Various theories for developing Alzheimer’s disease
Dr Md Anawar Hossain
Alzheimer’s disease
Alzheimer’s disease (AD) causes a neurodegenerative disorder, and slowly progressive impairment in memory and executive function in the older people, which currently affects >5.5 million individuals. Alzheimer’s disease largely causes dementia and morbidity in the global population. The extracellular amyloid beta (Aβ) plaques and neurofibrillary tangles are accumulated in the brain of the patients with Alzheimer’s disease, which is the main factor causing Alzheimer’s disease. Plaques contain Aβ fragments of various lengths (i.e., Aβ40 and Aβ42) formed by the sequential cleavage of the amyloid precursor protein (APP) by the enzymes β-secretase and γ-secretase (Eid et al., 2022).
The symptoms of Alzheimer’s disease or clinical diagnosis is normally observed in older age or late stage of life. But the process of developing Alzheimer’s disease actually starts early in life in a prolonged presymptomatic phase of life. Although some treatments can improve symptoms of memory loss, but these therapies can’t stop or prevent the progressive development of Alzheimer’s disease or death of cell. Although a lot of research has been conducted over the past decades, currently available therapies are not yet potentially successful, because the patients are already in the advanced stage of disease. Another reason is that clinical trials are not successful due to too late intervention in the disease process when therapies are unlikely to be effective (Paranjpe et al., 2022).
Piccirillo et al. (2022) reported that oxidative stress, metabolic alterations, and mitochondrial dysfunction play a key role in the development and worsening of Alzheimer’s disease. Therefore, researchers have taken different initiatives and efforts to develop neuroprotective strategies, which can prevent the impairment of mitochondrial dynamics and cell redox status.
Artificial intelligence to discover the cellular origins of Alzheimer’s disease
Mount Sinai researchers investigated the structural and cellular features of human brain tissues by using novel artificial intelligence (AI) methods, which helped to determine the causes of Alzheimer’s disease and other related disorders. They reported that the unbiased AI-based method was very effective than other methods to investigate the causes of cognitive impairment. The study demonstrated some unexpected microscopic abnormalities that can predict the presence of cognitive impairment. The authors published these findings in the journal Acta Neuropathologica Communications on September 20 (The Mount Sinai Hospital / Mount Sinai School of Medicine, 2022).
A genetic predictor for Alzheimer’s disease
Advanced neuroimaging or biomarker assessment from cerebrospinal fluid can perform risk classification, but it needs more resources, and it is unlikely to be useful when applied to asymptomatic individuals early in life (Paranjpe et al., 2022). The inherited DNA variation for patient classification has proven useful in providing insights into disease biology or enabling targeted therapy. DNA-based risk stratification involves polygenic scoring, which integrates information from many variants that confer individually modest increases in risk via many different pathways. Polygenic scoring has shown potential clinical utility for several important and preventable diseases, and it can identify individuals with risk equivalent to rare monogenic mutations.
Paranjpe et al. (2022) presented a new polygenic score for Alzheimer’s disease to test two key hypotheses: (i) a polygenic score can stratify the population into differing trajectories of clinical and subclinical cognitive decline with age; (ii) proteomic profiling of asymptomatic individuals with high or low polygenic score may nominate new circulating biomarkers of disease. They developed a genetic predictor for Alzheimer’s disease, which could identify asymptomatic individuals with higher risk of developing Alzheimer’s disease. They reported that the proteins levels changed in individuals with a high genetic risk of developing Alzheimer’s disease. Thus, they discovered new protein-based biomarkers in the early stages of disease progression.
Connection between microprotein and Alzheimer’s disease risk
In the mitochondria of cells, the researchers found a tiny microprotein, called SHMOOSE, which is encoded by a newly discovered gene (University of Southern California, 2022). When a mutation occurs within this gene, the SHMOOSE microprotein becomes partially inactivated leading to a rise as much as 20-50 % higher risk for Alzheimer’s disease. They found that about one-fourth of people of European ancestry have the mutated version of the protein. The research was published Wednesday, September 21 in the journal Molecular Psychiatry.
The substantial risk and high prevalence of mutation in SHMOOSE differentiate it from other proteins involved in Alzheimer’s disease. It can be easily administered, because the size of microprotein is about equal to that of insulin peptide, which increases its therapeutic potential. This discovery opens a new avenue for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area.
DDT exposure contributes to Alzheimer’s disease risk
DDT was extensively used between the 1940s and 1970s to combat insect-borne diseases like malaria and treat crop and livestock production. DDT is a persistent environmental pollutant that can enhance the amounts of toxic amyloid beta, which form the characteristic amyloid plaques found in the brains of those with Alzheimer’s disease. Researchers used cultured cells, transgenic flies, and mice models to demonstrate DDT’s effect on the amyloid pathway, a hallmark of Alzheimer’s disease.
Eid et al. (2002) reported that the interaction of aging-related, genetic, and environmental factors plays a significant role to cause sporadic Alzheimer’s disease (AD), because they found the high concentrations of p,p′-dichlorodiphenyldichloroethylene (DDE), a long-lasting metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) in patients with Alzheimer’s disease. Exposure to DDT increased the levels of amyloid precursor protein mRNA and protein in immortalized and primary neurons, as well as in wild-type and AD-models. Based on their experimental data and previous epidemiological findings, Eid et al. (2002) indicated that DDT exposure may contribute to increased risk of amyloid precursor protein by impacting the amyloid pathway. Furthermore, they reported a mechanism that linked the pesticide DDT to Alzheimer’s disease (Florida International University, 2022).
Predicting conversion of mild cognitive impairment to Alzheimer’s disease
Patients with Mild Cognitive Impairment (MCI) have an increased risk of Alzheimer’s disease. Treatment at the early stage of Alzheimer’s disease is more effective than that at the late stage. Therefore, early identification of Alzheimer’s disease can help clinicians to provide better treatment and improve the condition of the Alzheimer’s disease patients (Rye et al., 2022). Rye et al. (2022) used longitudinal data from the ADNI database to investigate prediction of a trajectory towards Alzheimer’s disease in a group of patients defined as mild cognitive impairment at a baseline study. One group remained stable over time (n = 357) and one converted to Alzheimer’s disease (n = 321). Mild cognitive impairment patients, who were on a trajectory towards Alzheimer’s disease, had impaired memory function as one of the core symptoms.
Synthesis of human amyloid restricted to liver results in an Alzheimer disease
Lam et al. (2021) identified that a probable cause of Alzheimer’s disease was the leakage from blood into the brain of fat-carrying particles transporting toxic proteins. Professor John Mamo and his collaborative group of Australian scientists had identified the probable ‘blood-to-brain pathway’ that can lead to Alzheimer’s disease, the most prevalent form of dementia globally. The toxic protein that accumulates in the brains of people living with Alzheimer’s disease most probably leaks into the brain from fat carrying particles in blood, called lipoproteins. If the levels of lipoprotein-amyloid in blood can be managed and their leakage into the brain can be stopped, then a new treatment pathway will be opened up to prevent the progression of Alzheimer’s disease and memory loss. Professor Mamo reported that the mouse models producing lipoprotein-amyloid in the liver suffered inflammation in the brain, and accelerated brain cell death and memory loss.
Is Alzheimer’s a brain disease or an autoimmune condition?
Researchers have been working for many years to find out the actual reasons of Alzheimer’s disease and development of new drugs, which can effectively prevent the formation of brain-damaging amyloid beta (Aβ) plaques and neurofibrillary tangles and improve the conditions of Alzheimer’s disease, such as memory loss. Weaver (2022) said that although a lot of research works have been conducted on the abnormal proteins of beta-amyloids, which cause Alzheimer’s disease, it could not develop a useful drug or therapy. Therefore, his research team pointed a new research direction that might cause Alzheimer’s disease. The research team at the Krembil Brain Institute, University of Toronto, hypothesized a new theory of Alzheimer’s disease.
They said that Alzheimer’s is not primarily a disease of the brain. But they presume that Alzheimer’s is principally a disorder of the immune system within the brain. The immune system, present in every organ of the human body, comprises of cells and molecules that work together to repair injuries, and damaged tissues of the body, protect from foreign invaders such as bacteria and viruses. The similar process of immune system works in the brain that protect brain from injuries and bacteria.
Autoimmune theory for Alzheimer’s disease
Weaver (2022) believes that beta-amyloid is a normally occurring molecule, but not an abnormally produced protein. The beta-amyloid is part of the brain’s immune system, which plays a significant role to repair the body injuries and fight against microbial attack. But there are great similarities between the fat molecules that make up both the membranes of bacteria and the membranes of brain cells. Therefore, beta-amyloid cannot differentiate the invading bacteria and host brain cells, and mistakenly attacks the very brain cells, while it should be protected. This process is believed to cause a chronic, progressive loss of brain cell function resulting in development of dementia. The brain’s immune system performs a misdirected attack on the very organ that should be defended by it. Thus, Alzheimer’s disease emerges as an autoimmune disease.
Rheumatoid arthritis is one type of autoimmune disease, in which autoantibodies play a crucial role in the development of the disease, and for which steroid-based therapies can be effective. But these therapies will not work against Alzheimer’s disease. Other drugs that are normally used in the treatment of autoimmune diseases, may not work against Alzheimer’s. Therefore, Weaver (2022) hypothesizes that other immune-regulating pathways in the brain can be targeted to develop new and effective treatment approaches for the disease.
COVID-19 increases risk factor for developing Alzheimer’s disease
COVID-19 affected older people demonstrated a substantially higher risk of developing Alzheimer’s disease within a year. Based on the results of a study of more than 6 million patients 65 and older, the researchers from Case Western Reserve University indicated that the risk factor was as much as 50% to 80% higher than a control group (Case Western Reserve University, 2022).
References
Case Western Reserve University. “Risk factor for developing Alzheimer’s disease increases by 50-80% in older adults who caught COVID-19.” ScienceDaily. ScienceDaily, 13 September 2022. <www.sciencedaily.com/releases/2022/09/220913140850.htm>.
Eid A, Mhatre-Winters I., Sammoura F.M., Edler M.K., von Stein R. et al., 2022. Effects of DDT on Amyloid Precursor Protein Levels and Amyloid Beta Pathology: Mechanistic Links to Alzheimer’s Disease Risk. Environmental Health Perspectives, 2022; 130 (8).
Florida International University. “How DDT exposure contributes to Alzheimer’s disease risk: New finding could help pave the way for early detection and potential therapy for people highly exposed to the pesticide.” ScienceDaily. ScienceDaily, 17 August 2022. <www.sciencedaily.com/releases/2022/08/220817104051.htm>.
Lam V, Takechi R, Hackett MJ, Francis R, Bynevelt M, Celliers LM, et al. (2021) Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype. PLoS Biol 19(9): e3001358.
The Mount Sinai Hospital / Mount Sinai School of Medicine. “Artificial intelligence used to uncover the cellular origins of Alzheimer’s disease and other cognitive disorders.” ScienceDaily. ScienceDaily, 20 September 2022. <www.sciencedaily.com/releases/2022/09/220920211228.htm>.
Paranjpe MD, Chaffin M, Zahid S, Ritchie S, Rotter JI, Rich SS, et al. (2022) Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease. PLoS Genet 18(9): e1010294.
Piccirillo, S., Preziuso, A., Amoroso, S. et al. A new K+ channel-independent mechanism is involved in the antioxidant effect of XE-991 in an in vitro model of glucose metabolism impairment: implications for Alzheimer’s disease. Cell Death Discov. 8, 391 (2022).
Rye, I., Vik, A., Kocinski, M. et al. Predicting conversion to Alzheimer’s disease in individuals with Mild Cognitive Impairment using clinically transferable features. Sci Rep 12, 15566 (2022).
University of Southern California. “Newly discovered protein connected to Alzheimer’s disease risk: A mutation in the small protein SHMOOSE is associated with Alzheimer’s risk and highlights a possible target for treatment.” ScienceDaily. ScienceDaily, 20 September 2022. <www.sciencedaily.com/releases/2022/09/220920211233.htm>.
Weaver D.,2022. Alzheimer’s might not be primarily a brain disease. A new theory suggests it’s an autoimmune condition. Published in The Conversation: September 20, 2022 3.42am AEST.
Treatment for Alzheimer’s diseases
The patients with Alzheimer’s diseases and their family members should know about the currently available treatment options and medications to treat Alzheimer’s diseases. The more they know about Alzheimer’s treatment and medications, the better they will be prepared to discuss them with their medical doctors and make informed choices about their treatment plan.
Efficacy of current Alzheimer’s drugs
- Current medications cannot cure Alzheimer’s disease,
- Some drugs may help to reduce symptoms, such as memory loss and confusion, for a limited time,
- Other medicines change disease progression helping cognition and function,
- Treatments may be available in different forms (pill, patch or other). An experienced medical doctor should monitor people who are taking this treatment.
Types of FDA-approved drugs for Alzheimer’s
The U.S. Food and Drug Administration (FDA) has approved medications that fall into two categories:
- drugs that may change disease progression in people living with Alzheimer’s,
- drugs that may temporarily mitigate some symptoms of the disease.
Drugs that may change disease progression
An anti-amyloid antibody drug called aducanumab (Aduhelm™) is the first therapy for the treatment of Alzheimer’s disease. The drug was indicated for people living with early Alzheimer’s disease, mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease.
- The drug targets beta-amyloid, a microscopic protein fragment that accumulates in the brain and forms into plaques,
- Removing amyloid from the brain is reasonably likely to reduce cognitive and functional decline in people living with early Alzheimer’s,
- Preventing beta-amyloid build-up may provide benefit,
- Side effects include ARIA, headache and fall.
Drugs to reduce cognitive (memory and thinking) symptoms
These drugs are prescribed for patients to treat their symptoms of loss of memory and thinking. These medications cannot stop the damage of brain cells caused by Alzheimer’s. But they may help reduce or stabilize symptoms for a limited time. The drugs currently approved to treat cognitive symptoms are cholinesterase inhibitors and glutamate regulators.
A few examples of these drugs include Donepezil Aricept®, Galantamine Razadyne®, Rivastigmine Exelon®, Memantine Namenda®, and Memantine + Donepezil Namzaric®. These drugs are indicated to use for mild to severe dementia due to Alzheimer’s diseases. These drugs have some common side effects, such as nausea, vomiting, loss of appetite, muscle cramps and increased frequency of bowel movements. Memantine Namenda® has side effects of headache, constipation, confusion and dizziness.
Non-cognitive (behavioral and psychological) symptoms
Alzheimer’s affects not only just memory and thinking, but also causes different behavioral and psychological symptoms that accompany dementia, such as sleep changes. Sleep changes may include difficulty in sleeping, taking daytime naps and/or experiencing other shifts in sleep pattern.
Suvorexant (Belsomra®) is prescribed to treat insomnia in people living with Alzheimer’s (mild to moderate).
Reference
Alzheimer’s Association, 2022. Treatments and Research, https://www.alz.org/help-support/i-have-alz/treatments-research. Accessed on 22/09/2022.