing valuable objects20
  • Issues remembering new names20
  • Difficulty with work, social tasks20or handling finances19
  • Forgetting personal history, information or events20
  • Moody or withdrawn20
  • Confusion about where they are20
  • Trouble with bladder and bowel control20
  • Changes in sleep20
  • Personality/behaviour changes20
  • Loss of awareness of recent experiences or surroundings20
  • Requires constant assistance with daily personal care20
  • Difficulty communicating20
  • Loss of physical abilities (walking, sitting, swallowing)20
  • Major areas of research in Alzheimer’s

    As described before, amyloid is one of the two main proteins thought to be associated with the neurodegeneration that causes Alzheimer’s.20,21

    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

    Amyloid beta

    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.

    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

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    References

    1. Alzheimer’s Disease International. 2018. World Alzheimer Report 2018. London: Alzheimer's Disease International.

    2. GBD Dementia Collaborators. Lancet Neurol. 2019;18:88–106.

    3. Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2021; 17(3).

    4. Selkoe DJ & Hardy J. EMBO Mol Med 2016;8:595-608

    5. Thordardottir S, et al. Alzheimer’s Res Ther 2017:9:9.

    6. Dai M-H, et al. Oncotarget 2017;9:15132-15143.

    7. Hoogmartens J, et al. Alzheimers Dement 2021;13:e12155.

    8. Guyon A, et al. PLoS One 2020;15:e0237122.

    9. AlzForum. More Support for Amyloid Hypothesis: Protective APP Mutation Lowers Aβ n Blood. www.alzforum.org/news/research-news/more-support-amyloid-hypothesis-protective-app-mutation-lowers-av-blood Accessed 5 April 2022.

    10. Reiss AB, et al. Rev Neurosci 2018;29:613–627.

    11. Hampel H, et al.  Mol Psychiatry 2021;26:5481–5503.

    12. Hutchins JB and Barger SW. Anat Rec. 1998;253:79-90

    13. Alzheimer’s Disease Fact Sheet. National Institute on Aging. Updated July 08, 2021. Accessed June 16, 2022. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet

    14. Agrawal M. 2020;447-460. Molecular basis of chronic neurodegeneration. 10.1016/B978-0-12-809356-6.00026-5

    15. Hippius H and Neundörfer G. Dialogues Clin Neurosci. 2003;5(1):101-108

    16. Scheltens P, et al. Lancet 2021;397:1577–1590

    17. Inside the Brain Part 2. Alzheimer’s Association. Accessed June 16, 2022. https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour_part_2

    18. Alzheimer’s Association. Mild Cognitive Impairment. https://www.alz.org/alzheimers-dementia/what-is-dementia/related_conditions/mild-cognitive-impairment. Accessed 1 December 2020.

    19. Alzheimer’s Association. Stages of Alzheimer’s. https://www.alz.org/alzheimers-dementia/stages. Accessed 1 December 2020.

    20. Albert MA. J Clin Sleep Med. 2011;7(5 Suppl):S9-S11.

    21. Brothers HM, et al. Front Aging Neurosci. 2018;10:1-16

    22. Chen G, et al. Acta Pharm Sin. 2017;38:1205-1235

    23. Mohamed LA, et al. ACS Chem Neurosci. 2015;6(5):725-736

    24. He Z, et al. Nat Med. 2018;24 :29–38

    25. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016 Jun 1;8(6):595-608. doi: 10.15252/emmm.201606210. PMID: 27025652; PMCID: PMC4888851.

    26. Giacobini E, Gold G. Alzheimer disease therapy--moving from amyloid-β to tau. Nat Rev Neurol. 2013 Dec;9(12):677-86. doi: 10.1038/nrneurol.2013.223. Epub 2013 Nov 12. PMID: 24217510.

    27. Leng F and Edison P. Nat Rev Neurol. 2020;17:157-172

    28. Alzheimer's Disease Genetics Fact Sheet. Nation Institute on Aging. Updated December 24, 2019. Accessed June 16, 2022. http://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

    29. Belloy M, et al. 2019;101(5):820-838

    30. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020 Mar 10.

    31. Leuzy A, et al. EMBO Mole Med 2022;14:e14408.

    32. Bullain S, et al. 2022. ADPD Oral presentation.

    33. How Biomarkers Help Diagnose Dementia. National Institute on Aging. Updated January 21, 2022. https://www.nia.nih.gov/health/how-biomarkers-help-diagnose-dementia#:~:text=The%20most%20widely%20used%20CSF,are%20another%20hallmark%20of%20Alzheimer's).


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