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Epidemiology and subtypes of dementia
Published in Marjolein de Vugt, Janet Carter, Understanding Young Onset Dementia, 2021
It was not until 1968 that Blessed and colleagues established that the plaques and neurofibrillary tangles described by Alzheimer in presenile dementia were also the key components of ‘senile dementia’ (Blessed et al., 1968). This led to the recognition that the senile plaques (later identified as amyloid plaques) and neurofibrillary tangles are seen in older patients with senile dementia were qualitatively the same as those found in presenile AD (Kang et al., 1987). This led to the recognition that Alzheimer's disease was the same underlying disease regardless of the age of onset and the terms presenile and senile dementia are no longer used. However, important phenotypic differences remain between patients with young onset and late onset Alzheimer's disease (M. N. Rossor et al., 2010). Compared with older patients, younger patients have fewer comorbidities like heart disease and renal impairment and therefore have lower medication usage. The burden of cerebrovascular disease is also typically lower in young patients, so it is more common for older patients to have vascular disease coexisting with Alzheimer's disease. The aforementioned comorbidities can exacerbate cognitive impairment and their potential contribution to presenting symptoms should be considered in such cases. In addition to comorbidity, phenotypic differences are also found (see below).
Ethanolic Extracts of Dysphania ambrosioides Alleviates Scopolamine-Induced Amnesia in Experimental Animals
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Rajashri Bezbaruah, Chandana C. Barua, Lipika Buragohain, Pobitra Borah, Iswar Chandra Barua, Ghanshyam Panigrahi
AD is a subtype of dementia and is the most common progressive neurodegenerative disorder with a slow onset. Alongside cognitive decline, it often shows non-cognitive symptoms like psychosis, depression, apathy, etc., which, if they remain untreated, may lead to death (Joshi and Malviya, 2017; Abiola et al., 2019). Pathologically, AD is characterized by atrophy of the cortex and hippocampus due to deposition of amyloid β (Aβ), as well as formation of senile plaques and neurofibrillary tangles (NFT). Senile plaques are collections of sinuous and decaying nerve terminals around an amyloid core. Formation of Aβ occurs as a result of enzymatic cleavage and improper processing of amyloid precursor protein. NFT contain hyperphosphorylated tau proteins. Abnormal accumulation of Aβ and tau proteins initiates neurotoxicity, which is facilitated by oxidative stress. Hence, oxidative stress plays an important role in the pathogenesis of AD. Acetylcholinesterase also plays an important role in the development of AD. Lack of acetylcholinesterase (AChE) causes damage to the central cholinergic system, which results in cognitive deficits, leading ultimately to AD (Dhingra and Kumar, 2012; Kim et al., 2016; Uddin et al., 2016). Reduction in the hippocampal nitric oxide- (NO-) containing neurons and decreased synthesis of NO are consequences of neuronal damage associated with AD. Moreover, loss of gamma aminobutyric acid A receptor (GABAA) and functional abnormality of the GABAergic system are also implicated in AD (Abiola et al., 2019).
Neuropsychological Characteristics of Early Alzheimer Disease
Published in Robert E. Becker, Ezio Giacobini, Alzheimer Disease, 2020
Maura Mitrushina, Paula Altman Fuld
With respect to the problem of early or pre-clinical diagnosis of AD, the strength and uniqueness of this association is crucial. Recent studies suggest that the presence of the biological substrate of AD, such as plaques and tangles, may or may not not be associated with AD-like cognitive deterioration. In a study reported by Fuld, Dickson, Crystal & Aronson (1987), senile plaques were significantly correlated with memory deterioration even in elderly persons without dementia. Correlation between the number of primitive plaques (which lack well-defined, compact, amyloid cores) with recall on the Fuld Object-Memory Evaluation was significant at .002 level (r=-.81). The authors suggested that these individuals were in the early, or “pre-clinical” stage of dementia, but it is also possible that they would not have gone on to manifest dementia had they not died.
Neuroprotective role of herbal alternatives in circumventing Alzheimer’s disease through multi-targeting approach - a review
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Sunil K Ravi, Balenahalli Narasingappa Ramesh, Shilpa Kj, Jagadesha Poyya, Jyothsna Karanth, N.G Raju, Chandrashekhar G Joshi
The formation of NFTs and senile plaques are the main histopathological hallmarks of AD [11]. The senile plaques contain amyloid-beta (Aβ) peptide, which consists of 37–49 amino acid residues and are formed by the extracellular and transmembrane domains of amyloid precursor protein (APP) [12]. In plaques, the oligomers might be trapped in fibrillar aggregates. Oligomers may be the hazardous Aβ species that contribute to signaling pathway deregulation (Fyn, FAK, GSK3b, and CDK5), causing changes in cytoskeletal and synaptic proteins, as well as synaptic and neural damage [13] (Figure 1). During sporadic AD, APP is cleaved by gamma and beta secretases to form 4 kDa Aβ peptide. The cleavage product has a strong tendency to form aggregates. Aβ accumulation has been one of the major pathological events resulting from an imbalance between production and clearance [14]. The Aβ aggregation process initiates by self-assembling of Aβ monomers into low molecular weight oligomers, which in turn results in the formation of high molecular weight oligomers known as soluble aggregation intermediates. These further aggregate to form fibrils and accumulate in the brain [15,16]. It is believed that microglia and astrocytes then mount an inflammatory response to clear the amyloid aggregates, and this inflammation likely causes the destruction of adjacent neurons and their neurites.
Amyloid-beta induced paralysis is reduced by cholecalciferol through inhibition of the steroid-signaling pathway in an Alzheimer model of Caenorhabditis elegans
Published in Nutritional Neuroscience, 2021
Anne Leiteritz, Tommy Schmiedl, Stefan Baumanns, Uwe Wenzel
Alzheimer’s disease (AD), the most common cause of dementia, develops due to the accumulation of aggregated amyloid-β (Aβ) in the human brain as senile plaques which cause a progressive neurodegeneration [1]. Epidemiological studies frequently linked hypercholesterolemia in midlife with AD development [2]. Since the blood–brain-barrier prevents direct transport of cholesterol between the peripheral circulation and the brain, the identification of permeable 27-hydroxycholesterol, an oxysterol that impairs memory functions, could provide the missing link between AD and hypercholesterolemia [3,4]. Likewise to the metabolism of cholesterol into steroid hormones or bile acids in mammals, there is a steroid-signaling pathway in Caenorhabditis elegans that in many ways resembles that found in mammals [5]. It includes the Rieske oxygenase family member DAF-36, which catalyzes the first step of cholesterol conversion into 7-dehydrocholesterol [6]. DAF-9, a cytochrome P450 family member, catalyzes the final metabolic steps by generating Δ4- and Δ7-dafachronic acids [7] which are ligands for the nuclear hormone receptor DAF-12 [8,9]. NHR-8 was identified later on as another member of the steroid-signaling in C. elegans [10]. It was suggested that NHR-8 works upstream of DAF-12 and that it maintains endogenous cholesterol levels in response to the absence of dietary cholesterol [10]. Moreover, it expression enhancing effects on DAF-36 demonstrates that besides the availability of the substrate it also controls the level of conversion to dafachronic acids within the steroid-signaling pathway [10].
Anti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs
Published in Expert Opinion on Emerging Drugs, 2020
Madia Lozupone, Vincenzo Solfrizzi, Francesca D’Urso, Ilaria Di Gioia, Rodolfo Sardone, Vittorio Dibello, Roberta Stallone, Angelo Liguori, Chiara Ciritella, Antonio Daniele, Antonello Bellomo, Davide Seripa, Francesco Panza
Alzheimer disease (AD), a multifactorial, heterogeneous, and progressive neurodegenerative disease with a long presymptomatic phase, is clinically characterized by cognitive, behavioral, and functional impairment with loss of independence. In the USA, an estimated 5.8 million people of all ages are living with AD in 2019 [1]. AD was the sixth most common cause of death in 2019 and by 2050, the number of people age 65 and older with AD may grow to a projected 13.8 million, barring the development of medical breakthroughs to prevent, slow, or cure AD [1]. In the last three decades, notwithstanding the great efforts spent in the search of a disease-modifying treatment for AD, current therapies are only symptomatic and do not affect disease progression [2]. The brain pathology of senile plaques (SP) has become the gold standard for diagnosing AD, although they seem not to be directly correlated with severity of deficits in patients with AD. The amyloid cascade hypothesis states that brain amyloid-β (Aβ) peptide deposition drives tau phosphorylation, tangle formation, synaptic loss, neuronal death, and cognitive impairment [2]. Aβ accumulation has also been linked to the apolipoprotein E (APOE) ε4 allele, the most important genetic risk factor associated with sporadic AD.