The GAB2 and BDNF polymorphisms and the risk for late-onset Alzheimer's disease in an elderly Brazilian sample

ABSTRACTBackground:Evidences suggest that GAB2 and BDNF genes may be associated with Alzheimer's disease (AD). We aimed to investigate the GAB2 rs2373115 and BDNF rs6265 polymorphisms and the risk of AD in a Brazilian sample.Methods:269 AD patients and 114 controls were genotyped with Real-time PCR. Multifactor dimensionality reduction (MDR) was employed to explore the effects of gene–gene interactions.Results:GAB2 and BDNF were not associated with AD in our sample. Nevertheless BDNF Val allele (rs6265) presented a synergic association with the APOE ε4 allele. A multiple logistic regression demonstrated that the APOE ε4 allele and years of education were the best predictors for AD. In ε4 non-carriers sex, education and hypertension were independently correlated with AD, while in ε4 carriers we did not observe any association. The findings were further confirmed by bootstrapping method.Conclusions:Our data suggest that the interaction of BDNF and APOE has significant effect on AD. Moreover in absence of ε4, female sex, low level of education and hypertension are independently associated with AD. Interventions aimed to prevent AD should focus on these factors and also taking into account the APOE alleles.

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Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

Current Gene Therapy ◽

10.2174/1566523220666201123112822 ◽

2020 ◽

Vol 20 ◽

Author(s):

Md. Sahab Uddin ◽

Sharifa Hasana ◽

Md. Farhad Hossain ◽

Md. Siddiqul Islam ◽

Tapan Behl ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Massively Parallel Sequencing ◽

Late Onset ◽

Current Knowledge ◽

The Elderly ◽

Apoe Ε4 ◽

Sequencing Technologies ◽

Genetic Components ◽

Ε4 Allele

: Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

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The GAB2 and BDNF polymorphisms and the risk for late-onset Alzheimer's disease in an elderly Brazilian sample – ERRATUM

International Psychogeriatrics ◽

10.1017/s1041610215001040 ◽

2015 ◽

Vol 27 (10) ◽

pp. 1693-1693

Author(s):

Renalice Neves Vieira ◽

Joalce Dornelas Magalhães ◽

Jemima Sant’Anna ◽

Mateus Massao Moriguti ◽

Débora Marques de Miranda ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Correct Order ◽

Brazilian Sample ◽

Made In

In the above mentioned article by Vieira et al., an error has been made in the order of which the authors appear. The correct order is stated below:Renalice Neves Vieira, Joalce Dornelas Magalhães, Jemima Sant’Anna, Mateus Massao Moriguti, Jonas Jardim de Paula, Marco Túlio Gualberto Cintra, Débora Marques de Miranda, Luiz De Marco, Edgar Nunes de Moraes, Marco Aurélio Romano-Silva, Maria Aparecida Camargos Bicalho.

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Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele

American Journal Of Pathology ◽

10.1016/s0002-9440(10)63822-9 ◽

2003 ◽

Vol 162 (1) ◽

pp. 313-319 ◽

Cited By ~ 213

Author(s):

David G. Cook ◽

James B. Leverenz ◽

Pamela J. McMillan ◽

J. Jacob Kulstad ◽

Sasha Ericksen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Late Onset ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Ε4 Allele

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Study of association between genetic polymorphisms of phospholipase A2 enzymes and Alzheimer's disease

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2010000200007 ◽

2010 ◽

Vol 68 (2) ◽

pp. 189-193 ◽

Cited By ~ 5

Author(s):

Quirino Cordeiro ◽

Ricardo Noguti ◽

Cássio M.C. Bottino ◽

Homero Vallada

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Control Sample ◽

Amyloid Plaque ◽

Amyloid Peptide ◽

Allelic Association ◽

Brazilian Sample ◽

Phospholipases A2 ◽

Genes Encoding

Several genes have been related to late-onset Alzheimer's disease (LOAD). Phospholipases A2 (PLA2) influence the processing and secretion of the amyloid precursor protein, which gives rise to the beta-amyloid peptide, the major component of the amyloid plaque in AD. Hence, in the present study, polymorphisms of three genes encoding PLA2 enzymes group (cytosolic PLA2: BanI cPLA2 polymorphism; calcium-independent PLA2: AvrII iPLA2 polymorphism; PAFAH: Val279Phe PAFAH polymorphism) were analysed in a case-control sample using 58 patients with LOAD and 107 matched healthy controls. There was a genotypic association between the BanI cPLA2 polymorphism and LOAD (χ2=6.25, 2df, p=0.04), however there was no allelic association. There were no associations between AvrII iPLA2 and Val279Phe PAFAH polymorphisms and LOAD. These data suggest that the BanI cPLA2 polymorphism may play a role in the susceptibility for LOAD in our Brazilian sample.

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The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

Neuronal Signaling ◽

10.1042/ns20180203 ◽

2019 ◽

Vol 3 (2) ◽

Cited By ~ 2

Author(s):

Holly C. Hunsberger ◽

Priyanka D. Pinky ◽

Warren Smith ◽

Vishnu Suppiramaniam ◽

Miranda N. Reed

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synapse Formation ◽

Late Onset ◽

Therapeutic Interventions ◽

Memory Decline ◽

Current Therapies ◽

Ε4 Allele ◽

The Impact

Abstract Alzheimer’s disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.

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Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211069006 ◽

2022 ◽

pp. 0271678X2110690

Author(s):

Charles E Seaks ◽

Erica M Weekman ◽

Tiffany L Sudduth ◽

Kevin Xie ◽

Brandi Wasek ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Apolipoprotein E ◽

Late Onset ◽

Apoe Ε4 ◽

Perivascular Inflammation ◽

Ε4 Allele ◽

Barrier Breakdown ◽

The Impact

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

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Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups

Molecular Psychiatry ◽

10.1038/s41380-018-0298-8 ◽

2018 ◽

Vol 25 (11) ◽

pp. 2942-2951 ◽

Cited By ~ 13

Author(s):

Shubhabrata Mukherjee ◽

◽

Jesse Mez ◽

Emily H. Trittschuh ◽

Andrew J. Saykin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Disease Diagnosis ◽

Single Nucleotide ◽

Cognitively Normal ◽

Snp Data ◽

Genotype Frequencies ◽

Genome Wide ◽

Ε4 Allele

Abstract Categorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10−5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10−27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10−5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

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Differences in Clinical Presentation of Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease According to Sex and Education Level

Journal of Alzheimer s Disease ◽

10.3233/jad-200507 ◽

2020 ◽

Vol 78 (2) ◽

pp. 711-719

Author(s):

Kuo-Hsuan Chang ◽

Chin-Chang Huang ◽

Chiung-Mei Chen ◽

Hsiu-Chuan Wu ◽

Hung-Chou Kuo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Education ◽

Psychological Symptoms ◽

Education Level ◽

Clinical Dementia Rating ◽

Level Of Education ◽

Mini Mental Status Examination ◽

High Level ◽

Behavioral And Psychological Symptoms

Background: The behavioral and psychological symptoms of dementia (BPSD) seriously affect the quality of life of patients with Alzheimer’s disease (AD) and their caregivers. Objective: We aimed to identify associations between demographic/genetic factors and clinical presentations of BPSD. Methods: In a cohort of 463 AD patients with BPSD, we retrospectively analyzed sex, education level, AD severity (assessed using the Clinical Dementia Rating and Mini-Mental Status Examination), and BPSD severity (assessed using the Neuropsychiatry Inventory, NPI). Severe BPSD was defined as NPI ≥10 for 3 consecutive years. Results: Among patients with severe BPSD (NPI ≥10), we observed more female patients (62.96%) and a lower level of education (6.03±4.77 years) as compared to those with mild BPSD (NPI <10) (female: 51.09%, p = 0.007; education years: 7.91±4.93, p < 0.001). Females had a lower level of education (5.72±4.50 years) and higher scores for depression/dysphoria (1.22±2.05) compared with males (education: 8.96±4.89 years, p < 0.001; depression/dysphoria: 0.78±1.42, p = 0.047). Patients with a high level of education (defined as ≥12 years) had higher scores for appetite/eating (0.90±2.02) than did those without (0.69±1.79; p = 0.001). Genetic analysis showed similar total and subscale NPI scores between patients with and without APOE4 and with and without the GRN rs5848 genotype. Conclusion: Our findings indicate potential contributions of sex and education to the presentation of BPSD. Further study is warranted to provide models for tailoring therapeutic programs to individual AD patients according to these factors.

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Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles

Genome Medicine ◽

10.1186/s13073-020-00808-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Rosie M. Walker ◽

Kadi Vaher ◽

Mairead L. Bermingham ◽

Stewart W. Morris ◽

Andrew D. Bretherick ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Meta Analysis ◽

Density Lipoprotein ◽

Differentially Methylated Region ◽

Carrier Status ◽

Ε4 Allele ◽

Methylation Patterns

Abstract Background The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Methods Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. Results We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10−100 ≤ P ≤ 2.44 × 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10−4 ≤ P ≤ 3.01 × 10−2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24. Conclusions APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

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Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets

Brain ◽

10.1093/brain/awz289 ◽

2019 ◽

Vol 142 (11) ◽

pp. 3375-3381 ◽

Cited By ~ 1

Author(s):

Ming Zhang ◽

Allison A Dilliott ◽

Roaa Khallaf ◽

John F Robinson ◽

Robert A Hegele ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Accelerated Ageing ◽

Disease Phenotypes ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Disease Family

Zhang, Dilliott et al. examine a unique family with early- and late-onset Alzheimer’s disease phenotypes, as well as disease-discordant monozygotic triplets. The triplets and the patient with early-onset disease are carriers of the APOE ε4-allele plus rare substitutions in other genes. Epigenetic analyses suggest accelerated ageing in the early-onset patient.

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