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Can Genetic Markers Predict the Sporadic Form of Alzheimer's Disease? An Updated Review on Genetic Peripheral Markers

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

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Complement receptor 1 is expressed on brain cells and in the human brain

Nikoleta Daskoulidou et al.

Summary: Genome wide association studies have found that Complement receptor 1 (CR1) is associated with increased risk for Alzheimer's disease (AD). However, the expression and role of CR1 in the brain are poorly understood. This study used various methods to demonstrate that CR1 is indeed expressed in human microglia and astrocytes in the brain, and that its expression is significantly increased in AD. These findings support the hypothesis that CR1 variants affect AD risk through their impact on glial functions.

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The Emerging Role of Autophagy-Associated lncRNAs in the Pathogenesis of Neurodegenerative Diseases

Yapei Jiang et al.

Summary: Neurodegenerative diseases are a major global health problem, and identifying molecular markers related to neurodegenerative processes is urgently important. Defects in autophagy, the process of removing aggregate-prone proteins in neurons, are often associated with the development of neurodegenerative diseases. Aberrant regulation of long non-coding RNAs (lncRNAs) also plays a role in neurological disorders. This review summarizes the recent progress in studying lncRNAs and autophagy in the context of neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), providing guidance for future research in this field.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

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Review Biochemistry & Molecular Biology

Alzheimer's Disease: An Updated Overview of Its Genetics

Jesus Andrade-Guerrero et al.

Summary: Alzheimer's disease (AD) is a common neurodegenerative disease that can be familial or sporadic. Genetic mutations in PSEN1, PSEN2, or APP are associated with familial early-onset AD, while sporadic late-onset AD is mainly linked to aging. Many polymorphisms associated with AD have been identified through GWAS. This review aims to analyze the new genetic findings related to AD pathophysiology and the mutations associated with high or low risk of developing this neurodegenerative disease identified by GWAS. Understanding genetic variability can help in early biomarker identification and the development of therapeutic targets for AD.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

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Article Neurosciences

A Group of Long Non-coding RNAs in Blood Acts as a Specific Biomarker of Alzheimer's Disease

Ziye Ren et al.

Summary: This study identifies a panel of seven lncRNAs that can serve as specific and promising biomarkers for the diagnosis of Alzheimer's disease.

MOLECULAR NEUROBIOLOGY (2023)

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Article Neurosciences

ABCA7 -Associated Clinical Features and Molecular Mechanisms in Alzheimer ' s Disease

Xiao-hang Qian et al.

Summary: Alzheimer's disease is the most common neurodegenerative disease and its pathogenesis is still uncertain. Genetic factors, particularly the ABCA7 gene variants, play a significant role in the development of the disease. These variants can affect protein expression, structure, and function, leading to abnormal lipid metabolism, amyloid precursor protein processing, immune cell dysfunction, and disrupted Aβ clearance. Understanding different ABCA7 variants and developing targeted therapies for Alzheimer's disease are areas of future research.

MOLECULAR NEUROBIOLOGY (2023)

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Article Clinical Neurology

Identification of novel genes for age-at-onset of Alzheimer's disease by combining quantitative and survival trait analyses

Yi Ju Li et al.

ALZHEIMERS & DEMENTIA (2023)

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Article Biochemistry & Molecular Biology

State of the Art of microRNAs Signatures as Biomarkers and Therapeutic Targets in Parkinson’s and Alzheimer’s Diseases: A Systematic Review and Meta-Analysis

Idiberto José Zotarelli-Filho et al.

Biomedicines (2023)

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Recent advances of exosomal circRNAs in cancer and their potential clinical applications

Qian Yi et al.

Summary: Circular RNA (circRNA) is a non-coding RNA that forms a closed loop structure and is aberrantly expressed in various diseases, including cancer. CircRNAs in exosomes play important roles in intercellular communication and the progression of carcinogenesis. This review summarizes the current knowledge about exosomal circRNAs in cancers, discusses their specific functions in tumorigenesis, and explores their potential as diagnostic biomarkers and for cancer therapy based on exosomal circRNAs.

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Plasma Extracellular Vesicle MicroRNA Analysis of Alzheimer's Disease Reveals Dysfunction of a Neural Correlation Network

Yuzhe Sun et al.

Summary: In this study, the role of microRNAs (miRNAs) in small extracellular vesicles (sEV) as potential biomarkers of Alzheimer's disease (AD) was investigated. The study conducted a comprehensive analysis of sEV-derived miRNAs using small RNA sequencing and coexpression network analysis. The results identified an miRNA network module (M1) that showed a strong association with AD diagnosis and cognitive impairment. The expression of miRNAs in this module was decreased in AD and mild cognitive impairment (MCI) patients. Further analysis revealed that changes in the expression of miRNAs in this module may be an early response to cognitive decline prior to the appearance of AD pathology. Overall, these findings suggest that sEV-derived miRNAs, especially those in the M1 module, may serve as potential biomarkers for the early diagnosis and monitoring of AD.

RESEARCH (2023)

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Review Medicine, Research & Experimental

MicroRNAs in Alzheimer's disease: Potential diagnostic markers and therapeutic targets

Sen Liu et al.

Summary: Alzheimer's disease is a common neurodegenerative disease affecting millions worldwide. Recent studies have shown differential abundance and varieties of miRNAs in central and peripheral tissues of AD patients.

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Development and validation of a circulating microRNA panel for the early detection of breast cancer

Ruiyang Zou et al.

Summary: This study conducted the largest comprehensive multi-center research to date and identified 30 dysregulated miRNAs associated with breast cancer. An optimized eight-miRNA panel was successfully validated in diverse ethnic groups and showed consistent performance. The panel has the potential to be used for breast cancer screening in conjunction with mammography.

BRITISH JOURNAL OF CANCER (2022)

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Alzheimer's disease susceptibility locus in CD2AP is associated with increased cerebrospinal fluid tau levels in mild cognitive impairment

Yan-Yan Xue et al.

Summary: The study found that rs9296559 was associated with higher levels of CSF t-tau and p-tau in MCI patients, suggesting that CD2AP modifies AD risk by altering tau-related neurodegeneration. This is the first study to evaluate the association between CD2AP genotypes and AD CSF biomarkers.

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The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline

Nicolai Franzmeier et al.

Summary: The study found that carriers of the BIN1 rs744373 risk allele showed faster global tau-PET accumulation and accelerated tau-PET accumulation at higher A beta levels. In the ADNI sample, the effects of rs744373 on cognitive decline were mediated by faster global tau-PET accumulation.

ALZHEIMERS & DEMENTIA (2022)

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Review Pathology

Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms

Nicole Koutsodendris et al.

Summary: Alzheimer's disease (AD) is a complex neurodegenerative disorder that is difficult to treat. Recent advancements in imaging technology and experimental techniques have allowed researchers to gain insights into the pathogenic mechanisms of AD. The major genetic risk factor for late-onset AD, apolipoprotein E4 (apoE4), plays a significant role in the initiation and progression of AD, although its exact mechanisms are not fully understood.

ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE (2022)

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Association of CD2AP neuronal deposits with Braak neurofibrillary stage in Alzheimer's disease

Jessica Camacho et al.

Summary: Genome-wide association studies have identified several genes as genetic susceptibility loci for Alzheimer's disease, with CD2AP being one of them. CD2AP was found to be present in brain endothelial cells and neuronal inclusions in AD cases, showing association with tau pathology. The distribution of CD2AP in neurons was correlated with Braak neurofibrillary stage, suggesting a link between CD2AP expression and tau-related diseases.

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Plasma biomarkers for Alzheimer's Disease in relation to neuropathology and cognitive change

Denis S. Smirnov et al.

Summary: Plasma biomarkers show promise in identifying the pathological features of Alzheimer's Disease. P-tau181 and P-tau231 are diagnostic biomarkers related to AD neuropathological change and can predict future cognitive decline. NfL can predict cognitive decline and is increased in non-AD cases. Plasma A beta 42/40 is a relatively weak predictor of amyloid pathology and may require different assay methods for improvement.

ACTA NEUROPATHOLOGICA (2022)

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New insights into the genetic etiology of Alzheimer's disease and related dementias

Celine Bellenguez et al.

Summary: By characterizing the genetic landscape of Alzheimer's disease and related dementias, new loci have been identified and a new genetic risk score associated with the risk of future Alzheimer's disease and dementia has been generated.

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The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner

Raja Bhattacharyya et al.

Summary: BIN1 and RIN3 have been identified as genetic risk factors for late-onset Alzheimer's disease (LOAD). The neuronal isoform of BIN1 (BIN1V1) regulates tau-pathology and A beta generation through endocytosis mediated by RAB5. BIN1 interacts directly with RIN3 to initiate RAB5-mediated endocytosis, which is essential for beta-secretase cleavage of beta-amyloid precursor protein (APP) to generate Amyloid-beta (A beta), a key component in AD. Understanding the role of BIN1 and RIN3 in beta-secretase mediated cleavage of APP and A beta generation is crucial for the development of new therapeutics for AD progression.

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Analysis of Genetic Association Between ABCA7 Polymorphism and Alzheimer's Disease Risk in the Southern Chinese Population

Lijun Wang et al.

Summary: This study revealed that the G allele at rs3764650 and the A allele at rs4147929 of the ABCA7 gene are associated with an increased risk of developing Alzheimer's disease (AD), particularly in APOE epsilon 4 carriers.

FRONTIERS IN AGING NEUROSCIENCE (2022)

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Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases

Giulia Gentile et al.

Summary: Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are representative neurodegenerative diseases (NDs) characterized by selective neuron degeneration, with a lack of effective biomarkers and therapies. MicroRNAs (miRNAs) have shown promise in diagnostics and therapy of these NDs due to their abnormal expression and ability to target multiple molecules and pathways.

JOURNAL OF PERSONALIZED MEDICINE (2022)

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Review Biochemistry & Molecular Biology

Alzheimer's Disease: Treatment Strategies and Their Limitations

Elodie Passeri et al.

Summary: Alzheimer's disease is a major public health issue worldwide, with prevention being the most crucial strategy. Drug treatments only provide symptomatic relief, with disease-modifying approaches still not available.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Geriatrics & Gerontology

Salivary inflammatory biomarkers are predictive of mild cognitive impairment and Alzheimer's disease in a feasibility study

Kym McNicholas et al.

Summary: This study identified biomarkers in saliva that can be used for early detection of cognitive impairment and Alzheimer's disease. The findings suggest that combinations of specific proteins can effectively distinguish patients with cognitive impairment and Alzheimer's disease from cognitively normal individuals.

FRONTIERS IN AGING NEUROSCIENCE (2022)

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PICALM and Alzheimer's Disease: An Update and Perspectives

Kunie Ando et al.

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PICALM rs3851179 Variants Modulate Left Postcentral Cortex Thickness, CSF Amyloid β42, and Phosphorylated Tau in the Elderly

Zhiwei Wu et al.

Summary: The study found that the PICALM rs3851179 gene variant is associated with susceptibility to late-onset Alzheimer's disease (LOAD) and plays a crucial role in regulating amyloid precursor protein and amyloid beta transcytosis. The research confirms the effects of PICALM on cortex thickness, CSF amyloid beta, and tau levels and suggests that the rs3851179 variant may protect cognitive function in LOAD patients.

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Inflammatory plasma biomarkers in subjects with preclinical Alzheimer's disease

Samantha Prins et al.

Summary: This study investigated plasma biomarkers for neuroinflammation associated with Alzheimer's disease (AD) in subjects with preclinical AD compared to healthy elderly. The results showed that the concentration of GFAP was significantly higher in subjects with preclinical AD compared to healthy elderly, which was consistent with previous studies. Additionally, when defining preclinical AD based on the Ptau181/A beta 1-42 ratio, YKL-40 was also significantly different between groups.

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Non-coding RNAs: The Neuroinflammatory Regulators in Neurodegenerative Diseases

Hao Jiang et al.

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FRONTIERS IN NEUROLOGY (2022)

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PSEN2 Thr421Met Mutation in a Patient with Early Onset Alzheimer's Disease

YoungSoon Yang et al.

Summary: A PSEN2 gene mutation related to early onset Alzheimer's disease was identified for the first time in Korea. This mutation may have significant effects on brain function and interact with other mutations to cause the disease.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Differential microRNA expression analyses across two brain regions in Alzheimer's disease

Valerija Dobricic et al.

Summary: Dysregulation of miRNAs is involved in the pathogenesis of neurodegenerative diseases. By studying six candidate miRNAs in a large collection of brain samples, we found differential expression of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD, and identified several target genes for these miRNAs.

TRANSLATIONAL PSYCHIATRY (2022)

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APOE ε4-dependent effects on the early amyloid pathology in induced neurons of patients with Alzheimer's disease

Hongwon Kim et al.

Summary: This study found that the presence of the APOE epsilon 4 gene aggravates the pathology of Alzheimer's disease during the early stages of amyloid deposition. In addition, IGFBP3 plays an important role in the molecular pathology of APOE epsilon 4-associated Alzheimer's disease.

TRANSLATIONAL NEURODEGENERATION (2022)

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A circular RNA blood panel that differentiates Alzheimer's disease from other dementia types

Ziye Ren et al.

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Amyloid-β and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer's disease polygenic risk score

Jori Tomassen et al.

Summary: This study investigated the associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-beta pathology, and cognitive decline in cognitively unimpaired older individuals. The results showed that APOE genotype was related to memory and language decline only in individuals with abnormal amyloid-beta. Additionally, other genetic risk variants contributed to memory decline independently of amyloid-beta status in initially cognitively unimpaired older individuals.

BMC NEUROLOGY (2022)

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Molecular recognition of the interaction between ApoE and the TREM2 protein

Zhenhua Mai et al.

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TRANSLATIONAL NEUROSCIENCE (2022)

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Review Cell Biology

The Mechanistic Role of Bridging Integrator 1 (BIN1) in Alzheimer's Disease

Peirong Gao et al.

Summary: Alzheimer's disease (AD) is the leading cause of dementia, most cases being late-onset and multifactorial. Bridging integrator 1 (BIN1) is one of more than 30 loci associated with sporadic AD (SAD) and considered the second strongest genetic risk factor for SAD. BIN1 is suggested to participate in multiple pathways in AD, including tau and amyloid pathology.

CELLULAR AND MOLECULAR NEUROBIOLOGY (2021)

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ABCA7 and the altered lipidostasis hypothesis of Alzheimer's disease

Nicholas N. Lyssenko et al.

Summary: The altered lipidostasis hypothesis of Alzheimer's disease suggests that ABCA7 plays a crucial role in protecting neurons from neurodegenerative lipid accumulation. Low levels of ABCA7 may lead to early development of AD pathology, while high levels may delay or prevent it. Further research is needed to identify the neurodegenerative lipid and explore therapeutic approaches involving ABCA7.

ALZHEIMERS & DEMENTIA (2021)

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Review Clinical Neurology

APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches

Alberto Serrano-Pozo et al.

Summary: The APOE ε4 allele and ε2 allele are respectively the strongest genetic risk factor and protective factor for Alzheimer's disease. While therapies targeting APOE are currently unavailable, recent research has expanded our understanding of APOE pathogenesis to include multiple pathological processes, offering valuable insights for therapy development.

LANCET NEUROLOGY (2021)

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Review Medicine, Research & Experimental

The role of miRNAs in colorectal cancer progression and chemoradiotherapy

Ning Zhang et al.

Summary: Colorectal cancer is the third most common and fourth most deadly cancer worldwide, with microRNAs playing essential roles in CRC and serving as potential targets for therapy.

BIOMEDICINE & PHARMACOTHERAPY (2021)

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Article Geriatrics & Gerontology

Neuroprotective effects of miR-331-3p through improved cell viability and inflammatory marker expression: Correlation of serum miR-331-3p levels with diagnosis and severity of Alzheimer's disease

Qingling Liu et al.

Summary: The study found that the expression of miR-331-3p was significantly downregulated in AD patients and Aβ(1-40) treated SH-SY5Y cells. Serum miR-331-3p showed diagnostic potential and was correlated with MMSE scores and serum proinflammatory cytokine levels in AD patients. Overexpression of miR-331-3p in Aβ(1-40) treated SH-SY5Y cells enhanced cell viability and inhibited inflammatory responses, indicating a potential neuroprotective role of miR-331-3p.

EXPERIMENTAL GERONTOLOGY (2021)

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Review Neurosciences

Microglia Biomarkers in Alzheimer's Disease

Peng-Fei Zhang et al.

Summary: Early detection and clinical diagnosis of Alzheimer's disease are crucial. Microglia, considered to be a potential factor in the pathological mechanisms, are being studied for specific and sensitive biomarkers to address the challenges of AD.

MOLECULAR NEUROBIOLOGY (2021)

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Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes

Jeremy Schwartzentruber et al.

Summary: A genome-wide AD meta-analysis identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2, and SPRED2. By fine-mapping SNPs and using functional annotation, 21 SNPs with >50% probability of being causally involved in AD risk were identified. Protein interaction networks and tissue-specific expression helped prioritize genes, leading to the discovery of likely causal genes.

NATURE GENETICS (2021)

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Review Neurosciences

Cerebrospinal Fluid Biomarkers of Alzheimer's Disease: Current Evidence and Future Perspectives

Donovan A. McGrowder et al.

Summary: This review presents the current evidence on CSF biomarkers for Alzheimer's disease, emphasizing the efficacy of existing core biomarkers and the need for further development of biomarkers reflecting other aspects of the disease mechanism. It also introduces new biomarkers that track Alzheimer's disease pathology and their potential in diagnosis and predicting cognitive decline.

BRAIN SCIENCES (2021)

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Genetic Insights into the Impact of Complement in Alzheimer's Disease

Megan Torvell et al.

Summary: The pivotal role of complement activation in AD has been well studied, with genetic variations contributing significant effects on the disease. While several complement genes have been identified in association with AD, the complexity of the complement pathway poses challenges in attributing their role in disease mechanisms.

GENES (2021)

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Review Biochemistry & Molecular Biology

Role of ABCA7 in Human Health and in Alzheimer's Disease

Shiraz Dib et al.

Summary: ABCA7 plays a central role in Alzheimer's disease by regulating molecular processes such as cholesterol metabolism and amyloid processing, impacting the onset and development of late onset Alzheimer disease. Its functions are implicated in brain functioning and disease progression.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo

Xulun Zhang et al.

Summary: The research identified a rare, partially penetrant variant in the APP gene that accelerates the production of A beta peptides, marking the first AD-linked mutation outside of exons 16 and 17 that enhances A beta production and deposition.

JOURNAL OF EXPERIMENTAL MEDICINE (2021)

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MicroRNA-Target Interaction Regulatory Network in Alzheimer's Disease

Aleksander Turk et al.

Summary: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, making early diagnosis challenging. Research on miRNAs as biomarkers for AD diagnostics has potential. An analysis using tools such as Cytoscape, STRING, and mirPath revealed potential disease modules for further biomarker development from experimentally validated AD-associated MTIs obtained from miRTarBase.

JOURNAL OF PERSONALIZED MEDICINE (2021)

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Article Neurosciences

The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer's Disease

Qing Xia et al.

Summary: Alzheimer's disease is a neurodegenerative disorder characterized by abnormal accumulation of amyloid beta peptides and Tau protein in the brain. Mutations in amyloid precursor protein gene can cause familial Alzheimer's disease, but the A673T mutation shows protective effects against it.

MOLECULAR NEUROBIOLOGY (2021)

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A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody

Chad J. Swanson et al.

Summary: BAN2401-G000-201 trial aimed to establish the effective dose and observe the treatment effect. While not meeting the primary endpoint at 12 months, results at 18 months demonstrated reduction in brain amyloid and improvement across multiple clinical and biomarker endpoints.

ALZHEIMERS RESEARCH & THERAPY (2021)

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PICALM regulates cathepsin D processing and lysosomal function

Kathryn J. Hattersley et al.

Summary: Disruption of the PICALM gene affects cellular degradative function, leading to an increase in early endosome numbers, abundance of lysosomal enzymes, and disruption to the processing and maturation of lysosomal protease, resulting in a deficit in autophagy.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2021)

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A current view on Tau protein phosphorylation in Alzheimer's disease

Susanne Wegmann et al.

Summary: The functions of Tau in the central nervous system are regulated by various posttranslational modifications, with phosphorylation being widely recognized as a pathological hallmark in diseases like AD. However, the similarities and heterogeneity of phosphorylation patterns between physiological and pathological Tau make it challenging to identify specific modifications as therapeutic targets and biomarkers.

CURRENT OPINION IN NEUROBIOLOGY (2021)

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Article Neurosciences

Role of TREM2 in Alzheimer's Disease: A Long Road Ahead

Bhargavi Kulkarni et al.

Summary: The role and variants of TREM2 play an important role in the progression of AD, with studies showing its relationship with neuroinflammation, β-amyloid burden, and tau pathology. The potential of soluble TREM2 as an effective biomarker and neuroprotection in AD is discussed, with a focus on developing therapeutic agents targeting TREM2.

MOLECULAR NEUROBIOLOGY (2021)

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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease

Douglas P. Wightman et al.

Summary: This study identified seven new genetic loci associated with Alzheimer's disease through a genome-wide association study, implicating microglia and immune cells in late-onset disease. The research highlights the relevance of microglia, immune cells, and protein catabolism to late-onset Alzheimer's disease, while prioritizing previously unidentified genes for further investigation. The results are expected to contribute to larger meta-analyses to uncover additional genetic variants affecting Alzheimer's pathology.

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Article Multidisciplinary Sciences

A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex

Rebecca G. Smith et al.

Summary: Epigenome-wide association studies of Alzheimer's disease have identified DNA methylation differences associated with neuropathology, with 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus, and ten CpGs in the entorhinal cortex being significant. Cross-cortex meta-analysis revealed 220 CpGs associated with neuropathology, annotated to 121 genes, with 84 genes not previously reported at this significance threshold.

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Serum miR-128 Serves as a Potential Diagnostic Biomarker for Alzheimer's Disease

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Correction Clinical Neurology

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