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1.
Bird TD 《The New England journal of medicine》2005,352(9):862-864
2.
Typical, late-onset Alzheimer's disease is familial but shows no clear Mendelian pattern of inheritance. Strategies that could help to reveal its genetics are: 1) identification of genetically homogeneous phenotypes, 2) identification of early or alternate manifestations of AD gene expression in relatives, and 3) use of small multiplex families with cases of typical AD for linkage studies. 相似文献
3.
《Genetics in medicine》2008,10(4):231-239
Alzheimer disease is the most common cause of dementia and represents a major public health problem. The neuropathologic findings of amyloid-β plaques and tau containing neurofibrillary tangles represent important molecular clues to the underlying pathogenesis. Genetic factors are well recognized, but complicated. Three rare forms of autosomal-dominant early-onset familial Alzheimer disease have been identified and are associated with mutations in amyloid precursor protein, presenilin 1, and presenilin 2 genes. The more common late-onset form of Alzheimer disease is assumed to be polygenic/multifactorial. However, thus far the only clearly identified genetic risk factor for Alzheimer disease is Apo lipoprotein E. The ε4 allele of Apo lipoprotein E influences age at onset of Alzheimer disease, but is neither necessary nor sufficient for the disease. The search continues for the discovery of additional genetic influences. 相似文献
4.
Renato X Santos S��nia C Correia Xinglong Wang George Perry Mark A Smith Paula I Moreira Xiongwei Zhu 《International journal of clinical and experimental pathology》2010,3(6):570-581
Alzheimer''s disease is a progressive neurodegenerative disorder, either assuming a sporadic, age-associated, late-onset form, or a familial form, with early onset, in a smaller fraction of the cases. Whereas in the familial cases several mutations have been identified in genes encoding proteins related with the pathogenesis of the disease, for the sporadic form several causes have been proposed and are currently under debate. Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses acting as a trigger for the pathogenesis of Alzheimer''s disease. Mitochondria assume central functions in the cell, including ATP production, calcium homeostasis, reactive oxygen species generation, and apoptotic signaling. Although their role as the cause of the disease may be controversial, there is no doubt that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to its onset and progression. 相似文献
5.
Genetic risk factors in Alzheimer's disease. 总被引:1,自引:0,他引:1
Following a brief introduction and discussion of the pathological features of Alzheimer's disease, the main emphasis of this review article will be the genetic factors that have been implicated in this disease. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial Alzheimer's disease will be discussed. These are well characterised but account for only a small proportion of Alzheimer's disease cases. Late onset, sporadic Alzheimer's disease is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease. Many of these are controversial and studies have shown conflicting results, which are discussed in this section. Finally, a brief discussion of some of the mechanisms suggested to play a role in the pathogenesis of Alzheimer's disease is included. It is hoped that this will show why particular genes have been implicated in Alzheimer's disease and how they might be able to influence the development of the disease. 相似文献
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Sorbi S Forleo P Tedde A Cellini E Ciantelli M Bagnoli S Nacmias B 《Mechanisms of ageing and development》2001,122(16):1951-1960
In the last 10 years significant progress has been made to describe and identify the underlying biological mechanisms that cause the different manifestation of Alzheimer's disease. Since the first report of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer's disease (FAD), considerable progress has been made. Results from linkage analysis and gene sequencing has provided evidence that a minority of early onset FAD families develops the disease as a result of mutations in the gene coding for the Abeta-amyloid precursor protein, and that mutations in presenilin 1 and 2 genes account for a larger subgroup of early onset families. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other genetic risk factors may exist. Recent genome-wide scanning studies have revealed the existence of a new locus on chromosome 12, which, together with inheritance of the epsilon4 allele of apolipoprotein E gene, on chromosome 19, represent the most important genetic factors associated with an increased risk of developing the disease in late onset FAD families. 相似文献
8.
As neurodegenerative disorders are better characterized, the importance of genetic and environmental interactions is becoming more evident. Among the neurodegenerative disorders, Alzheimer's disease and Parkinson's disease are both characterized by large losses of nicotinic binding sites in brain. In addition, losses in nicotinic receptors occur during normal aging. Chronic administration of nicotine in man or experimental animals increases the number of nicotinic receptors in brain. Nicotine has been shown to possess some neuroprotective properties for both cholinergic and dopaminergic neurons. These neuroprotective properties, when better understood, may provide important information on normal aging and neurodegenerative disorder related neuronal cell death. Understanding the functional aspects of neuronal nicotinic receptor subtypes may lead to successful therapeutic treatments or disease preventative strategies for neurodegenerative disorders. 相似文献
9.
Genetic and clinical aspects of Charcot-Marie-Tooth''s disease 总被引:23,自引:0,他引:23
H. Skre 《Clinical genetics》1974,6(2):98-118
The prevalence of Charcot-Marie-Tooth's disease (CMT) was studied in Western Norway, an area with several isolated districts with a population of 725,000 (1968). Three hereditary types were distinguished in the area: autosomal dominant CMT with an estimated prevalence of 36/100,000; X-linked recessive CMT with a prevalence of 3.6/100,000; and autosomal recessive CMT with a prevalence of 1.4/100,00. Gene frequencies were 3 · 7. 10-4, 1 · 9. 10-4, and 4 · 8. 10-4 in autosomal dominant, X-linked, and autosomal recessive CMT, respectively, while the corresponding mutation rates were 13 · 0, 5 · 5, and 3 · 5 per million gametes per generation. The penetrance was almost complete for all three variants of CMT. Strict diagnostic criteria were followed in the selection of the 37 index cases. A family investigation was carried out with 238 subjects, during which 69 secondary cases were detected. Another 57 subjects had unspecific neuropathy (Un), which did not fit a diagnosis of CMT or other neurological disease. In the diagnosis of Un, a score system was used, with age and sex corrections based on findings in a normal population. Generally, the most severe disease course was found in the recessive CMT types, but there was also more clinical variation, suggesting CNS involvement in some cases (upper motor neuron affection, cerebellar signs). Scoliosis and spinal ataxia were not infrequent, even in cases with autosomal dominant CMT. The prevalence cf Un was highest in the relatives of recessive CMT cases, with a ratio of affected to normal in sibs compatible with a hypothesis of several cases of heterozygous manifestation. In the relatives of autosomal dominant CMT cases, Un prevalence was also higher than in the population, but lower in 2nd degree relatives than in 1st degree; the ratios fitted a hypothesis of polygenic Un inheritance. Significant differences were found in the score patterns of Un in the recessive CMT families and in the autosomal dominant families, suggesting their difference of origin. The reason for clustering of Un cases in autosomal dominant CMT families is obscure, since it can be only partly attributed to early manifestation of CMT. It is suggested that Un and CMT, mainly in autosomal dominant CMT, interact to form a spectrum of differing phenotypes, so explaining the problem of “transitional forms” between CMT and other hereditary nervous disorders. Recessive CMT, being a more generalized nervous disease, attains, through differing expressivity, phenotypes which vary between individual cases. 相似文献
10.
Pintér M Kolesárová M 《Acta medica (Hradec Králové). Supplementum Universitas Carolina, Facultas Medica Hradec Králové》2004,47(2):83-87
Idiopatic bowel disease, Crohn' s disease and ulcerative colitis, are grave illneses of gastrointestinal tract. Mechanisms that lead to the development of inflammatory bowel disease are not well understood, but genetic play an important role. The main arguments gathered are ethnic/racial difference in disease frequency, positive family history, increased concordance rate in monozygotic twins relative to dizygotic and genes associated with Crohn's disease and ulcerative colitis. The enviromental factors play also an important role. 相似文献
11.
Lämsä R Helisalmi S Herukka SK Tapiola T Pirttilä T Vepsäläinen S Hiltunen M Soininen H 《Neurobiology of aging》2008,29(6):848-855
We genotyped SNPs rs11668477, rs12983082, rs11669576, rs2738444, rs5925 and rs1433099 in 405 Finnish AD cases and 463 controls and conducted a single allele and genotypic distribution comparison and estimated the haplotype frequencies between cases and controls and evaluated the level of biomarkers in haplotype carriers. We observed that T allele of rs2738444 was overrepresented in AD women with p = 0.014 (Bonferroni corrected p = 0.252). A specific haplotype block consisting of SNPs rs11669576, rs2738444 and rs5925 was identified and in women the haplotype GTT was overrepresented in AD cases when compared to controls with p = 0.008. We measured CSF Aβ42, tau and phosphorylated tau (ptau) levels in a subgroup of cases and controls and found that some genotypes were associated with increased levels of tau and ptau or a decreased Aβ42 level in women. The specific risk haplotype GTT was associated with an increased level of tau and ptau in both men and women. Our findings suggest that LDLR gene may be associated with AD risk and its CSF biomarkers, especially in women. 相似文献
12.
R. Hargrave M. Stoeklin M. Haan B. Reed 《Journal of the National Medical Association》1998,90(2):78-84
This article examines the association between ethnicity and psychiatric symptoms in patients with Alzheimer''s disease. Data from a cross-sectional study of patients evaluated at nine California Department of Health Alzheimer''s Disease Diagnostic and Treatment Centers (ADDTCs) were used. Using the ADDTC patient database, sociodemographic and clinical variables in 207 black patients and 1818 white patients with probable and possible Alzheimer''s disease were compared. Logistic and linear regression analysis indicated the following results: 1) black patients had fewer years of education and more often had hypertension, 2) black patients reported shorter duration of illness at the time of initial diagnosis of dementia, 3) black patients had lower Mini-Mental State Examination scores and higher Blessed Roth Dementia Rating Scale scores at the time of initial diagnosis, and 4) black patients more frequently reported insomnia and less frequently reported anxiety. Additional studies are needed to validate these findings and to generate hypotheses about the role of cardiovascular disease and pathophysiology of psychiatric symptoms in ethnic populations with Alzheimer''s disease. 相似文献
13.
Gopalraj RK Zhu H Kelly JF Mendiondo M Pulliam JF Bennett DA Estus S 《Neurobiology of aging》2005,26(1):1-7
The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) LDLR modulates the homeostasis of cholesterol, which itself appears associated with AD. Therefore, we evaluated whether LDLR haplotypes alter the odds of AD by performing an association study examining three LDLR single nucleotide polymorphisms (SNPs) in 118 AD patients and 133 non-AD subjects. LDLR genotypes were obtained by TaqMan allelic discrimination assays. Although individual LDLR SNPs were not associated with AD, analyses of unambiguous haplotypes suggested the hypothesis that the 211 LDLR haplotype was associated with reduced odds of AD. We then evaluated this hypothesis in a second study cohort, i.e., the Religious Orders Study. These results supported the hypothesis that the 211 LDLR haplotype is associated with reduced odds of AD. Moreover, these data suggested further associations between LDLR variants and AD. Thus, LDLR variants appear significantly associated with AD and merit additional study. 相似文献
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Cervantes S Samaranch L Vidal-Taboada JM Lamet I Bullido MJ Frank-García A Coria F Lleó A Clarimón J Lorenzo E Alonso E Sánchez-Juan P Rodríguez-Rodríguez E Combarros O Rosich M Vilella E Pastor P 《Neurobiology of aging》2011,32(11):2107-2107.17
We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3′ to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk. 相似文献
16.
Miyashita A Arai H Asada T Imagawa M Matsubara E Shoji M Higuchi S Urakami K Kakita A Takahashi H Toyabe S Akazawa K Kanazawa I Ihara Y Kuwano R;Japanese Genetic Study Consortium for Alzeheimer's Disease 《Human molecular genetics》2007,16(23):2854-2869
Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal the ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60-107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Abeta42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-epsilon3*3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3 were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P-values(MH-F) = 0.000005945-0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-epsilon4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-epsilon4 allele. 相似文献
17.
Genetic epidemiological study of maternal and paternal transmission of Alzheimer's disease. 总被引:2,自引:0,他引:2
D Ehrenkrantz J M Silverman C J Smith S Birstein D Marin R C Mohs K L Davis 《American journal of medical genetics》1999,88(4):378-382
Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission. 相似文献
18.
Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin 总被引:7,自引:0,他引:7
Saunders AJ Bertram L Mullin K Sampson AJ Latifzai K Basu S Jones J Kinney D MacKenzie-Ingano L Yu S Albert MS Moscarillo TJ Go RC Bassett SS Daly MJ Laird NM Wang X Velicelebi G Wagner SL Becker DK Tanzi RE Blacker D 《Human molecular genetics》2003,12(21):2765-2776
Alpha-2-Macroglobulin (A2M) is a highly plausible candidate gene for Alzheimer's disease (AD) in a region of chromosome 12 that has numerous independent reports of genetic linkage. We previously reported that a 5 bp deletion in A2M was associated with AD in a subset of the National Institute of Health (NIMH) Genetics Initiative AD family sample. Efforts to replicate this association finding in case - control samples have been largely negative, while those in family samples have been more positive. We hypothesized that variable findings regarding this deletion, along with variable reports of association with V1000I, another polymorphism in the gene, result from linkage disequilibrium in the area as well as ascertainment differences between family-based and case-control studies. Thus, we resequenced the A2M locus to identify novel polymorphisms to test for genetic association with AD. We identified seven novel polymorphisms and tested them in the full NIMH sample of 1439 individuals in 437 families. We found significant genetic association of the 5 bp deletion and two novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remain significantly associated with AD even after correction for multiple testing. Taken together, these findings, and the positive reports in other family-based studies, continue to support a potential role for A2M or a nearby gene in AD. However, the negative case - control studies suggest that any underlying pathogenic polymorphisms have a modest effect, and may operate primarily among individuals with a family history of AD. 相似文献
19.
Genetic studies have demonstrated very high heritability for Alzheimer's disease (AD) risk in humans; however, these genetic contributions have proven extremely challenging to map in large studies of AD patients. Processing of the amyloid precursor protein (APP) to produce amyloid-beta (Aβ) peptide is increasingly believed to be of central importance in AD pathogenesis. Intriguingly, mice from the C57BL/6J and DBA2/J inbred strains carrying the R1.40 APP transgene produce identical levels of unprocessed APP, but demonstrate significant, heritable differences in Aβ levels. To identify specific loci responsible for the observed genetic control of Aβ metabolism in this model system, we have performed a whole-genome quantitative trait locus (QTL) mapping experiment on a total of 516 animals from a C57BL/6J × DBA/2J intercross using a dense set of SNP genetic markers. Our studies have identified three loci on mouse chromosomes 1, 2, and 7 showing significant or suggestive associations with brain Aβ levels, several of which contain regions syntenic to previous reports of linkage in human AD. 相似文献
20.
Alzheimer's disease 总被引:9,自引:0,他引:9
R Katzman 《The New England journal of medicine》1986,314(15):964-973