By: Mint Suetrong, Contributing Writer
Edited by: Olivia Storti, Editor; Elias Azizi, Editor in Chief
What is Alzheimer’s?
Alzheimer’s disease (AD), is the most common neurodegenerative disease, meaning nerve cells progressively lose function over time which ultimately leads to cell death. [1] AD can be identified by early signs and symptoms such as memory loss or difficulty in solving problems. [2] The degree of knock-on effects caused by AD directly affects the prognosis of the patient, especially at the stage of diagnosis.[3]
What is the cause?
Although the true cause of Alzheimer’s is still under investigation, it is believed that AD is the result of the interaction of numerous factors including:
Age
Genetics and Family history
Changes in the brain years before first symptoms presenting
Lifestyles and underlying diseases
Currently, age is the most known risk factor for developing Alzheimer’s: approximately one third of all people over the age of 85 are living with AD, with the number of individuals with AD doubling every 5 years beyond the age of 65. In a research paper written by Genome Medicine, BMC as part of Springer Nature, a genome-wide study identified a specific variant in the CCL11 gene, located on chromosome 17, which could be responsible for the association between age and Alzheimer’s disease.
The relationship between age as the cause of Alzheimer’s can be explored in various ways, including the idea of the age of onset (AAO) being a highly heritable factor and the interaction of age and immune response, particularly focusing on auto-immune responses. In both divisions, however, associations have been identified through genetics.
An article from Neurogenetics titled, ‘Novel mutations and repeated findings of mutations in familial Alzheimer disease’, located 3 gene mutations that are associated as the cause of approximately half of inherited cases of AD. [5] These are the three known familial Alzheimer’s disease (FAD) genes coding for Amyloid Precursor Protein (APP), Presenilin-1 (PSEN1) and Presenilin-2 (PSEN2) genes. The mutation detection rate in these regions was 57%.
Although the genes associated with the age of onset (AAO) are currently still being studied, the strongest genetic risk locus for the development of the disease is in the Apolipoprotein E (APOE) which accounts for 3.7% of AD cases with the AAO variation. [6] An analysis by Molecular Psychiatry of an autosomal dominant mutation in the PSEN1 gene identified a haplotype of single-nucleotide polymorphisms (SNPs) with a chemokine gene cluster associated with delayed onset of mild cognitive impairment and dementia. [7] Furthermore, a recent genome-wide study by Naj et al. confirmed the association of the APOE Ɛ4 allele with earlier onset along with identifying associations with CR1, BIN1 and PICALM genes. [8]
As a neurodegenerative condition, the role of inflammatory and immune responses are significant in the progression of AD. Genes associated with AD contain known roles in inflammation. Pathway analyses by the International Genomics of Alzheimer's Disease Consortium (IGAP) and authors from ‘Cell’ determined that the immune and microglia, cells that become resident macrophages, are significant to AD with the TYROBP gene as the main driver for this module. [9, 10]
How is it diagnosed?
As an age-related disease, early symptoms of Alzheimer’s could be mistakenly interpreted as natural lapses in memory by aging. The true extent of AD on one’s body, however, makes communicating, learning, thinking, and reasoning increasingly difficult. Early diagnosis and care are crucial: the Alzheimer’s Association has developed a checklist of common symptoms to help aid diagnosis. [11]
Memory loss, especially with short-term memory or recently learned information.
Difficulty performing familiar tasks, such as preparing a certain meal.
Problems with language, such as forgetting simple words or using unusual substitute words, such as “that thing for my mouth” when asking for a toothbrush.
Disorientation to time and place, such as where they are, how they got there, or how to find their way back home.
Poor or decreased judgment, such as dressing without taking regard of the weather or spending large amounts of money on products they do not need.
Problems with abstract thinking, particularly with numbers. A person with AD may struggle to balance a checkbook or forget what numbers are entirely.
Misplacing things in unusual places, such as placing a clothing iron in the fridge or putting fruits in the makeup drawer.
Changes in mood or behavior, showing rapid mood swings from calm to tears to anger for no apparent reason.
Personality changes to become extremely confused, suspicious, or fearful of a family member.
Loss of initiative, becoming very passive and not enjoying activities they used to enjoy.
Additional tests are used in conjunction with the list to help the diagnosis. Conduction of memory, problem-solving, and language tests or other standard medical tests such as blood and urine tests could help identify other causes for the symptoms. Brain scans such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) could be used to support the diagnosis and rule out other conditions such as Parkinson’s disease or other types of dementia.
What is the progression and prognosis?
Much like the ongoing research into the cause of Alzheimer’s disease, the factors affecting the progression continue to be researched. In a study published on PubMed, 50% of the 160 AD patients at the Neurology Unit of Careggi University Hospital of Florence presented rapid cognitive changes as defined in the Mini-Mental State Examination after a 2-year follow up period. Extrapyramidal signs, or drug-induced movement disorders such as uncontrollable movements and tremors, were predictors of the worst outcome, especially among the APOE ɛ4 allele carriers. Interestingly, patients with a family history of dementia showed an approximately 50% decrease in risk of rapid progression. [12]
The progression of AD also depends on age: depending on the stage of the disease at the diagnosis, patients on average live between 3 to 11 years after their diagnosis. A study of the Neurobiology of Aging suggests that age-related alterations in the blood-brain barrier could be responsible for damage to nerve terminals and limited formation of senile plaques within the cerebral cortex. Coupled with the uptake of ‘neurotoxin’ at damaged terminals and retrograde transport to perikarya, the movement of molecules from the axon towards the cell body of a neuron inevitably leads to cell death and loss of neurons in the brain. The loss of cells catalyzes further brain barrier dysfunction, new plaque formation, and, unfortunately, continued cell loss in the brain cortex and subcortex. [13] This self-perpetuating cycle continues to damage brain regions including the hippocampus which has a major role in learning and memory, resulting in the progressively worsening symptoms of AD.
The speed of progression could also be influenced by untreated underlying diseases; a common example is hypertension. A common cause of death for AD patients is secondary infections, such as pneumonia, which can be due to the inhalation of food or drinks as a result of impaired swallowing. Other causes of death may include dehydration, malnutrition, and falls.
What is the treatment?
While there currently is no cure for Alzheimer’s, several therapies have been developed with the goal of improving the quality of life in people with AD. These therapeutic approaches can be broken down into three broad categories: symptomatic, disease-modifying, and regenerative.
[14]
Approved treatments for symptomatic therapies include the usage of cholinesterase inhibitors, which act to prevent the breakdown of acetylcholine, which is a crucial neurotransmitter, and glutamate antagonists, targeting glutamate receptors. [15, 16] At present, these therapies remain the most common. Its mechanism is within the premise that it speeds up communication between nerve cells as they are much less active in people with advanced AD and to reduce neuron damage. It is important to note that studies of these treatments are usually within a 6-months to a year time period. Therefore, the long-term significance is still unknown. [17]
As the first approved disease-modifying drug for Alzheimer’s, ‘aducanumab’ aims to slow down the progression of AD by interfering with mechanisms that lead to cell death; in this case, it is to reduce production and accumulation of beta-amyloid (Aβ) plaques which are believed to be one of the root causes for neurodegeneration. Aducanumab is administered intravenously (IV) for 45 mins to an hour every four weeks and is best for patients with mild cognitive impairment or mild dementia due to AD with amyloid plaque build-up. While there is currently no evidence that this treatment can restore memory and function, or the safety and effectiveness at other stages of the disease, this breakthrough has been the first of over 15 years for Alzheimer’s disease and has the potential of helping millions of people, and their beloved families and caregivers, around the world. [18, 19]
Regenerative treatments which aim to restore brain tissue, its neurons and circuitry remains a largely hypothetical approach and is unfortunately too far-fetched at this current time and state of technology. Clinical trials of all AD treatments are challenging: rate of progression is long and trials must match the period, often lasting 18 months or more. Endpoints are difficult to determine as measures of cognitive performance are less robust than biochemical or physiological measures. Research into pharmacodynamic endpoints, demonstrated by measuring Aβ concentrations as a biomarkers for analyzing enzymes which inhibit its generation, and advancements in technology, displayed by positron emission tomography (PET) ligand to support visualization and quantification of Aβ plaques and tau tangles, have shown strong potential to help innovate treatments for Alzheimer’s. [20, 21]
Future advancements in treatments for Alzheimer’s?
The identification of a 10-year delay between the onset of symptoms and the identification of the variant, suggests future applications in developing immunomodulators that have the potential to halve the disease incidence. Every 5 years the number of people with mild or moderate AD doubles for those over the age of 65. This accounts as many as 5.8 million Americans in 2020, according to the CDC. [22] With the first phase of the in-human clinical trial to assess gene therapy for treating Alzheimer’s and the approval of the disease modifying drug ‘Aducanumab’ underway, this is a pivotal point in the future of Alzheimer’s and other dementia or neurological diseases. [23]
Citations:
Guerreiro, R., Bras, J. The age factor in Alzheimer’s disease. Genome Med 7, 106 (2015). https://doi.org/10.1186/s13073-015-0232-5
Finckh, U., Kuschel, C., Anagnostouli, M., Patsouris, E., Pantes, G. V., Gatzonis, S., ... & Gal, A. (2005). Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics, 6(2), 85-89.
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G., ... & Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 261(5123), 921-923. https://doi.org/10.1126/science.8346443
Lalli, M., Bettcher, B., Arcila, M. et al. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease. Mol Psychiatry 20, 1294–1300 (2015). https://doi.org/10.1038/mp.2015.131
Naj, A. C., Jun, G., Reitz, C., Kunkle, B. W., Perry, W., Park, Y. S., ... & Schneider, L. S. (2014). Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA neurology, 71(11), 1394-1404.
International Genomics of Alzheimer's Disease Consortium (IGAP), Jones, L., Lambert, J. C., Wang, L. S., Choi, S. H., Harold, D., ... & Rotter, J. I. (2015). Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimer's & Dementia, 11(6), 658-671.
Zhang, B., Gaiteri, C., Bodea, L. G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., ... & Emilsson, V. (2013). Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell, 153(3), 707-720.
Ferrari, C., Lombardi, G., Polito, C., Lucidi, G., Bagnoli, S., Piaceri, I., Nacmias, B., Berti, V., Rizzuto, D., Fratiglioni, L., & Sorbi, S. (2018). Alzheimer's Disease Progression: Factors Influencing Cognitive Decline. Journal of Alzheimer's disease : JAD, 61(2), 785–791.
Hardy, J. A., Mann, D. M. A., Wester, P., & Winblad, B. (1986). An integrative hypothesis concerning the pathogenesis and progression of Alzheimer's disease. Neurobiology of aging, 7(6), 489-502.
Hardy, J. A., Mann, D. M. A., Wester, P., & Winblad, B. (1986). An integrative hypothesis concerning the pathogenesis and progression of Alzheimer's disease. Neurobiology of aging, 7(6), 489-502.
Gella, A., & Durany, N. (2009). Oxidative stress in Alzheimer disease. Cell adhesion & migration, 3(1), 88–93. https://doi.org/10.4161/cam.3.1.7402
InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Alzheimer's disease: How effective are cholinesterase inhibitors? 2009 Apr 15 [Updated 2017 Jun 29].
Villemagne, V. L., Doré, V., Burnham, S. C., Masters, C. L., & Rowe, C. C. (2018). Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nature reviews. Neurology, 14(4), 225–236. https://doi.org/10.1038/nrneurol.2018.9
Villemagne, V. L., Doré, V., Burnham, S. C., Masters, C. L., & Rowe, C. C. (2018). Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nature reviews. Neurology, 14(4), 225–236. https://doi.org/10.1038/nrneurol.2018.9