The aim of the study was to investigate whether possession of the epsilon4 allelic form of the apolipoprotein E (APOE) gene increases the risk of developing vascular dementia (VaD).
APOE allele and ...genotype frequencies were determined by PCR in 89 patients with possible and probable VaD and compared with those in 97 patients with possible and probable Alzheimer's disease (AD) of similar age of disease onset and ethnic background, and with 766 control subjects drawn from the same geographical region.
The APOE epsilon4 allele frequency in all 97 patients with possible and probable AD was significantly higher (p < 0.001) than that in control subjects. However, the APOE epsilon4 allele frequency in all 89 patients with possible and probable VaD was also significantly higher (p < 0.001) than that in control subjects, but not significantly different from that in AD. The APOE epsilon4 allele frequency was similarly, and still significantly (p < 0.001), increased when only those patients with probable AD or probable VaD were considered.
Possession of APOE epsilon4 allele increases the risk of VaD.
Cognitive impairment occurs in at least 10% of community-dwelling people aged 65 years and over and accounts for 35% of disabilities in England and Wales. The determination of genes that influence ...both cognitive ability and its decline with age may allow the identification of individuals predisposed to developing cognitive disability, and early trea™ent of "high-risk" individuals could even delay or prevent impairment. A clearer understanding of the biological pathways involved in cognitive functions may also provide new routes for drug development. In an increasingly long-lived population this research has clear social and economic relevance. The term general intelligence (g) is an artificial construct used to describe the relationships between diverse measures of cognitive abilities such as processing speed, vocabulary and memory. Twin and family-based studies have shown that general intelligence and its decline with age has a strong genetic component. Despite general intelligence being a heritable trait, only a small number of genes have been reported and no reports have yet been confirmed using a sufficiently powered cohort. I have screened several genes that comprise cholinergic muscarinic 2 receptor (CHRM2), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and insulin-like growth factor 2 receptor (IGF2R) for polymorphisms using an automated dHPLC technique (WAVE technology). I have identified 4 single nucleotide polymorphisms (SNPs) in the CHRM2 gene, 22 SNPs in the ChAT/VAChT locus and 13 SNPs in the IGF2R genes. Genotyping of these polymorphisms and also polymorphisms in the apolipoprotein E (APOE) and cathepsin D (CTSD) genes was performed using a group of over 750 healthy older volunteers that have been analysed for cross sectional and longitudinal trends in cognitive ability over a period of at least 10 years using two extensive batteries of cognitive tests that differentiated general fluid intelligence, vocabulary, processing speed and multiple domains of memory. A preliminary analysis of dopaminergic (dopamine receptor D4, dopamine hydroxylase, dopamine transporter, adrenergic receptor 2A) and inflammatory genes (interleukin-la, interleukin-1β (IL-1β), human leukocyte antigen (HLA) DRB1, and endothelial nitric oxide synthase genes) was also performed using a randomly selected subgroup of 170 healthy older volunteers that were selected from the total cohort. Using cross sectional analysis I observed that a functional CTSD exon 2 C>T polymorphism is associated with general fluid intelligence and processing speed. Also of interest was the finding that common haplotypes in the CHRM2 gene were significantly associated with picture recognition ability and coding memory. Finally, in men but not in women, the IL-1β -511 T allele was associated with reduced semantic memory, verbal memory and processing speed but not vocabulary ability or fluid intelligence. Preliminary longitudinal analysis comparing CTSD and APOE genotype against the rate of decline of general fluid intelligence found no association. My results suggest that intelligence genes may function in a cognitive domain-specific and/or a sex-specific manner.
The age distribution of the epsilon4 allelic form of the apolipoprotein E gene (APOE) was investigated in 630 patients with Alzheimer's disease (AD) with onset age ranging from 35 to 90 years. ...Overall, mean age at onset in APOE epsilon4 allele bearers was significantly later than that in nonbearers. However, when stratified into early onset AD (EOAD) and late onset (LOAD) groups, mean age at onset in EOAD cases bearing APOE epsilon4 allele was later than that in those EOAD cases without epsilon4 allele, whereas in LOAD mean age at onset in cases bearing APOE epsilon4 allele was earlier than in those without epsilon4 allele. When analysed by decade, it was observed that 37% of the total number of APOE epsilon4 allele bearers, and 43% of total number of cases with APOE epsilon4/epsilon4 genotype fell into the 60-69 years age class. Hence, APOE epsilon4 allele frequency, at 0.44, was highest in the 60-69 years age class, progressively decreasing either side of this age group. APOE epsilon4 allele therefore has its maximum impact between onset ages of between 60 and 70 years.
Evening-oriented sleep timing preferences have been associated with risk of diabetes, cardiovascular diseases, obesity, psychiatric disorders, and increased mortality. This research aims to explore ...the relationship between diurnal preferences (chronotype), daily habits, metabolic health, and mortality, using longitudinal data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (6375 participants at inception, recruited in the North of England) with a long follow-up period (up to 35.5 years). Mixed models were used to investigate the influence of aging, socio-demographic, and seasonal factors on sleep timing. Results show that sleep timing shifted towards earlier time with aging. Test seasons influence chronotype of older adults but working schedules challenge seasonality of sleep timing. Moreover, the season of birth may set chronotype in adulthood. Individual chronotype trajectories were clustered using latent class analysis and analyzed against metabolic health and mortality. We observed a higher risk of hypertension in the evening-type cluster compared to morning-type individuals (Odds ratio = 1.88, 95%CI = 1.02/3.47, p = .04). Evening-type cluster was also associated with traits related to lower health such as reduced sport participation, increased risk of depression and psychoticism personality, late eating, and increased smoking and alcohol usage. Finally, Cox regression of proportional hazards was used to study the effects of chronotype on longevity after adjusting for sleep duration, age, gender, smoking, alcohol usage, general health, and social class. The survival analysis (82.6% censored by death) revealed that evening-type chronotype increased the likelihood of mortality (Hazard ratio = 1.15, 95%CI = 1.04/1.26, p = .005). Taken together, chronotype is influenced by aging and seasonal effects. Evening-type preference may have detrimental outcomes for human well-being and longevity.
There has been a recent resurgence in interest in the role of autoimmunity in childhood neuropsychiatric disorders. Significant association between HLA-DRB1 and attention deficit hyperactivity ...disorder (ADHD) in a case-control study of 31 subjects has been reported but there have been no other published studies following up these results. We attempted to replicate these findings.
In a well-characterized sample of 173 children with ADHD, using a fully automated sequence-specific oligonucleotide method for HLA genotyping, association between ADHD and HLA-DRB1 was tested for using the Transmission Disequilibrium Test and case-control analysis.
Transmission Disequilibrium Test analysis yielded a chi-square of 10.694 with a simulated global P value of 0.1641 for the full sample, and a chi-square value of 11.307 with a simulated global P value of 0.1323 for the complete trios only.
There was no evidence of association of HLA-DRB1 and ADHD.
Onchocerciasis is associated with a spectrum of cutaneous changes, ranging from clinically normal skin to acute and chronic pathology. An important aspect of disease expression may be the level of ...immune response to parasite antigens, which is likely to be regulated by MHC-encoded molecules. We therefore investigated HLA class I and class II phenotypes in Nigerian residents of an area endemic for onchocerciasis. All study subjects were carefully characterized for parasite load and skin pathology. Individuals with depigmentation had increased frequencies of DQA1∗0501 and DQB1∗0301 compared with persons with normal skin and high microfilarial load (NSHMF) (Odds Ratios 3.6 (95% CI 1.0 to 13.2) and 3.8 (1.0 to 15.2), respectively). Conversely, individuals with depigmentation had a decreased frequency of DQA1∗0101 and Cw6 compared with NSHMF (Odds Ratios 0.2 (0.1 to 0.9) and 0.1 (0.02 to 0.8), respectively). When NSHMF subjects were examined by age, a further decrease in DQA1∗0501 frequency and increase in DQA1∗0101 frequency were observed in older NSHMF individuals. These results strongly suggest that there is an immunogenetic basis for the spectrum of cutaneous presentations in onchocerciasis and that HLA-DQ molecules are associated with the level of immune response to parasite antigens.
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