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Background Catechol-O-methyl transferase ( COMT) and brain-derived neurotrophic factor ( BDNF) are neuro-modulatory proteins that have been demonstrated to affect cortical plasticity, which in turn has been shown to affect age-related changes and neuronal functioning in humans. Here, we tested the hypothesis that single nucleotide polymorphisms ( SNP) within COMT and BDNF genes are associated with dysphagia in older adults. Methods A total of 800 community-dwelling older individuals were sent the Sydney Oropharyngeal Dysphagia Questionnaire to identify swallowing difficulties. DNA from this population was available for study and used to genotype 18 COMT and 12 BDNF polymorphisms. Logistic regression statistical models were used to identify potential associations between dysphagia and the genotypes. Key Results A total of 638 individuals completed the questionnaire, giving an 80% response rate. Of these, 538 were genotyped for COMT and BDNF polymorphisms. Age was found to predict dysphagia ( p = 0.018, OR = 1.08, CI = 1.01-1.14). The COMT polymorphism rs165599 and the BDNF polymorphism rs10835211 were found to predict dysphagia and have an interactive effect ( p = 0.028), which varied according to the carrier status of the other. In the case of SNP rs10835211, the effect of heterozygosity was protective or harmful dependent on the respective status of rs165599. Conclusions & Inferences These results suggest that certain interactions between plasticity genes contribute to the development of dysphagia with increasing age. This highlights a possible role for genetic factors in future monitoring and treating individuals affected by dysphagia. [ABSTRACT FROM AUTHOR]

Apolipoprotein E ( ApoE) is the most well-described genetic risk factor for Alzheimer's disease and nonpathological cognitive decline. While possession of the E2 allele may have protective properties, substantial research evidence suggests the E4 allele increases the risk of cognitive degeneration. As neurodegenerative processes are implicated in swallowing dysfunction, we hypothesized that the presence of ApoE 4 would be predictive of dysphagia symptoms in older adults. Eight hundred members of a genetically well characterized community dwelling elderly cohort received the Sydney oropharyngeal dysphagia questionnaire via mail. Cognitive function was also measured using the modified Telephone Interview of Cognitive Status ( TiCS-m) and depression with the Geriatric Depression Score ( GDS). ApoE allele was genotyped on blood samples from all subjects and data analyzed using standard statistical software ( SPSS version 16). Completed questionnaire response rate was 79% (23.5% men, 76.5% women; mean age 81 ± 5 years; range 69-98 years). Possession of one or more of the ApoE 4 and 2 alleles was found in 23.5% and 16%, respectively. Swallowing score was significantly related to GDS (rho 0.133, P < 0.001**) and age (rho 0.107, P < 0.007**) but not general cognitive function as measured by TICS-m. Self-reported swallowing function was not significantly associated with heterozygosity of any allele or homozygosity for E2 or E3 alleles. Although infrequent (1.1% of all subjects) ApoE E4 homozygosity was significantly associated with higher swallowing scores compared to all other allele combinations ( P = 0.033) and while attenuated, was still predicted in multivariate regression modeling ( B = 0.812; SE = 0.323; P = 0.012). We report the association between ApoE 4 homozygous genotype and self-reported oropharyngeal dysphagia symptoms in community-dwelling older adults. As this association is weakened by the multivariate analysis and the population frequency of ApoE 4 allele homozygosity is low, this finding while intriguing requires replication in larger independent cohorts. [ABSTRACT FROM AUTHOR]

Aims To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. Methods Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. Results Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. Conclusions To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is a pleiotropic protein involved in neuronal proliferation, differentiation, synaptic plasticity and survival. Independent studies investigating association between the functional BDNF Val66Met polymorphism and cognitive abilities have reported some conflicting findings, which may reflect inadequate sample size, variation in testing methods, population stratification or the confounding effects of other genes. To test the latter hypothesis, we screened and genotyped polymorphisms in the RE1-silencing transcription factor (REST) gene whose function includes the downregulation of BDNF expression. We identified an exon 4 hexadecapeptide variable number tandem repeat (VNTR) with either four or five copies that was located within a proline-rich domain and investigated a further five single nucleotide polymorphisms (SNPs). Using a cohort of 746 community-dwelling older volunteers, we analysed REST genotype data both independently and in combination with the BDNF Val66Met polymorphism. A haplotype within the REST gene containing the four copy VNTR and a non-synonymous SNP showed a weak but significant association with a higher score of general intelligence ( P = 0.05). Analysis of this haplotype and the BDNF Val66Met polymorphism in combination showed a significant interaction (global P-value = 0.0003) with an additive increase in cognitive performance for those possessing the BDNF Val66 allele and the REST haplotype containing the four copy repeat ( P = 0.004). The REST haplotypes in combination with the BDNF Met66 polymorphism did not reduce cognitive performance more than the independent influence of the Met66 allele. Our results suggest that investigation of a common REST polymorphism may be necessary to help reduce contrasting reports based around BDNF Val66Met and cognition. [ABSTRACT FROM AUTHOR]

A functional brain-derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity-dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long-term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non-verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype-tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed ( P = 0.001), delayed recall ( P = 0.037) and general intelligence (g) ( P = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non-demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non-significant trend was observed. [ABSTRACT FROM AUTHOR]

Venous ulcers are characterized by excessive inflammation and raised levels of proinflammatory cytokines. Estrogen has been shown to accelerate the rate of wound healing in elderly subjects by dampening the inflammatory response. The estrogen receptor (ER) proteins, ER-alpha (ERα) and ER-beta (ERβ) mediate the actions of estrogen during wound repair through the activation or repression of target gene transcription. Recent evidence implicates the chromosomal region harboring the ERβ gene with venous ulceration in a British Caucasian population, highlighting the need to conduct further genetic interrogation. To address this, we conducted a case-control study to investigate whether single nucleotide polymorphisms in the ERβ gene are associated with venous ulceration in elderly (age >50 years) subjects. We recruited a case group ( n = 124, 56 males and 68 females) consisting of patients with an active venous ulcer and a control group consisting of individuals from the general population with no evidence of venous disease or history of venous ulceration ( n = 380, 189 males and 191 females). Polymorphisms in close proximity to upstream regulatory regions of the ERβ gene, including the 0N exon and promoter transcribed in inflammatory cells, were significantly (p < 0.05) associated with venous ulceration. A major susceptibility haplotype carried by 23% (26/112) of cases compared with only 10% (27/276) of controls (odds ratio = 2.8, 95% confidence interval = 1.6−5.0) was significantly (p < 0.01) associated with elevated serum levels of tumor necrosis factor-alpha. In conclusion, common variation in the regulatory regions of the ERβ gene may pre-dispose to venous ulceration in a British Caucasian population. [ABSTRACT FROM AUTHOR]

Objective: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent. Methods: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE ∈4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex. Results: The APOE ∈4 allele frequency (19.4%) was increased (p = 0.01 ) in FTLD v the whole control group (14.1%), while the APOE ∈2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE ∈4 allele frequency in men with FTLD (22.3%) was greater (p=0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE ∈2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE ∈2 nor APOE ∈4 allele frequency varied significantly between any of the clinical subtypes. Conclusions: In FTLD not associated with mutations in tau gene, possession of APOE ∈4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women. [ABSTRACT FROM AUTHOR]

Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P=0.002, AH2 P=0.014), the test of semantic memory (P=0.010) and general cognitive ability (P=0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly.Molecular Psychiatry (2005) 10, 1133–1139. doi:10.1038/sj.mp.4001733; published online 16 August 2005 [ABSTRACT FROM AUTHOR]

General intelligence is a heritable trait that is a risk factor for both the onset of dementia and the rate of cognitive decline in community-dwelling older persons. Previous studies screening for quantitative trait loci (QTLs) that influence general intelligence in healthy individuals have identified four loci, two of which are located within the genes insulin-like growth factor 2 receptor (IGF2R) and the Msx1 homeobox. Here, we report the finding of another QTL associated with general intelligence that is located within exon 2 of the cathepsin D (CTSD) gene. A group of 767 healthy adults with a follow-up period of over 15 years have been analyzed for cross-sectional and longitudinal trends in cognitive change using the Heim intelligence test score (AH4-1). We observed a significant association (P = 0.01) between a functional C > T (Ala > Val) transition within exon 2 of the CTSD gene that increases the secretion of pro-CTSD from the cell, and the AH4-1 score at initial testing on entry to the longitudinal study. Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome. [ABSTRACT FROM AUTHOR]

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C→T (224Ala→Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid β protein (Aβ), as plaque Aβ40 and Aβ42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Aβ40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Aβ40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Aβ42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Aβ deposited as senile plaques in the brain in the form of Aβ40. [ABSTRACT FROM AUTHOR]