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Geriatrics & Gerontology International Feb 2021Heredity plays an important role in the pathogenesis of Alzheimer's disease (AD) especially for single-nucleotide polymorphism (SNPs) of susceptible genes, which is one... (Meta-Analysis)
Meta-Analysis
AIM
Heredity plays an important role in the pathogenesis of Alzheimer's disease (AD) especially for single-nucleotide polymorphism (SNPs) of susceptible genes, which is one of the significant factors in the pathogenesis of AD. The SNPs of BIN1 rs744373, BIN1 rs7561528 and GAB2 rs2373115 are associated with AD in Asian and white people.
METHODS
We included 34 studies with a total of 38 291 patients with AD and 55 538 controls of diverse races from four main databases. We used meta-analysis to obtain I -values and odds ratios of five genetic models in three SNPs. We carried out analysis of sensitivity, subgroup, publication bias and linkage disequilibrium test.
RESULTS
The forest plots showed the odds ratio value of the three SNPs was >1 in white individuals, but not Asian individuals, in their genetic model. The funnel plot was symmetrical, and the D'-value was 0.986 between rs744373 and rs7561528.
CONCLUSIONS
BIN1 rs744373, BIN1 rs7561528 and GAB2 rs2373115 are pathogenicity sites for AD in white people, and also rs7561528 belongs to a risk site in Asian people. The rs7561528 and rs744373 SNPs have strong linkage disequilibrium in Chinese people. In addition, apolipoprotein E ε4 status promotes them to result in the pathogenesis of AD. Geriatr Gerontol Int 2021; 21: 185-191.
Topics: Adaptor Proteins, Signal Transducing; Alzheimer Disease; Genetic Predisposition to Disease; Humans; Nuclear Proteins; Polymorphism, Single Nucleotide; Tumor Suppressor Proteins; White People
PubMed: 33331110
DOI: 10.1111/ggi.14109 -
Frontiers in Aging Neuroscience 2022Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure, and available treatments are only able to postpone the progression of the disease....
BACKGROUND AND PURPOSE
Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure, and available treatments are only able to postpone the progression of the disease. Mild cognitive impairment (MCI) is considered to be a transitional stage preceding AD. Therefore, prediction models for conversion from MCI to AD are desperately required. These will allow early treatment of patients with MCI before they develop AD. This study performed a systematic review and meta-analysis to summarize the reported risk prediction models and identify the most prevalent factors for conversion from MCI to AD.
METHODS
We systematically reviewed the studies from the databases of PubMed, CINAHL Plus, Web of Science, Embase, and Cochrane Library, which were searched through September 2021. Two reviewers independently identified eligible articles and extracted the data. We used the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) checklist for the risk of bias assessment.
RESULTS
In total, 18 articles describing the prediction models for conversion from MCI to AD were identified. The dementia conversion rate of elderly patients with MCI ranged from 14.49 to 87%. Models in 12 studies were developed using the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). C-index/area under the receiver operating characteristic curve (AUC) of development models were 0.67-0.98, and the validation models were 0.62-0.96. MRI, apolipoprotein E genotype 4 (APOE4), older age, Mini-Mental State Examination (MMSE) score, and Alzheimer's Disease Assessment Scale cognitive (ADAS-cog) score were the most common and strongest predictors included in the models.
CONCLUSION
In this systematic review, many prediction models have been developed and have good predictive performance, but the lack of external validation of models limited the extensive application in the general population. In clinical practice, it is recommended that medical professionals adopt a comprehensive forecasting method rather than a single predictive factor to screen patients with a high risk of MCI. Future research should pay attention to the improvement, calibration, and validation of existing models while considering new variables, new methods, and differences in risk profiles across populations.
PubMed: 35493941
DOI: 10.3389/fnagi.2022.840386 -
Journal of Alzheimer's Disease Reports 2023Alzheimer's disease (AD) has several risk factors. is the main one, and it has been suggested that there may be a synergy between it and as a risk factor.
Confirmed Synergy Between the ɛ4 Allele of Apolipoprotein E and the Variant K of Butyrylcholinesterase as a Risk Factor for Alzheimer's Disease: A Systematic Review and Meta-Analysis.
BACKGROUND
Alzheimer's disease (AD) has several risk factors. is the main one, and it has been suggested that there may be a synergy between it and as a risk factor.
OBJECTIVE
To investigate the association between and as a risk factor for AD.
METHODS
We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of and with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with the meta-analysis data to verify if the effect found is not associated only with the E4 allele.
RESULTS
Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558.
CONCLUSION
The synergy between and is a risk factor for late-onset AD.
PubMed: 37483326
DOI: 10.3233/ADR-220084 -
Acta Neuropathologica Communications Jan 2022The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain...
Association between single moderate to severe traumatic brain injury and long-term tauopathy in humans and preclinical animal models: a systematic narrative review of the literature.
BACKGROUND
The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain controversial. Some studies suggest that moderate to severe TBI is sufficient to promote tau pathology; however, others suggest that it is simply a consequence of aging. We therefore conducted a systematic narrative review of the literature addressing whether a single moderate to severe head injury leads to long-term development of tauopathy in both humans and animal models.
METHODS
Studies considered for inclusion in this review assessed a single moderate to severe TBI, assessed tau pathology at long-term timepoints post-injury, comprised experimental or observational studies, and were peer-reviewed and published in English. Databases searched included: PUBMED, NCBI-PMC, EMBASE, Web of Science, Academic Search Premiere, and APA Psychnet. Search results were uploaded to Covidence®, duplicates were removed, and articles underwent an abstract and full-text screening process. Data were then extracted and articles assessed for risk of bias.
FINDINGS
Of 4,150 studies screened, 26 were eligible for inclusion, of which 17 were human studies, 8 were preclinical animal studies, and 1 included both human and preclinical animal studies. Most studies had low to moderate risk of bias. Most human and animal studies (n = 12 and 9, respectively) suggested that a single moderate to severe TBI resulted in greater development of long-term tauopathy compared to no history of head injury. This conclusion should be interpreted with caution, however, due to several limitations: small sample sizes; inconsistencies in controlling for confounding factors that may have affected tau pathology (e.g., family history of dementia or neurological illnesses, apolipoprotein E genotype, etc.), inclusion of mostly males, and variation in reporting injury parameters.
INTERPRETATION
Results indicate that a single moderate to severe TBI leads to greater chronic development of tauopathy compared to no history of head injury. This implies that tau pathology induced may not be transient, but can progressively develop over time in both humans and animal models. Targeting these tau changes for therapeutic intervention should be further explored to elucidate if disease progression can be reversed or mitigated.
Topics: Animals; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Humans; Tauopathies
PubMed: 35101132
DOI: 10.1186/s40478-022-01311-0 -
Sleep Medicine Jan 2023The glymphatic system is thought to be responsible for waste clearance in the brain. As it is primarily active during sleep, different components of sleep, subjective... (Review)
Review
OBJECTIVE
The glymphatic system is thought to be responsible for waste clearance in the brain. As it is primarily active during sleep, different components of sleep, subjective sleep quality, and sleep patterns may contribute to glymphatic functioning. This systematic review aimed at exploring the effect of sleep components, sleep quality, and sleep patterns on outcomes associated with the glymphatic system in healthy adults.
METHODS
PubMed®, Scopus, and Web of Science were searched for studies published in English until December 2021. Articles subjectively or objectively investigating sleep components (total sleep time, time in bed, sleep efficiency, sleep onset latency, wake-up after sleep onset, sleep stage, awakenings), sleep quality, or sleep pattern in healthy individuals, on outcomes associated with glymphatic system (levels of amyloid-β, tau, α-synuclein; cerebrospinal fluid, perivascular spaces; apolipoprotein E) were selected.
RESULTS
Out of 8359 records screened, 51 studies were included. Overall, contradictory findings were observed according to different sleep assessment method. The most frequently assessed sleep parameters were total sleep time, sleep quality, and sleep efficiency. No association was found between sleep efficiency and amyloid-β, and between slow-wave activity and tau. Most of the studies did not find any correlation between total sleep time and amyloid-β nor tau level. Opposing results correlated sleep quality with amyloid-β and tau.
CONCLUSIONS
This review highlighted inconsistent results across the studies; as such, the specific association between the glymphatic system and sleep parameters in healthy adults remains poorly understood. Due to the heterogeneity of sleep assessment methods and the self-reported data representing the majority of the observations, future studies with universal study design and sleep methodology in healthy individuals are advocated.
Topics: Adult; Humans; Amyloid beta-Peptides; Brain; Glymphatic System; Sleep; Sleep Wake Disorders
PubMed: 36481512
DOI: 10.1016/j.sleep.2022.11.012 -
Neuroscience and Biobehavioral Reviews Jun 2020This systematic review examines the genetic and epigenetic factors associated with resting-state functional connectivity (RSFC) in healthy human adult brains across the... (Review)
Review
This systematic review examines the genetic and epigenetic factors associated with resting-state functional connectivity (RSFC) in healthy human adult brains across the lifespan, with a focus on genes associated with Alzheimer's disease (AD). There were 58 studies included. The key findings are: (i) genetic factors have a low to moderate contribution; (ii) the apolipoprotein E ε2/3/4 polymorphism was the most studied genetic variant, with the APOE-ε4 allele most consistently associated with deficits of the default mode network, but there were insufficient studies to determine the relationships with other AD candidate risk genes; (iii) a single genome-wide association study identified several variants related to RSFC; (iv) two epigenetic independent studies showed a positive relationship between blood DNA methylation of the SLC6A4 promoter and RSFC measures. Thus, there is emerging evidence that genetic and epigenetic variation influence the brain's functional organisation and connectivity over the adult lifespan. However, more studies are required to elucidate the roles genetic and epigenetic factors play in RSFC measures across the adult lifespan.
Topics: Adult; Aging; Brain; Brain Mapping; Genome-Wide Association Study; Humans; Magnetic Resonance Imaging; Neural Pathways; Rest; Serotonin Plasma Membrane Transport Proteins
PubMed: 32169413
DOI: 10.1016/j.neubiorev.2020.03.011 -
Frontiers in Psychiatry 2022Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The...
Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The identification of specific genetic factors and their biological pathways underpinning resilient functioning can help in the identification of common key factors, but heterogeneities in the operationalisation of resilience have hampered advances. We conducted a systematic review of genetic variants associated with resilience to enable the identification of general resilience mechanisms. We adopted broad inclusion criteria for the definition of resilience to capture both human and animal model studies, which use a wide range of resilience definitions and measure very different outcomes. Analyzing 158 studies, we found 71 candidate genes associated with resilience. OPRM1 (Opioid receptor mu 1), NPY (neuropeptide Y), CACNA1C (calcium voltage-gated channel subunit alpha1 C), DCC (deleted in colorectal carcinoma), and FKBP5 (FKBP prolyl isomerase 5) had both animal and human variants associated with resilience, supporting the idea of shared biological pathways. Further, for OPRM1, OXTR (oxytocin receptor), CRHR1 (corticotropin-releasing hormone receptor 1), COMT (catechol-O-methyltransferase), BDNF (brain-derived neurotrophic factor), APOE (apolipoprotein E), and SLC6A4 (solute carrier family 6 member 4), the same allele was associated with resilience across divergent resilience definitions, which suggests these genes may therefore provide a starting point for further research examining commonality in resilience pathways.
PubMed: 35669264
DOI: 10.3389/fpsyt.2022.840120 -
International Journal of Geriatric... May 2020Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are...
OBJECTIVES
Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
METHODS
We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the quality of genetic association studies tool.
RESULTS
Eight thousand five hundred twenty-one articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA, and SNCA variants have been replicated by two or more good quality studies. Our meta-analyses confirmed that APOE-ε4 is significantly associated with dementia with Lewy bodies (pooled odds ratio [POR] = 2.70; 95% CI, 2.37-3.07; P < .001) and Parkinson's disease dementia (POR = 1.60; 95% CI, 1.21-2.11; P = .001). Other reported genetic associations that need further replication include variants in A2M, BCHE-K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mitochondrial DNA (mtDNA) haplogroup H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1.
CONCLUSIONS
The reported genetic associations and their potential interactions indicate the importance of α-synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress, and mitochondrial dysfunction in LBD. There is a need for larger genome-wide association study (GWAS) for identifying more LBD-associated genes. Future hypothesis-driven studies should aim to replicate reported genetic associations of LBD and to explore their functional implications.
Topics: Aged, 80 and over; Alzheimer Disease; Biomarkers; Female; Genome-Wide Association Study; Humans; Lewy Bodies; Lewy Body Disease; Lysosomal Membrane Proteins; Male; Membrane Glycoproteins; Receptors, Immunologic; Receptors, Scavenger; alpha-Synuclein
PubMed: 31898332
DOI: 10.1002/gps.5260 -
PloS One 2022Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic... (Meta-Analysis)
Meta-Analysis
Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic variants may also be involved in the disease. Thus, the aim of this study was to perform a systematic review with meta-analysis of the literature to identify genetic polymorphisms that are likely to contribute to COVID-19 pathogenesis. Pubmed, Embase and GWAS Catalog repositories were systematically searched to retrieve articles that investigated associations between polymorphisms and COVID-19. For polymorphisms analyzed in 3 or more studies, pooled OR with 95% CI were calculated using random or fixed effect models in the Stata Software. Sixty-four eligible articles were included in this review. In total, 8 polymorphisms in 7 candidate genes and 74 alleles of the HLA loci were analyzed in 3 or more studies. The HLA-A*30 and CCR5 rs333Del alleles were associated with protection against COVID-19 infection, while the APOE rs429358C allele was associated with risk for this disease. Regarding COVID-19 severity, the HLA-A*33, ACE1 Ins, and TMPRSS2 rs12329760T alleles were associated with protection against severe forms, while the HLA-B*38, HLA-C*6, and ApoE rs429358C alleles were associated with risk for severe forms of COVID-19. In conclusion, polymorphisms in the ApoE, ACE1, TMPRSS2, CCR5, and HLA loci appear to be involved in the susceptibility to and/or severity of COVID-19.
Topics: Apolipoproteins E; COVID-19; Genetic Predisposition to Disease; HLA-A Antigens; Humans; Polymorphism, Genetic
PubMed: 35793369
DOI: 10.1371/journal.pone.0270627 -
Expert Review of Neurotherapeutics Aug 2021The apolipoprotein E ɛ4-allele (-ɛ4) increases the risk not only for Alzheimer's disease (AD) but also for Parkinson's disease dementia and dementia with Lewy bodies...
The ε4 variant and hippocampal atrophy in Alzheimer's disease and Lewy body dementia: a systematic review of magnetic resonance imaging studies and therapeutic relevance.
The apolipoprotein E ɛ4-allele (-ɛ4) increases the risk not only for Alzheimer's disease (AD) but also for Parkinson's disease dementia and dementia with Lewy bodies (collectively, Lewy body dementia [LBD]). Hippocampal volume is an important neuroimaging biomarker for AD and LBD, although its association with -ɛ4 is inconsistently reported. We investigated the association of -ε4 with hippocampal atrophy quantified using magnetic resonance imaging in AD and LBD. Databases were searched for volumetric and voxel-based morphometric studies published up until December 31, 2020. Thirty-nine studies (25 cross-sectional, 14 longitudinal) were included. We observed that (1) -ε4 was associated with greater rate of hippocampal atrophy in longitudinal studies in AD and in those who progressed from mild cognitive impairment to AD, (2) association of -ε4 with hippocampal atrophy in cross-sectional studies was inconsistent, (3) -ɛ4 may influence hippocampal atrophy in dementia with Lewy bodies, although longitudinal investigations are needed. We comprehensively discussed methodological aspects, -based therapeutic approaches, and the association of -ε4 with hippocampal sub-regions and cognitive performance. The role of -ɛ4 in modulating hippocampal phenotypes may be further clarified through more homogenous, well-powered, and pathology-proven, longitudinal investigations. Understanding the underlying mechanisms will facilitate the development of prevention strategies targeting -ɛ4.
Topics: Alzheimer Disease; Apolipoprotein E4; Atrophy; Cross-Sectional Studies; Dementia; Hippocampus; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Parkinson Disease
PubMed: 34311631
DOI: 10.1080/14737175.2021.1956904