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CNS Drugs Oct 2016Differential responses to donepezil treatment in patients with Alzheimer's disease (AD) have been observed in clinical practice. It remains controversial whether, and to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Differential responses to donepezil treatment in patients with Alzheimer's disease (AD) have been observed in clinical practice. It remains controversial whether, and to what extent, individual variation in the genes responsible for drug metabolism (CYP2D6) or those associated with AD pathogenesis (APOE) modulate the response to donepezil treatment.
OBJECTIVE
The aim of this study was to better understand the potential link between donepezil treatment response and CYP2D6 or APOE polymorphisms.
METHODS
We performed a meta-analysis based on data collected from 1266 donepezil-treated AD patients, and evaluated the association of CYP2D6 or APOE polymorphisms with treatment effectiveness.
RESULTS
No significant difference was observed in the responder rate of donepezil treatment between the normal function CYP2D6 alleles group and the decreased/non-functional group [odds ratio (OR) 1.34, 95 % confidence interval (CI) 0.5-3.58; p = 0.56]. However, compared with the increased function CYP2D6 alleles group, the normal function group had a better response to donepezil treatment (OR 1.52, 95 % CI 1.14-2.03; p = 0.005). For the specific CYP2D6 single nucleotide polymorphism rs1080985, patients who carried the G allele had a significantly higher risk of poor response to donepezil treatment. After adjusting the data based on APOE genotype, it was observed that only individuals bearing both the APOE-ε4 allele and the rs1080985-G allele showed a significant increase in the frequency of treatment non-response (OR 1.73, 95 % CI 1.07-2.09; p = 0.03). No independent effect of APOE polymorphism on donepezil clinical responses was found (OR 1.08, 95 % CI 0.85-1.38; p = 0.53). Lastly, in a subgroup analysis based on ethnicity, all results remained consistent.
CONCLUSION
The CYP2D6 genotype may be potentially effective for predicting the response to donepezil treatment in AD patients.
Topics: Alzheimer Disease; Animals; Apolipoproteins E; Cytochrome P-450 CYP2D6; Donepezil; Humans; Indans; Nootropic Agents; Pharmacogenetics; Piperidines; Polymorphism, Single Nucleotide
PubMed: 27282366
DOI: 10.1007/s40263-016-0356-1 -
World Neurosurgery Oct 2015The pathophysiology on cerebral vasospasm and delayed cerebral ischemia (DCI) remains poorly understood. Much research has been dedicated to finding genetic loci... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The pathophysiology on cerebral vasospasm and delayed cerebral ischemia (DCI) remains poorly understood. Much research has been dedicated to finding genetic loci associated with vasospasm and ischemia. We present a systematic review and meta-analysis to identify genetic polymorphisms associated with delayed ischemic neurologic deficit (DIND), radiographic infarction attributed to ischemia, and radiographic vasospasm.
METHODS
PubMed, the Cochrane Library, and Excerpta Medica dataBASE (EMBASE) databases were used to identify relevant studies published up to March 2015 containing the subject terms cerebral or intracranial vasospasm and DCI in combination with genetics, gene, polymorphism or marker. Meta-analyses were performed using a random-effects model to calculate summary odds ratio (ORs) and 95% confidence intervals for each respective gene.
RESULTS
Of 269 articles initially identified, 20 studies with 1670 patients were included in our comprehensive review, including 27 polymorphisms in 11 genes. The following 6 polymorphisms in 3 genes were selected for subsequent meta-analyses: apolipoprotein E (ApoE2, E4); endothelial nitric oxide (eNOS T786C, VNTR intron 4 a/b, G894T); and haptoglobin (Hp) 1/2 phenotypes. The eNOS VNTR a allele was associated with DIND (a vs. b allele: OR 1.92 [1.31-2.81], padj = 0.008). The Hp 2-2 allele was associated with radiographic vasospasm (2-2 vs. 2-1 and 1-1: OR 3.86 [1.86-8.03], padj = 0.003) but did not reach significance for DIND.
CONCLUSIONS
This is the first systemic review and meta-analysis to study and evaluate the associations between genetic polymorphism with DCI and radiographic vasospasm independently. In our study, eNOS VNTR and Hp polymorphisms appear to have the strongest associations with DIND and radiographic vasospasm, respectively.
Topics: Brain Ischemia; Cerebral Infarction; Humans; Nitric Oxide Synthase Type III; Polymorphism, Genetic; Radiography; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 26074429
DOI: 10.1016/j.wneu.2015.05.070 -
Rejuvenation Research Feb 2015The objective of this meta-analysis was to determine the association of the apolipoprotein E (ApoE) gene with exceptional longevity (EL) (i.e., reaching 100+ years) by... (Meta-Analysis)
Meta-Analysis Review
The objective of this meta-analysis was to determine the association of the apolipoprotein E (ApoE) gene with exceptional longevity (EL) (i.e., reaching 100+ years) by identifying possible unequal distribution of alleles/genotypes in the common variants ε2, ε3, and ε4 among centenarians and younger population. The association of ApoE with EL was analyzed in a total of 2776 centenarians (cases) and 11,941 younger controls (from 13 case-control studies) using the chi-squared test with the Yates correction. We conducted combined and separate analyses for all ethnic groups studied in the literature (Caucasian and Asian). The main result for all ethnic groups combined was that the likelihood of reaching EL was negatively associated with ε4 allele carriage [pooled odds ratio (OR)=0.43; 95% confidence interval (CI) 0.36, 0.50; p<0.001] and with ε4/ε4 (OR=0.18; 95% CI 0.08, 0.39; p<0.001), ε3/ε4 (OR=0.44; 95% CI 0.37, 0.53; p<0.001) and ε2/ε4 genotypes (OR=0.48; 95% CI 0.31, 0.74; p<0.001). In contrast, the ε2/ε3 genotype was positively associated with EL (OR=1.35; 95% CI 1.06, 1.72; p=0.017). When compared with the ε3 allele, the ε2 allele was not associated with increased odds of EL (OR=1.08; 95% CI 0.77, 1.50, p=0.660). The present meta-analysis confirms that, besides its previously documented influence on Alzheimer's and cardiovascular disease risk, the ApoE gene is associated with the likelihood of reaching EL.
Topics: Aged, 80 and over; Alleles; Apolipoproteins E; Case-Control Studies; Ethnicity; Genetic Predisposition to Disease; Genotype; Humans; Longevity; Odds Ratio; Polymorphism, Single Nucleotide
PubMed: 25385258
DOI: 10.1089/rej.2014.1605 -
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 -
Molecular Neurobiology Sep 2016Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive functions. AD can be classified into familial AD... (Review)
Review
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive functions. AD can be classified into familial AD (FAD) and sporadic AD (SAD) based on heritability and into early onset AD (EOAD) and late onset AD (LOAD) based on age of onset. LOAD cases are more prevalent with genetically complex architecture. In spite of significant research focused on understanding the etiological mechanisms, search for diagnostic biomarker(s) and disease-modifying therapy is still on. In this article, we aim to comprehensively review AD literature on established etiological mechanisms including role of beta-amyloid and apolipoprotein E (APOE) along with promising newer etiological factors such as epigenetic modifications that have been associated with AD suggesting its multifactorial nature. As genomic studies have recently played a significant role in elucidating AD pathophysiology, a systematic review of findings from genome-wide linkage (GWL), genome-wide association (GWA), genome-wide expression (GWE), and epigenome-wide association studies (EWAS) was conducted. The availability of multi-dimensional genomic data has further coincided with the advent of computational and network biology approaches in recent years. Our review highlights the importance of integrative approaches involving genomics and systems biology perspective in elucidating AD pathophysiology. The promising newer approaches may provide reliable means of early and more specific diagnosis and help identify therapeutic interventions for LOAD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Epigenomics; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Systems Biology
PubMed: 26351077
DOI: 10.1007/s12035-015-9390-0 -
Viral Immunology Dec 2017The aim of this study was to realize a systematic review to identify data reported in the literature involving people infected by hepatitis C virus (HCV) with cognitive... (Review)
Review
The aim of this study was to realize a systematic review to identify data reported in the literature involving people infected by hepatitis C virus (HCV) with cognitive dysfunctions and single nucleotide polymorphisms (SNPs). The research was realized in six databases and the selection of studies was performed in two stages. Initially, we searched indexed articles from the following electronic databases: SciELO, MEDLINE, PubMed, HighWire, LILACS, and ScienceDirect. Then the articles were completely read and those that did not meet the eligibility criteria were excluded. Therefore, 5,669 articles were obtained and, of these, 25 were selected. Finally, one article involving people with HCV and cognitive impairment was included in the review. The frequency of the APOE-ɛ4 allele in people with HCV and mild liver disease was significantly lower in those with work memory impairment (p = 0.003) and attention (p = 0.008). This situation differs from other studies that showed an association between ɛ4 allele high frequency and cognitive decline. Thus, studies with larger samples involving people with HCV, cognitive alterations, and SNPs are necessary, in view of the lack of this theme in the literature and the divergences in the findings.
Topics: Apolipoprotein E4; Cognitive Dysfunction; Databases, Factual; Gene Frequency; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Diseases; Polymorphism, Single Nucleotide
PubMed: 29016246
DOI: 10.1089/vim.2017.0084 -
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 -
Neuroscience and Biobehavioral Reviews Jan 2019APOE status has been associated to affective symptoms in cognitively impaired subjects, with conflicting results. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
APOE status has been associated to affective symptoms in cognitively impaired subjects, with conflicting results.
METHODS
Databases CINAHL, Embase, PsychINFO and PubMed were searched for studies evaluating APOE genotype with affective symptoms in MCI and AD dementia. Symptoms were meta-analyzed separately and possible sources of heterogeneity were examined.
RESULTS
Fifty-three abstracts fulfilled the eligibility criteria. No association was found between the individual symptoms and APOE ε4 carriership or zygosity. For depression and anxiety, only pooled unadjusted estimates showed positive associations with between-study heterogeneity, which could be explained by variation in study design, setting and way of symptom assessment.
CONCLUSIONS
There is no evidence that APOE ε4 carriership or zygosity is associated with the presence of depression, anxiety, apathy, agitation, irritability or sleep disturbances in cognitively impaired subjects. Future research should shift its focus from this single polymorphism to a more integrated view of other biological factors.
Topics: Affective Symptoms; Alzheimer Disease; Apolipoproteins E; Cognitive Dysfunction; Emotions; Humans
PubMed: 30513312
DOI: 10.1016/j.neubiorev.2018.11.020 -
Alzheimer's Research & Therapy Nov 2016Current Alzheimer's disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is... (Review)
Review
BACKGROUND
Current Alzheimer's disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is unclear whether biomarker results should be returned to research participants and what the psychological, behavioral and social effects of disclosure are. This systematic review therefore examines the psychological, behavioral and social effects of disclosing genetic and nongenetic AD-related biomarkers to cognitively healthy research participants.
METHODS
We performed a systematic literature search in eight scientific databases. Three independent reviewers screened the identified records and selected relevant articles. Results extracted from the included articles were aggregated and presented per effect group.
RESULTS
Fourteen studies met the inclusion criteria and were included in the data synthesis. None of the identified studies examined the effects of disclosing nongenetic biomarkers. All studies but one concerned the disclosure of APOE genotype and were conducted in the USA. Study populations consisted largely of cognitively healthy first-degree relatives of AD patients. In this group, disclosure of an increased risk was not associated with anxiety, depression or changes in perceived risk in relation to family history. Disclosure of an increased risk did lead to an increase in specific test-related distress levels, health-related behavior changes and long-term care insurance uptake and possibly diminished memory functioning.
CONCLUSION
In cognitively healthy research participants with a first-degree relative with AD, disclosure of APOE ε4-positivity does not lead to elevated anxiety and depression levels, but does increase test-related distress and results in behavior changes concerning insurance and health. We did not find studies reporting the effects of disclosing nongenetic biomarkers and only one study included people without a family history of AD. Empirical studies on the effects of disclosing nongenetic biomarkers and of disclosure to persons without a family history of AD are urgently needed.
TRIAL REGISTRATION
PROSPERO international prospective register for systematic reviews CRD42016035388 . Registered 19 February 2016.
Topics: Alzheimer Disease; Apolipoprotein E4; Biomarkers; Biomedical Research; Cognition Disorders; Databases, Factual; Disclosure; Female; Humans; Male; Psychotic Disorders; Social Behavior
PubMed: 27832826
DOI: 10.1186/s13195-016-0212-z