Is Dementia And Alzheimer's The Same Thing – Alzheimer’s disease (AD), the most common form of dementia, is an interesting example of the relationship between neurophysiological abnormalities and higher-order cognitive deficits. Since its initial description in 1906, research into the pathophysiology and etiology of AD has revealed an incredibly complex set of genetic and molecular mechanisms for disease progression, which characterize much more than the neuropathological features of beta-amyloid (Aβ). plaques and neurofibrillary tangles (NFTs). In this review, findings regarding the neurodegeneration present in AD are summarized along with its clinical presentation and treatment, emphasizing the relationship to the pathophysiology of the disease. Subsequently, diagnostic guidelines are provided based on the clinical recommendations of the National Institute on Aging-Alzheimer’s Association (NIA-AA) workgroup. Through the proliferation of such detailed but digestible open access resources, we can move toward increasing the equity and accessibility of education for modern physicians.
Since its discovery and classification, the pathophysiology of Alzheimer’s disease has been extensively studied, confirming the two main neuropathological forms identified by Alois Alzheimer (1) and Oscar Fischer (2) in the early 1900s: plaques and neurofibrillary tangles (2) ). . First, senile plaques are defined as extracellular deposits of beta-amyloid protein (Aβ), formed by proteolytic cleavage of the critical membrane glycoprotein, amyloid precursor protein (APP) ( 4 ). APP can be cleaved by β-secretase and γ-secretase to produce Aβ peptides of various lengths, but it is the 42 amino acid form that is primarily involved in plaque formation (5), due to its low solubility and increased propensity for fibril assembly. These fibrils, although primarily involved in Aβ plaque formation, represent one of the possible polymeric forms of Aβ.
Is Dementia And Alzheimer's The Same Thing
Since several studies have shown that Aβ plaque formation is not related to the incidence or severity of Alzheimer’s (6), attention has largely shifted to the oligomeric form of Aβ, which is soluble and able to diffuse throughout the brain via the cerebrospinal fluid. (CSF) (7). These oligomers have the ability to bind to several extracellular receptors (8), including at least one (PRP
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) appears to recognize and bind Aβ fibrils and oligomers, inhibit their growth, and contribute to the formation of small and highly neurotoxic Aβ polymers ( 9 ). Upon binding, their cytotoxic effects appear to be mediated by disrupted Ca
Signaling, oxidative stress and mitochondrial dysfunction (10). Notably, a 2002 paper published in Nature showed that Aβ oligomers, in the absence of monomers and fibrils, significantly inhibited long-term potentiation in the rat hippocampus ( 11 ). Several studies have attempted to determine the mechanism of this neuronal loss; For example, a 2020 study showed that incubation with soluble Aβ oligomers sensitized Toll-like receptor 4 (TLR4) and increased the production of tumor necrosis factor-ɑ (TNF-ɑ) in murine microglia and astrocytes (12). However, research into the role of Aβ in Alzheimer’s is far from over—in light of the news that a critical 2006 study implicating a role for the 56 kDa Aβ oligomer in murine dementia ( 13 ) was falsified, the new findings are critical. Importance of validating existing research.
Another widely recognized component of Alzheimer’s pathophysiology is the presence of intracellular neurofibrillary tangles (NFTs) (4). The primary structural components of these tangles, paired helical filaments (PHFs), and single filaments (SFs), have a common structural origin and differ primarily in their method of assembly (14). These filaments contain abnormally hyperphosphorylated tau protein (15); Since this protein plays an important role in microtubule assembly and maintenance, its phosphorylation at some serine/threonine residues alters its chemical and physical properties so that it cannot perform its biological function (16). Specifically, it was found that hyperphosphorylated tau protein cannot bind to tubulin (which is important for its role in microtubule assembly), but readily binds to normal tau protein and other microtubule-associated proteins (17), causing cytoskeletal damage. Microtubules (18) and increased intracellular tau aggregates have been observed in Alzheimer’s brain. Further, tau hyperphosphorylation contributes to intracellular tau mislocalization including dendritic spines where it contributes to synaptic dysfunction (19).
Further, degeneration of cholinergic neurons in the nucleus basalis has been extensively documented in the brains of patients with Alzheimer’s ( 20 ), creating an alternative, cholinergic hypothesis for the cognitive deficits observed in AD. However, research increasingly suggests that the various proposed mechanisms for Alzheimer’s pathophysiology may not be mutually exclusive; For example, exposure of cholinergic neurons to Aβ peptide induces cytotoxicity, while activation of these neurons has been shown to alter amyloid protein processing and tau protein phosphorylation ( 21 ). Further, acetylcholinesterase (AchE) and presenilin 1 (the catalytic subunit of γ-secretase) have been shown to interact and modulate each other’s expression and activity ( 22 ). A simplified representation of the primary components of AD pathophysiology can be seen in Figure 1.
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Figure 1. Graphical representation of the three primary pathophysiological manifestations of Alzheimer’s disease. (A) Cerebral cortex APP cleavage results in amyloid plaque formation of amyloid-beta monomers, which can then form soluble oligomers. These oligomers can have similar neurotoxic effects, but they can also degrade into insoluble protofibrils and then into fibrils, which form plaques. (B) Illustrated in a pyramidal neuron of the hippocampus, neurofibrillary tangles (NFT) are localized to the cell body and are caused by hyperphosphorylation of tau protein, which assembles into paired helical filaments (PHFs). (C) Death of basal forebrain cholinergic neurons is a major marker of Alzheimer’s disease.
As the complex and multifaceted pathophysiology of Alzheimer’s continues to be studied, the genetic, environmental, and social factors that play a role in the development of this neurological degeneration have received major attention. Initially, aging was considered a major risk factor for the development of Alzheimer’s disease; Only 1–6% of cases develop early-onset AD (EOAD), characterized by an onset between the ages of 30–65 (23). Late-onset AD (LOAD) is more common, currently accounting for approximately 6.5 million cases in the United States and projected to increase to 13.8 million by 2065 (23). The annual incidence of LOAD in the United States varies widely by age, further reflecting the relationship between aging and AD: in 2011, the incidence was 0.4% in 65–74 year olds, 3.2% in 75–75 year olds, and 7.6% in 75–75 year olds. 84. Above the age of 85 (23). Of the current 6.5 million cases, about 4 million are in women, while only 2.5 million are in men (23); However, the basis for this difference is unclear, with one major factor being the increased life expectancy of women alone. Furthermore, disparities exist in the incidence of Alzheimer’s along racial and ethnic lines, with black and Hispanic Americans having significantly higher Alzheimer’s diagnosis rates than white Americans (23). The origins of these disparities are difficult to determine, but evidence suggests that they are the result of interactions between structural and biological factors at work in the social construction of race (24). The cumulative impact of systemic racism on health cannot be underestimated (25); The influence of social and environmental factors such as exposure to pollutants/toxic substances, health care and education standards has documented an increase in several conditions that modify the risk of AD, such as cardiovascular disease, diabetes and depression (26).
Worldwide, more than 50 million people are estimated to be living with Alzheimer’s disease, and this number is projected to increase significantly (27); This increase is largely driven by population growth and an increase in average life expectancy, as well as improved methods of detecting and diagnosing Alzheimer’s disease (especially in less developed countries and poor communities in the United States).
Returning to the association of aging with Alzheimer’s disease, many common features of aging (cognitive decline, metabolic deficits, and senile plaque/NFT formation) are likely to contribute to the pathology of AD (28)—however, these factors complicate it. Development of biomarker-based diagnostic tests, since many molecular patterns associated with AD pathology may not always be indicative of the condition, as is true for Aβ plaque formation (29).
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By far, the most explored risk factors for the development of AD are the presence of specific determinants or predisposing genes; Indeed, studies show that the heritability of AD is 50% or more (30). Using genome-wide association studies, several genes have been identified so far, many of which are directly related to the aforementioned amyloid hypothesis. The first of these is APP, which encodes the amyloid precursor protein. As of 2020, there are 30 identified mutations in this gene, 25 of which cause excessive production and accumulation of Aβ.
As a result of changes in the amino acid composition of the cleavage site of APP (4). Mutations in the PSEN1 and PSEN2 genes, whose protein products are involved in the activation of the γ-secretase complex, are also thought to be associated with AD development ( 31 ). However, the most prominent genetic risk factor is the ε4 allele of the Apolipoprotein E (ApoE) gene, which accounts for approx.
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