Alzheimer's disease and COVID-19

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Studies have shown that Alzheimer's disease (AD) patients are at an increased risk of morbidity and mortality from SARS-CoV-2, the virus that causes COVID-19. [1] AD is the most common cause of dementia worldwide and is clinically defined by amyloid beta plaques, neurofibrillary tangles, and activation of the brain's immune system. [2] [3] While COVID-19 has been known to more severely impact elderly populations, AD patients have been shown to have a higher rate of SARS-CoV-2 infection compared to cognitively normal patients. [1] The disproportionate risk of COVID-19 in AD patients is thought to arise from an interplay of biological and social factors between the two diseases. Many common biological pathways are shared between COVID-19 and AD, notably those involved in inflammation. [4] Genetic factors that put individuals at risk for AD, such as the APOE4 genotype, are associated with worse outcomes during SARS-CoV-2 infection. [5] Cognitive impairment in AD may prevent patients from following proper public health guidelines, such as masking and social distancing, increasing their risk of infection. [6] Additionally, studies have shown cognitively normal COVID-19 patients are at an increased risk of AD diagnosis following recovery, suggesting that COVID-19 has the potential to cause AD. [4] [2]

Contents

Contribution of AD to increased risk of COVID-19

Multiple studies have shown that AD patients are at a significantly increased risk of death due to COVID-19. [1] AD diagnosis was one of the major risk factors in predicting death due to complications from COVID-19. [1] Patients with AD were also at a higher risk of death due to COVID-19 compared to patients with frontotemporal dementia. [1] A separate study assessing the contribution of underlying conditions towards death due to COVID-19 found that the three strongest predictors of mortality were age, chronic lung disease, and AD. [1] Data collected from 93 countries shows that AD has a stronger association with mortality due to COVID-19 than both asthma and chronic obstructive pulmonary disease (COPD). [1]

Factors in Alzheimer's disease that lead to an increased risk of COVID-19 infection
FactorRole in ADContribution to COVID-19 riskCitation
AgeIncreased risk of developing ADIncreased risk of severe COVID-19 [7]
APOE4 genotypeIncreased risk of developing ADIncreased risk of severe COVID-19 [5] [8] [9]
Blood-brain barrier Breaks down in ADIncreased risk of brain infection [10] [11]
Requirement for caretakerRequired for many AD patientsIncreased risk of transmission from caretaker [12]
Memory deficitsIncreased in ADDecreased ability to remember public health measures [6] [13]
WanderingSeen in ADIncreased risk of contacting infected persons [12]

Age

Age is one of the primary contributors to the risk of AD, over 10% of individuals over 65 years of age are thought to have the disease. [7] Likewise age is also a primary risk factor for morbidity and mortality associated with COVID-19. [7] As AD patients are generally older, they are more susceptible to negative outcomes in COVID-19 infection. In aged individuals and those with AD, chronic inflammation present at baseline is thought to play a role in the poor prognosis observed following viral infection. [7]

Social factors influencing infection

The COVID-19 pandemic prompted the introduction of numerous public health measures to curb the virus' spread, including recommendations on hand washing, social distancing, and masking. [13] Due to the effect of dementia on memory and cognition, AD patients often are unable to remember or properly follow public health measures. As such, this increases the risk of contracting COVID-19. Moreover, as dementia patients are susceptible to wandering which, when combined with lack of adherence to public health protocols, can increase contact with infected people. [6] In addition, many dementia patients live in assisted living facilities, which have an overall higher rate of COVID-19 transmission due to poor social distancing between residents and staff. Many AD patients, especially those with advanced disease, are dependent on others to provide basic care, such as hygiene and feeding. In these situations, social distancing is not possible, thus increasing the risk of infection from caregivers. [12]

APOE4 genotype

How APOE4 genotype influences COVID-19 pathology APOE4 and COVID-19.jpg
How APOE4 genotype influences COVID-19 pathology

Studies have shown a degree of overlap between genetic risk factors for AD and severity of COVID-19. The primary genetic risk factor for late onset AD is the presence of the Apolipoprotein E (APOE) 4 allele. [9] APOE is a protein that is responsible for transporting cholesterol and other lipids between cells. [9] It is present in the brain, where it is secreted by resident immune cells, as well as in the cardiovascular system. [9] [8] Patients carrying the APOE4 gene variant are at a higher risk of developing AD due to impaired clearance of Aβ from the brain. [9] Approximately 14.8% of AD patients carry two copies of the APOE4 allele, in comparison to 1.9% of the general population. [9] In addition to its role in AD, APOE4 carriers are also at an increased risk of developing severe COVID-19 and dying due to the disease. [5] Aside from its role in Aβ clearance, APOE4 increases the risk of cardiovascular disease, which is associated with mortality and morbidity due to SARS-CoV-2 infection. [5] Furthermore, APOE4 carriers may show a decreased ability to express key genes involved in the antiviral response, which may compromise the ability to fight the virus in AD patients carrying the allele. [7] Additionally, APOE4 carriers show increased secretion of pro-inflammatory cytokines in response to viral stimulation and show increased BBB permeability, respectively increasing the risk of severe disease and neuroinvasion. [7] In induced pluripotent stem cell (iPSC)-derived neurons, APOE4 genotype has been shown to increase the rate of SARS-CoV-2 Infection. [7]

Blood-brain barrier

Dysfunction of the blood brain barrier in Alzheimer's disease Blood brain barrier Alzheimer's.jpg
Dysfunction of the blood brain barrier in Alzheimer's disease

The blood-brain barrier is integral in protecting the brain from external objects, including waste, circulating blood cells, and infectious agents. [11] It is formed by tight junctions between the endothelial cells of blood vessels, only allowing certain molecules from the blood to access the central nervous system. A decline in the integrity of the BBB has long been associated with AD and contributes to disease progression by allowing neurotoxic factors from the blood to enter the brain. [11] As the BBB declines in AD, it is thought to allow increased passage of SARS-CoV-2 particles into the brain, enhancing the risk of severe neurological complications resulting from infection. [10]

Contribution of COVID-19 to AD risk and progression

Research has shown that there is a link between prior infection with certain viruses and the development of neurodegenerative diseases later in life. [14] This extends to AD, where infection with viruses such as herpes simplex virus (HSV), varicella zoster virus (VZV), or Epstein-Barr virus (EBV), among others, increases risk of developing AD. [15] In a study of 6,245,282 patients, it was observed that cognitively normal individuals over 65 are at an increased risk of a new dementia diagnosis following COVID-19 infection. [16] Moreover, COVID-19 has been shown to potentially exacerbate the progression of existing AD, leading to increased research interest into the interaction between the two diseases [1]

Factors in COVID-19 infection and management that increase risk of developing Alzheimer's disease
FactorEffect of COVID-19Contribution to AD risk and progressionCitation
Renin-angiotensin SystemIncreased angiotensin II and AT1R signalingHigh angiotensin II can increase progression of neurodegeneration in AD [17] [18] [2] [19] [4]
ACE2 enzymeReceptor for SARS-CoV-2 infection, decreased due to COVID-19 infectionIncreased risk of AD due to accumulation of beta-amyloid [7] [2] [19] [4]
NLRP3 inflammasomeIncreased activity in COVID-19 infection to fight virusIncreased risk of AD due to increased deposition of beta-amyloid [20] [21] [22]
CytokinesIncreased levels in COVID-19 infection to fight virusContribute to neurodegeneration in AD [23] [24] [25] [26]
Face maskingRequired in many care scenarios to prevent viral spreadWorsen psychiatric symptoms, such as agitation and distress, in AD patients due to impaired facial recognition [27]
Social isolationRequired in many cases to prevent viral spreadIsolation leads to worsening of psychiatric symptoms in AD, chronic isolation may lead to increased risk of AD later in life [28] [6]

Renin-angiotensin system and ACE family enzymes

The renin-angiotensin system (RAS), which is involved in blood pressure regulation, plays a unique and important role in the brain. [17] The RAS system involves the proteins angiotensinogen, renin, and ACE, all of which are present in the brain. [18] Renin is an enzyme that cleaves angiotensinogen into angiotensin I (Ang I), while ACE converts Ang I into Ang II. [18] Ang II can either bind to the angiotensin II type 1 receptor (AT1R), which promotes inflammation and damages neurons, or the AT2R, which reduces inflammation and protects neurons. [18] At higher levels of Ang II, the AT1R is preferably activated, causing inflammation, decreased blood flow to the brain, and cognitive impairment in the long term. [18] Ang II can be cleaved by ACE2 into more neuroprotective species, such as Ang III and IV, which counteract the effect of Ang II. [18] In AD, AT1R signaling has been shown to be increased, contributing to neurodegeneration and cognitive impairment. [29]

Brain renin-angiotensin pathway and effectors Brain Renin Angiotensin Pathway.jpg
Brain renin-angiotensin pathway and effectors

Some studies have found a link between increased ACE2 in the brain and AD, however this remains controversial. [7] ACE2 has been shown to potentially play a protective role in AD, as ACE2 decreases activity of the Ang II/AT1R axis. Additionally, ACE2 has been shown to have benefits in AD besides the classical RAS. Administration of ACE2 activating drugs can reduce amyloid plaques and prevent cognitive symptoms in mouse models of AD. [7] One of the targets of ACE2 is brain derived neurotrophic factor (BDNF), a protein that supports proper neuron function and is decreased in AD. [2] [19] Additionally, ACE2 has been shown to convert toxic Aβ43 into protective Aβ40, decreasing amyloid burden. [7]

Binding of SARS-CoV-2 to ACE2 inhibits its function. [2] This is exacerbated in AD, as one of the major toxic species of Aβ, Aβ42, has been shown to interact with the SARS-CoV-2 spike protein to increase its binding to ACE2. [2] Inhibition of ACE2 due to infection ultimately leads to increased accumulation of Aβ peptides and decreased activation of BDNF, accelerating neurodegeneration in AD. Additionally, inhibition of ACE2 by SARS-CoV-2 causes increased Ang II, contributing to neuronal stress in AD. [4] As such, SARS-CoV-2 infection can accelerate AD progression through both the classic RAS pathway and alternative mechanisms.

NLRP3 inflammasome

The nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) family of proteins are crucial mediators of the innate immune response to pathogens. [20] NLRP3 is one protein in this family that is involved in the body's response to bacteria, fungi, and viruses. [20] Upon recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), an immune cell will initially prime an inflammatory response by increasing expression of NLRP3 (signal 1). [20] NLRP3 will become active once the cell receives an additional "activation signal", normally consisting of toxins, viral RNA, or signs of cell damage. [20] Once activated, NLRP3 will interact with two other proteins, ASC and pro-caspase-1, to form the inflammasome, a circular structure made of multiple copies of each involved protein. [30] From here, the NLRP3 inflammasome will cleave inactive pro-inflammatory proteins such as pro-interleukin(IL)-1β and pro-IL-18 to their active forms, which continue to promote inflammation. [30]

Pathways involved in increased risk of AD following COVID-19 infection COVID-19 ACE2 and NLRP3 Interaction.jpg
Pathways involved in increased risk of AD following COVID-19 infection

Studies have shown involvement of the NLRP3 inflammasome in AD. [21] The expression of genes related to inflammasome activation were shown to be increased in AD, while stimulation of immune cells with Aβ42 can directly activate it. [21] Aβ plaques and oligomers can function similar to DAMPs, priming and activating the NLRP3 inflammasome. Additionally, Aβ that has been phagocytosed by microglia can damage lysosomes, cellular structures containing waste, causing release of cathepsin B, an endogenous molecule that can activate the NLRP3 inflammasome. [21] Consequently, activation of the NLRP3 inflammasome prevents microglia from ingesting Aβ42, creating a positive feedback loop towards neuroinflammation as Aβ buildup can further activate additional inflammasomes. [21] NLRP3 activation can also arise from hyperphosphorylated tau, and can consequently lead to additional tau phosphorylation. This chronic activation of the NLRP3 inflammasome ultimately contributes to chronic inflammation and neurodegeneration in AD. Being a virus, SARS-CoV-2 can activate the NLRP3 inflammasome, triggering inflammation required to fight infection. [22] It is through this mechanism that SARS-CoV-2 is thought to increase deposition of toxic Aβ42 and hyperphosphorylated tau, worsening AD pathology. The subsequent increase in inflammatory cytokines can further lead to neurodegeneration and cognitive impairment.

Cytokines

Cytokines are cellular messages given off by immune cells and different tissues that can help promote or stop an immune response. [23] These molecules are produced as a part of the normal immune response and are greatly increased due to SARS-CoV-2 infection. However, uncontrolled cytokine release can be detrimental or even fatal, especially in cases of severe COVID-19. [31] In addition to their role in viral infections, cytokines are highly abundant in the brains of AD patients. [23] While initially produced to help clear toxic Aβ , chronic cytokine release is thought to play an important role in causing and progressing neuroinflammation. [23] Many cytokines involved in AD are also increased due to COVID-19 infection, such as IL-6, IL-1, and tumor necrosis factor alpha (TNF-α). [24] [25] [26] While these cytokines are essential in mounting a response to COVID-19 infection, they may consequently drive neurodegeneration in AD patients.

Social factors influencing worsening of AD symptoms

The onset of the COVID-19 pandemic brought many public health measures into the spotlight, such as lockdowns and mandatory face mask use. Social isolation of AD patients due to COVID-related lockdowns has been shown to worsen the psychiatric symptoms of AD, including depression, agitation, and hallucinations. [6] [28] This partially is thought to arise from lack of socialization and mental stimulation associated with caregiver programs and social interaction. [28]

Multiple studies have shown that regular physical exercise can reduce the risk of developing AD or other forms of dementia. [32] Exercise is associated with increased blood flow to the brain and improved cognitive function. Exercise has also been shown to potentially improve psychiatric symptoms and slow the decline in the ability to perform daily tasks in AD patients. [33] [32] Lockdowns during the early stages of the COVID-19 pandemic have greatly hindered the ability for many individuals to engage in physical activities, which may worsen dementia risk and progression. [34]

Additionally, AD patients often require a sense of familiarity in their surroundings and those they interact with. [27] Despite the need for familiarity, AD patients often have trouble recognizing faces. [27] Mandatory face masking, while essential to prevent viral spread, can further impair facial recognition in AD. [27] This has been proposed to contribute to distress and declining mental health in AD patients. [27]

Related Research Articles

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Inflammasome</span> Cytosolic multiprotein complex that mediates the activation of Caspase 1

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Additionally, inflammasomes can be incorporated into larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

<span class="mw-page-title-main">Symptoms of COVID-19</span> Overview of the symptoms of COVID-19

The symptoms of COVID-19 are variable depending on the type of variant contracted, ranging from mild symptoms to a potentially fatal illness. Common symptoms include coughing, fever, loss of smell (anosmia) and taste (ageusia), with less common ones including headaches, nasal congestion and runny nose, muscle pain, sore throat, diarrhea, eye irritation, and toes swelling or turning purple, and in moderate to severe cases, breathing difficulties. People with the COVID-19 infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; and a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, or throat disorders, loss of taste combined with loss of smell is associated with COVID-19 and is reported in as many as 88% of symptomatic cases.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

<span class="mw-page-title-main">Impact of the COVID-19 pandemic on neurological, psychological and other mental health outcomes</span> Effects of the COVID-19 pandemic and associated lockdowns on mental health

There is increasing evidence suggesting that COVID-19 causes both acute and chronic neurologicalor psychological symptoms. Caregivers of COVID-19 patients also show a higher than average prevalence of mental health concerns. These symptoms result from multiple different factors.

PANoptosis is an inflammatory cell death pathway. Genetic, molecular, and biochemical studies identified extensive crosstalk among the molecular components across cell death pathways in response to a variety of pathogens and innate immune triggers, leading to the conceptualization of PANoptosis. PANoptosis is defined as a unique innate immune inflammatory cell death pathway driven by caspases and RIPKs and regulated by multi protein PANoptosome complexes. PANoptosis is implicated in driving innate immune responses and inflammation in disease. PANoptosome formation and PANoptosis occur during pathogenic infections, including bacterial, viral, and fungal infections, as well as during inflammatory diseases and can be beneficial in the context of cancer.

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

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