Alzheimer\'s disease (AD) remains one of the most challenging and prevalent neurodegenerative disorders worldwide. Despite extensive research efforts, effective treatments for AD are lacking, emphasising the need for a deeper understanding of its underlying molecular mechanisms. Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase primarily associated with cell cycle regulation and neuronal development, has emerged as a key player in AD pathology. This review article comprehensively explores the multifaceted roles of CDK5 in the pathogenesis of AD. We begin by elucidating the physiological functions of CDK5 in normal brain development and neuronal maintenance, highlighting its involvement in synaptic plasticity, neurotransmitter release, and cytoskeletal dynamics. Subsequently, we delve into the dysregulation of CDK5 activity observed in AD, encompassing aberrant hyperactivation, and dysregulated protein interactions. Moreover, we discuss the intricate interplay between CDK5 and AD-related proteins, including amyloid-beta precursor protein (APP) and tau protein, elucidating their collective impact on disease progression. Finally, we described various approaches available for the inhibition of CDK-5, which can be explored as future therapeutic intervention for AD. Through synthesizing evidence from in vitro studies, animal models, and clinical investigations, this review provides a comprehensive overview of the intricate relationship between CDK5 dysregulation and AD pathogenesis, offering insights that may inform future therapeutic interventions strategies.

 Alzheimer\'s disease is the most common cause of dementia, and it is one of the leading causes of death globally. Identification and validation of biomarkers that herald the onset and progression of Alzheimer\'s disease is of paramount importance for early reliable diagnosis and effective pharmacological therapy commencement. A substantial body of evidence has emerged demonstrating that olfactory dysfunction is a preclinical symptom of neurodegenerative diseases including Alzheimer\'s disease. While a correlation between olfactory dysfunction and Alzheimer\'s disease onset and progression in humans exists, the mechanism underlying this relationship remains unknown. The aim of this article is to review the current state of knowledge regarding the range of potential factors that may contribute to the development of Alzheimer\'s disease-related olfactory dysfunction. This review predominantly focuses on genetic mutations associated with Alzheimer\'s disease including amyloid-β protein precursor, presenilin 1 and 2, and apolipoprotein E mutations, that may (in varying ways) drive the cellular events that lead to and sustain olfactory dysfunction.

Transgenic models of familial Alzheimer\'s disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology. In this meta-analysis, we sought to evaluate levels of phosphorylated tau (p-tau) and explore potential age-related variations in tau hyperphosphorylation, within mouse models of AD. The PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD, APPswe/PSEN1de9, J20 and APP23 mice. Data were extracted and analyzed using standardized procedures. For the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the relationship between genotype and CT phosphorylated tau in studies using hybrid mice, female mice, and preparations from the neocortex. For the APPswe/PSEN1de9 model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the relationship between genotype and PR domain phosphorylated tau in the neocortex of APPswe/PSEN1de9 mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (<10 studies). Although tau is hyperphosphorylated in both 5xFAD and APPswe/PSEN1de9 mice, the effects of ageing on p-tau are contingent upon the model being examined. These observations emphasize the importance of tailoring model selection to the appropriate disease stage when considering the relationship between Aβ and tau, and suggest that there are optimal intervention points for the administration of both anti-amyloid and anti-tau therapies.

Alzheimer\'s disease (AD) is a neurological disease that affects the memory. AD has been attributed to the aggregations of amyloid-β (Aβ) peptides which result in the formation of plaques that block the neuron-transferring process done by the brain memory cells. These plaques are formed upon cleavage of Amyloid Precursor Protein (APP) by Gamma-Secretase (GS). GS protein has around 141 substrates, the important two are APP and Notch. Considering one of the hot spots in AD research, we focused on GS and its relation to AD. Moreover, a lot of research was done on beta-secretase and drugs were developed to target it however, few drugs are established for GS. GS contains four subunits: Presenilin (PS), PEN-2, Nicastrin, and APH-1. The catalytic subunit is PS, which contains the active site for substrate binding, as well as the allosteric and docking sites. Both PEN-2 and APH-1 are regulators for the stability and activity of GS. Nicastrin, helps the substrates bind to the PS. Additionally, the role of the immuno-protein named \"IFITM3\" and how it affects the immune system and its relation to AD is presented. GS is one of the most studied proteins with many developed candidates as inhibitors (GSI) and modulators (GSM). Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted.

Alzheimer\'s disease (AD), the most common neurodegenerative disease worldwide, is caused by loss of neurons and synapses in central nervous system. Several causes for neuronal death in AD have been introduced, the most important of which are extracellular amyloid β (Aβ) accumulation and aggregated tau proteins. Increasing evidence suggest that targeting the process of Aβ production to reduce its deposition can serve as a therapeutic option for AD management. In this regard, therapeutic interventions shown that a disintegrin and metalloproteinase domain-containing protein (ADAM) 10, involved in non-amyloidogenic pathway of amyloid precursor protein processing, is known to be a suitable candidate. Therefore, this review aims to examine the molecular properties of ADAM10, its role in AD, and introduce it as a therapeutic target to reduce the progression of the disease. Video abstract.

Alzheimer\'s Disease (AD) is a complex and progressive neurodegenerative disease, and the most common cause of dementia usually occurs due to old age. Production and accumulation of amyloid-β peptide (Aβ) represent the major pathological event of the disease. The formation of amyloid- β results due to proteolytic cleavage of amyloid precursor protein (APP) by beta-site amyloid precursor protein cleaving enzyme (BACE1) shown as the amyloid hypothesis, a prevalent theory for AD pathogenesis. Thus, BACE1 represents a novel target to decrease cerebral Aβ concentration and slow down the disease\'s progression. The structure-based drug design approach led to a wide variety of small molecules with the mechanism of action centered around inhibition of β-secretase protease (BACE1), which are shown to have drug-like properties and reduce brain Aβ levels. Based on transition state isosteres, BACE1 inhibitors can largely be classified as peptidomimetics and non-peptidomimetics. The subclasses of the two categories have been covered with different scaffolds like statin, norstatin, carbinamine, hydroxyethylene, hydroxyethylamine, acyl guanidine, 2- aminopyridine, aminoimidazole, aminohydantoin, aminothiazoline, aminooxazoline, aminoquinoline, piperazine-based. Among these small molecules, those who fulfilled general requirements for a drug aimed at the central nervous system (CNS) and selectivity over other aspartyl proteases reached the final pipeline of clinical trials. Here, in this review, we summarize the journey of BACE1 inhibitors through different practices of drug design development, Structural Activity Relationship (SAR), and other inhibitor candidates that are currently in clinical trials as BACE1 inhibitors.

Alzheimer\'s disease (AD) is a neurodegenerative disorder that has a significant association with age. Despite its increasing incidence in the population, the etiology of the disease remains poorly understood, and there are currently no effective treatments readily available. The main genes that are associated with AD are the amyloid precursor protein, presenilin‑1 and presenilin‑2, as well as the apolipoprotein E gene. In addition to genetic factors, a wide range of environmental and lifestyle factors are equally characterized as risk factors for the development of AD, while non‑coding RNAs (ncRNAs) and other epigenetic mechanisms play a key role in their detrimental effects. Multiple types of ncRNAs, such as microRNAs, circular RNAs, Piwi‑interacting RNAs and long non‑coding RNAs are being increasingly implicated in AD. Alterations in ncRNAs can be detected in cerebrospinal fluid, as well in as the brain, highlighting these as promising biomarkers for the detection and treatment of AD. Developments in high‑throughput technologies have led to the so‑called \'omics\' era, which involves the collection of big data and information at both molecular and protein levels, while combining the development of novel computational and statistical tools capable of analyzing and filtering such data. The present review discusses the role of ncRNAs and their use as biomarkers for AD, and summarizes the findings from the application of omics technologies in AD.

Determining the association between genetic variation and phenotype is a key step to study the mechanism of Alzheimer\'s disease (AD), laying the foundation for studying drug therapies and biomarkers. AD is the most common type of dementia in the aged population. At present, three early-onset AD genes (APP, PSEN1, PSEN2) and one late-onset AD susceptibility gene apolipoprotein E (APOE) have been determined. However, the pathogenesis of AD remains unknown. Imaging genetics, an emerging interdisciplinary field, is able to reveal the complex mechanisms from the genetic level to human cognition and mental disorders via macroscopic intermediates. This paper reviews methods of establishing genotype-phenotype to explore correlations, including sparse canonical correlation analysis, sparse reduced rank regression, sparse partial least squares and so on. We found that most research work did poorly in supervised learning and exploring the nonlinear relationship between SNP-QT.

The excessive deposition of β-amyloid proteins (Aβ) is directly correlated with the establishment and development of Alzheimer\'s Disease (AD). Current treatments for AD only reduce symptoms instead of acting on Aβ, the primary etiological agent. Hence, the anti-amyloid effect of regular exercise has been widely investigated as an alternative therapy. This systematic review and meta-analysis examined the anti-amyloid effect of regular physical exercise in animal models of AD. The search was conducted on the electronic databases Pubmed, Embase, Scopus and Web of Science without data limitation and using the following describers: \"amyloid beta\" (OR senile plaque OR amyloid plaque) and \"exercise\" (OR physical activity OR training). The risk of bias was evaluated using the SYRCLE\'s tool. Meta-analyses were conducted using models of random continuous effects. A total of 36 studies were selected and most used: transgenic mice (n = 29), treadmill training, duration of 12 weeks (interval of 4 to 28 weeks), rate of 60 min/day (interval of 30 min and up until free access) and speed of 12 m/min (interval of 3.2 to 32 m/min). The hippocampus and cortex were the most frequently investigated regions. Meta-analysis demonstrated a decrease in Aβ with greater effect in unspecified isoforms Meta-analysis demonstrated a decrease in Aβ with greater effect in unspecified isoforms (N = 4; SMD = -2.71, IC 95%: -3.59, -1.84, p < 0.00001, Q2 = 3.38, I2 = 11%) and Aβ1-42 (N = 21; SMD = -1.94, IC 95%: -2.37, -1.51, p < 0.00001, Q2 = 33,37, I2 = 40%). Concerning training, greater effect was found with: 1) swimming (N = 4; SMD = -1.98, IC 95%: -3,28 - -0,68, p = 0.003, Q2 = 9.74, I2 = 69%), 2) moderate intensity (N = 4; SMD = -2.03, IC 95%: -3.31 - -0.75, p < 0.005, Q2 = 12.68, I2 = 76%); 3) duration up to six weeks (N = 6; N = 6; SMD = -2.35, IC 95%: -3.15 - -1.55, p < 0.00001, Q2 = 8.38, I2 = 40%); 4) young animals (SMD = -2.00, IC 95%: -2.59 - -1.42, p < 0.00001, Q2 = 24.90, I2 = 52%); 5) in the amygdala region (N = 1; SMD = -8.56, IC 95%: -12.88 - -4.23, p = 0.0001) and females (N = 4; SMD = -2.14, IC 95%: -3.48 - -0.79, p = 0.002, Q2 = 10.31, I2 = 71%). However, the reduction of Aβ was associated with decrease of amyloidogenic pathway and increase of non-amyloidogenic. Hence, regular physical exercise demonstrated anti-amyloid effect in experimental models of AD through positive alterations in APP processing through different signaling pathways.

Alzheimer disease (AD) is a progressive and complex neurodegenerative disease. Approximately 70% of AD risk is attributed to genetic risk factors, including variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Several studies have revealed a considerable number of candidate loci and genes for AD among different ethnic populations. However, the outcomes of these studies have been inconsistent. In this study, we aimed to investigate the spectrum of variants that are associated with the onset and development of AD among 22 Arab countries.
We systematically searched 4 literature databases (Science Direct, Scopus, PubMed, and Web of Science) from the date of inception until July 2020 using various search terms to obtain all the reported genetic data on Arab AD cases.
In total, 18 studies were included, comprising a total of 2173 individuals, of whom 888 were clinically diagnosed AD patients and were genetically tested for genes and variants associated with AD. A total of 27 variants in 8 genes were found to be associated with AD. Of these variants, 17 were unique to the Arab population and 10 were shared with other ethnic groups.
There is a dearth of studies on the genetics of AD in the Arab world. There seems to be distinctive genetic and clinical susceptibility profiles for Arab patients with AD.