Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease

Tunstall, Nigel; Owen, Michael John; Williams, Julie; Rice, Frances; Carty, Stephanie; Lillystone, Sara; Fraser, Lindsay; Kehoe, Patrick Gavin; Neill, D. W.; Rudrasingham, Varuni; Sham, Pak-Chung; Lovestone, Simon

doi:10.1192/bjp.176.2.156

Cited by 55 publications

(39 citation statements)

References 27 publications

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“…It has been reported that APOE explains only 4% of the age at onset variability in familiar AD [44] making it difficult to detect. Second, microsatellite markers, spaced at an average distance of 9 cM in a genome wide search, may not have insufficient marker information content for mapping, thereby further reducing statistical power.…”

Section: Discussionmentioning

confidence: 99%

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

et al. 2007

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The aim of the study was to identify chromosomal regions containing putative genetic variants influencing age-at-onset in familial late-onset Alzheimer's disease. Data from a genome-wide scan that included genotyping of APOE was analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age-at-onset of 73.3 years multiply affected by late-onset Alzheimer's disease. Two-point and multipoint analyses were conducted using variance component methods from 376 microsatellite markers with an average inter-marker distance of 9.3 cM. Family-based test of association were also conducted for the same set of markers. Age-at-onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ε4 lowered the age-at-onset by three years. Using linkage analysis strategy, the highest LOD scores were obtained using a conservative definition of LOAD at 5q15 (LOD 3.1) 17q25.1 (LOD=2.94) and 14q32.12 (LOD=2.36) and 7q36.3 (LOD=2.29) in covariate adjusted models that included APOE-ε4. Both linkage and family-based association identified 17p13 as a candidate region. In addition, family-based association analysis showed markers at 12q13 (p=0.00002), 13q (p=0.00043) and 14q23 (p=0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age-at-onset of late onset

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Section: Discussionmentioning

confidence: 99%

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

et al. 2007

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“…Familial aggregation studies of probands and siblings with AD have shown a higher chance of concordance for AD+D in siblings and probands than by chance alone [33]. Using genome scans of 148 AD pedigrees, Avramopoulos and colleagues [34] identified a locus on chromosome 2p that is linked with AD+D and a locus on 14q that predisposes individuals to a form of dementia without comorbid psychotic features.…”

Section: Geneticsmentioning

confidence: 99%

Neurobiology of Delusions in Alzheimer’s Disease

Ismail

Nguyen

Fischer

et al. 2011

Curr Psychiatry Rep

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Alzheimer's disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities.Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.

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“…More than 550 other genes have been proposed as candidates for AD susceptibility, but so far none have been firmly established to have a role in the pathogenesis of the disease [12]. Family, linkage, and association studies [13][14][15][16] have considered BPSD a genetically determined factor. Also, dopaminergic neurotransmission has been implicated in many human behaviors and several studies have investigated its relationship with BPSD.…”

Section: Catechol-o-methyltransferase Genetic Variantmentioning

confidence: 99%

Catechol-O-Methyltransferase GeneticVariant Associated with the Risk of Alzheimers Disease in a Brazilian Population

Pereira

Romano-Silva

Bicalho

et al. 2012

Dement Geriatr Cogn Disord

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The aim of the present study was to examinethe association between polymorphism in thecatechol-O-methyltransferase(COMT) gene and Alzheimer’s disease (AD) in a Brazilianpopulation. The case-control method was used to study the association between AD and geneticvariants of COMT. Six tag single-nucleotide polymorphisms(SNPs) in the COMT gene were genotyped by RT-PCR. Ourfindings showed that the 6 tag SNPs analyzed in this study were not associated with AD at the alleleand genotype levels in comparison with the control group. No statistical difference was foundbetween groups with and without behavioral and psychological symptoms of dementia (BPSD). Ourresults do not support the hypothesis that the polymorphisms of theCOMT gene may be associated with susceptibility to AD withand without BPSD.

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Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease

Abstract: Substantial familial influence on age of onset, depression and agitation suggests that genotype does influence phenotype in Alzheimer's disease. Establishing the molecular basis for this phenotypic variation may prove relevant to other neuropsychiatric disorders.

Cited by 55 publications

References 27 publications

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Neurobiology of Delusions in Alzheimer’s Disease

Catechol-O-Methyltransferase GeneticVariant Associated with the Risk of Alzheimers Disease in a Brazilian Population

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Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease

Abstract: Substantial familial influence on age of onset, depression and agitation suggests that genotype does influence phenotype in Alzheimer's disease. Establishing the molecular basis for this phenotypic variation may prove relevant to other neuropsychiatric disorders.

Cited by 55 publications

References 27 publications

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Neurobiology of Delusions in Alzheimer’s Disease

Catechol-O-Methyltransferase GeneticVariant Associated with the Risk of Alzheimers Disease in a Brazilian Population

Contact Info

Product

Resources

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Catechol-O-Methyltransferase GeneticVariant Associated with the Risk of Alzheimers Disease in a Brazilian Population