RESUMO
Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.
Assuntos
Disfunção Cognitiva/genética , DNA (Citosina-5-)-Metiltransferases/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Cognição , DNA Metiltransferase 3A , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To understand the relation between risk genes for Alzheimer's disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aß(1-42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). METHODS: We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland. RESULTS: APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aß(1-42) (corrected p<0.05). At an uncorrected p<0.05, PPP3R1 rs1868402 and MAPT rs2435211 were related with increased t-tau; while SORL1 rs73595277 and MAPT rs16940758, with increased p-tau. Only TOMM40 rs2075650 showed association with clinical AD after adjusting for APOE-ε4 (p = 0.007), but not after multiple test correction (p>0.05). CONCLUSIONS: We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aß1-42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aß1-42.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Clusterina/genética , Proteínas de Membrana/genética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Feminino , Finlândia , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fosforilação , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-Traducional , Fatores de RiscoRESUMO
We assessed the interaction between the APOE ε4 allele and education level in the etiology of Alzheimer's disease (AD) among memory clinic patients from the multicenter DESCRIPA study. Subjects (n = 544) were followed for 1 to 5 years. We used Cox's stratified survival modeling, adjusted for age, gender, and center. APOE ε4 predicted the onset of AD-type dementia in middle (HR 3.45 95% CI 1.79-6.65, n = 222) and high (HR 3.67 95% CI 1.36-9.89, n = 139) but not in low educated subjects (HR 0.81, 95% CI 0.38-1.72, n = 183). This suggests that mechanisms in developing Alzheimer-type dementia may differ between educational groups that raises questions related to Alzheimer-type dementia prevention.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Escolaridade , Interação Gene-Ambiente , Transtornos da Memória/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Estudos de Coortes , DNA/genética , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Transtornos da Memória/epidemiologia , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores Sexuais , Análise de SobrevidaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (main constituent: ß-amyloid [Aß]) and neurofibrillary tangles (hyperphosphorylated tau protein) in the brain. Abnormalities in Aß and tau can be measured upon neuropathological examination, in cerebrospinal fluid or by PET. Etiologically, a growing body of evidence suggests that susceptibility to AD is genetically controlled. However, the precise nature of the underlying risk genes and their relation to AD biomarkers remains largely elusive. To this end, we performed a qualitative review of 17 studies (covering 47 polymorphisms in 26 genes) and investigated the potential relation between the most compelling AD risk genes and markers for Aß and tau in cerebrospinal fluid, PET imaging and neuropathological examination. Of all covered genes, only APOE and PICALM showed consistent effects on Aß but not on tau, while no obvious effects were observed for CLU, CR1, ACE, SORL and MAPT.
Assuntos
Doença de Alzheimer/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Clusterina/genética , Clusterina/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Proteínas Monoméricas de Montagem de Clatrina/genética , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Polimorfismo Genético , Receptores de Complemento 3b/genética , Receptores de Complemento 3b/metabolismo , Fatores de Risco , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND: The identification of subjects with mild cognitive impairment (MCI) at high risk for Alzheimer's disease (AD) is important for prognosis and early intervention. The APOE-ε4 allele is the strongest known genetic risk factor for AD. The authors performed a meta-analysis to establish the predictive accuracy of the APOE-ε4 allele for progression from MCI to AD-type dementia. METHODS: The authors included 35 prospective cohort studies of subjects with MCI, including 6095 subjects, of whom 1236 progressed to AD-type dementia after 2.9 years of follow-up. Pooled estimates of the OR, sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (LR+ and LR-) were obtained using random-effects models. RESULTS: The OR for subjects with MCI who are carriers of APOE-ε4 allele to progress to AD-type dementia was 2.29 (95% CI 1.88 to 2.80), the sensitivity was 0.53 (95% CI 0.46 to 0.61), the specificity was 0.67 (95% CI 0.62 to 0.71), the PPV was 0.57 (95% CI 0.48 to 0.66), the NPV was 0.75 (95% CI 0.70 to 0.80), the LR+ was 1.60 (95% CI 1.48 to 1.72), and the LR- was 0.75 (95% CI 0.67 to 0.82). Meta-regression showed that sensitivity, specificity and NPV were dependent on age, APOE-ε4 allele background prevalence or follow-up length. CONCLUSIONS: The APOE-ε4 allele is associated with a moderately increased risk for progression from MCI to AD-type dementia. The low sensitivity and PPV makes genotyping of limited value for predicting AD-type dementia in clinical practice. For trials aiming to prevent progression from MCI to AD-type dementia, APOE genotyping may be useful in selecting subjects with a higher risk for progression to AD-type dementia.
