This article summarizes the changes to the brain that lead to the development of Alzheimer’s disease (AD), a specific type of dementia, and discusses several risk factors associated with its development.
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What is Alzheimer’s disease?
Dementia is a general term for a decline in several brain functions such as language, memory and problem-solving skills. There are many different types of dementia, including Lewy Body dementia, Korsakoff syndrome and Huntington’s disease, but Alzheimer’s disease (AD) is the most common form and accounts for between 60% - 80% of all dementia cases.
AD is a degenerative brain disease that leads to dementia symptoms that get worse over time. Early-stage symptoms include memory loss, difficulties completing familiar tasks or mood disturbance, whilst late-stage symptoms include losing the ability to hold a conversation, difficulty moving or a lack of awareness of one’s surroundings.
What causes Alzheimer’s disease?
Alzheimer’s disease is caused by complex changes to nerve cells in the brain leading to neurons becoming damaged and eventually dying.
Research has indicated that deposits of the protein beta-amyloid (referred to as amyloid plaques) and twisted fibers of the protein tau (neurofibrillary tangles), which develop in most brains as they age, appear more prevalent in the brains of people with AD. They also emerge in a distinctive pattern, beginning in the perirhinal cortex before spreading to the hippocampus and primary neocortex.
Plaques are thought to destroy cells by triggering an immune response in the surrounding area whilst tangles form within the cell, disrupting the processes that recycle and create new proteins, and ultimately killing the cell.
Risk factors for Alzheimer’s disease
Age
The most important risk factor for Alzheimer’s disease is aging, with the age-specific prevalence of the disease doubling every five years after age 65. AD has a prevalence of 1% amongst those aged 65-69, rising to approximately 30% amongst those aged 90 years and over. Several age-related processes may be implicated in the pathogenesis of the disease:
Oxidative stress: Free radicals are oxygen-containing molecules that are a normal by-product of energy production by cells. In high concentrations, they can damage cell membranes and proteins causing tissue damage. Antioxidants are molecules that neutralize free radicals, and oxidative stress occurs when there is an imbalance between free radicals and antioxidants. Age-related AD is thought to be due to an accumulation of oxidative damage.
Beta-amyloid: Thought to be a prime driver of AD, evidence shows that the brains’ ability to clear beta-amyloid slows with age. One study showed that it takes a person in their 30’s approximately four hours to clear half of the beta-amyloid in their brain. By age 80, this increases to ten hours.
Lifespan experiences: The strong correlation between AD and age may be in part due to the cumulative impact of a complex interplay between risk and protective factors across the lifespan.
Although AD and age are strongly correlated, age is not a necessary pre-requisite for the development of AD. A small minority of patients develop early-onset AD in their forties and fifties.
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Beta-amyloid protein disrupting nerve cells function in a brain with Alzheimer's disease. Image Credit: nobeastsofierce / Shutterstock.com
Genetics
The development of a given disease is influenced by risk genes and deterministic genes. Risk genes increase the likelihood of a disease but do not guarantee it, whilst the inheritance of a deterministic gene guarantees the development of the corresponding disease. Research has identified both hereditary Alzheimer’s risk and deterministic genes.
Risk gene: Several genes have been implicated in the risk of AD, with the APOE-e4 gene exerting the greatest impact on risk. APOE-e4 promotes the build-up of beta-amyloid, creating the distinctive plaques seen in the brains of patients with AD and is present in 40 – 65% of patients with AD. APOE-e4 appears to have a dose-response effect; those who inherit it from both parents are at a higher risk of developing AD. Furthermore, inheriting APOE-e4 may increase the likelihood of earlier-onset symptoms.
Deterministic genes: Early-onset AD has been strongly linked to mutations in three genes; amyloid precursor protein, presenilin 1 and presenilin 2. Individuals who inherit one of these mutations from either parent will develop the disease, although such individuals comprise less than 5% of all people with AD. All three mutations cause an excess of beta-amyloid.
Cardiovascular disease (CVD)
There is growing evidence of a possible causal link between CVD and cardiovascular risk factors and Alzheimer’s disease. As the brain is highly vascularized and uses a fifth of the body’s oxygen supply, it is particularly vulnerable to cerebral hypoperfusion, a state which occurs when the supply of blood to the brain is inadequate.
Cerebral hypoperfusion is hypothesized to contribute to the development of amyloid plaques and tau via the state of oxidative stress. Furthermore, cerebral hypoperfusion also causes a breakdown to the blood-brain barrier, reducing the clearance of plaques and tangles.
Although several risk factors associated with CVD such as smoking, obesity and diabetes are also risk factors for AD, high blood pressure in middle-age increases the risk of older-onset AD independently of other cardiovascular risk factors. Interestingly, high blood pressure in later life does not correlate with AD. Although no causal mechanism between hypertension and AD has been proven, one hypothesis is that long term hypertension is linked with cerebral hypoperfusion.
Down’s syndrome
By the age of forty, the brains of most people with Down’s syndrome (DS) will show the characteristic pattern of plaques and tangles seen in Alzheimer’s disease. However, although the prevalence of AD is high in people with DS, AD does not develop in all cases. AD is seen in approximately 30% of people with DS in their fifties, rising to 50% of people with DS in their sixties. Understanding why, despite the presence of such changes in the brain, AD only develops in some people is an area of great interest to researchers.
Head injury
Several studies have shown that incurring a moderate or severe head injury can increase the risk of developing Alzheimer’s disease many years later. One key study found that sustaining a moderate head injury increased the risk of AD by 2.3 times, whilst severe head injury had a 4.5 times greater risk.
Prospective studies have shown that traumatic brain injury is associated with an earlier onset of AD. As with CVD, the mechanism by which this occurs is thought to be linked to cerebral hypoperfusion leading to the chain of causative events that ultimately result in hallmark protein-linked brain changes observed in AD.
References
Alzheimer's Disease and Dementia. 2020. Primary Care Physicians On The Front Lines Of Diagnosing And Providing Alzheimer’S And Dementia Care. [online] Available at: <https://www.alz.org/news/2020/primary-care-physicians-on-the-front-lines-of-diag> [AccessedDecember 2020].
Alzheimer’s Disease and Mild Cognitive Impairment, 2009. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. 11(2), pp.111-128.
Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., Gargiulo, G., Testa, G., Cacciatore, F., Bonaduce, D., & Abete, P. (2018). Oxidative stress, aging, and diseases. Clinical interventions in aging, 13, 757–772. https://doi.org/10.2147/CIA.S158513
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Safieh, M., Korczyn, A.D. & Michaelson, D.M. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med 17, 64 (2019). https://doi.org/10.1186/s12916-019-1299-4
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Further Reading
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