The total number of subjects in each diagnostic category.

<p>(AD: Alzheimer’s disease; OD: Other dementia; AD/PD: Alzheimer’s disease with Parkinson’s disease; MCI: Mild cognitive impairment; PD: Parkinson’s disease; PD D: Parkinson’s disease with dementia; OPTIMA: Oxford Project to Investigate Memory and Ageing; PD GEN: Parkinson’s disease DNA bank).</p><p>The total number of subjects in each diagnostic category.</p

Odds ratios for disease in relation to the rare p21^cip1 variant.

<p>The OPTIMA and PD Gen cohorts were separated into groups defined by diagnosis based on the diagnostic criteria outlined in the methods. Odds ratios in relation to the p21^cip1 variant were calculated for the disease groups compared to age-matched controls.</p><p>Odds ratios for disease in relation to the rare p21^cip1 variant.</p

The effect of the p21^cip1 genotype on the age of onset of AD.

<p>Of the subjects with advanced AD at post-mortem, the subjects with the variant p21^cip1 had a significantly lower age of onset than subjects with the common p21^cip1 (p-value: 0.016). The x-axis represents the p21^cip1 genotype, with com and var representing subjects with the common and variant p21^cip1 respectively. The y-axis represents the age at onset of AD in years. The top of the bars represent the mean. The error bars represent the standard error of the mean (SEM). Statistical test: one-way ANOVA.</p

The allele frequency of the p21cip1 variant in groups defined by the severity of AD.

<p>The diagnosis was defined according to the Braak staging system: with entorhinal, limbic and neocortical stage subjects in a pre-clinical, mild and advanced stage of AD respectively.</p><p>The allele frequency of the p21cip1 variant in groups defined by the severity of AD.</p

Kaplan-Meier probability distribution of disease free survival prior to the age of 75.

<p>The disease in question was dementia in Parkinson’s disease. The graph shows the disease free survival probability of subjects prior to the age of 75, in subgroups defined by the p21^cip1 genotype. Prior to the age of 75, the variant p21^cip1 was significantly associated with a reduction in the disease free survival compared to the common p21^cip1 (hazard ratio: 3.239, p-value < 0.001). The x-axis represents the age in years. The y-axis represents the survival probability expressed as a percentage. The solid black line represents subjects that were homozygous for the common p21^cip1. The broken grey line represents subjects that were heterozygous or homozygous for the variant p21^cip1.</p

The effect of the p21^cip1 genotype on the spread of p-tau pathology in the brain.

<p>Panel A and B. The spread of p-tau pathology was defined as the ratio of the amount of p-tau in the region less severely affected by AD (Panel A: frontal lobe; Panel B: occipital lobe) over that in the more severely affected region (temporal lobe). Z-scores were calculated for the spread of p-tau taking into account the disease severity as defined by Braak, which eliminated the need for subgroups defined by the disease severity. The graphs show the mean z-scores of p-tau spread in subgroups defined by the p21^cip1 genotype. The x-axis represents the p21^cip1 genotype, with com and var representing subjects with the common and variant p21^cip1 respectively. The y-axis represents the spread of p-tau calculated from data determined by ELISA with a marker for AT8 (arbitrary units). The error bars represent the SEM. Statistical test: one-way ANOVA of z-scores.</p

The effect of the p21^cip1 genotype on the expression of p21^cip1.

<p>The graphs plot the amount of p21^cip1 protein expressed per cell (Panel A); the p21^cip1 protein density per nucleus (Panel B) and the percentage of nuclear positive cells (Panel C) of cells transfected with either the common or variant p21^cip1. Only cells that were positive for p21^cip1 protein, as determined by Acumen Cytometry, were included in the analysis. To allow comparison of the cells transfected with the different variants of p21^cip1, the expression of p21^cip1 in each transfected population was normalised to that in the common p21^cip1 transfected population. All results concerning p21^cip1 expression in the common population are therefore displayed as 100%. On the x-axis: com p21 represents cells transfected with common p21^cip1; var p21 represents cells transfected with variant p21^cip1. The y-axis represents the p21^cip1 protein expression per cell (Panel A), the p21^cip1 density per nucleus (Panel B), and the percentage of nuclear positive cells (Panel C) expressed as a percentage of that in the population transfected with common p21^cip1. The top of the bars represent the mean. The error bars represent the SEM. Analysis was carried out from 8 technical replicates of more than 5000 cells each.</p

Vitamin B-12 Status during Pregnancy and Child’s IQ at Age 8: A Mendelian Randomization Study in the Avon Longitudinal Study of Parents and Children

<div><p>Vitamin B-12 is essential for the development and maintenance of a healthy nervous system. Brain development occurs primarily <em>in utero</em> and early infancy, but the role of maternal vitamin B-12 status during pregnancy on offspring cognitive function is unclear. In this study we assessed the effect of vitamin B-12 status in well-nourished pregnant women on the cognitive ability of their offspring in a UK birth cohort (ALSPAC). We then examined the association of SNPs in maternal genes <em>FUT2</em> (rs492602) and <em>TCN2</em> (rs1801198, rs9606756) that are related to plasma vitamin B-12, with offspring IQ. Observationally, there was a positive association between maternal vitamin B-12 intake and child’s IQ that was markedly attenuated after adjustment for potential confounders (mean difference in offspring IQ score per doubling of maternal B-12 intake, before adjustment: 2.0 (95% CI 1.3, 2.8); after adjustment: 0.7 (95% CI −0.04, 1.4)). Maternal <em>FUT2</em> was weakly associated with offspring IQ: mean difference in IQ per allele was 0.9 (95% CI 0.1, 1.6). The expected effect of maternal vitamin B-12 on offspring IQ, given the relationships between SNPs and vitamin B-12, and SNPs and IQ was consistent with the observational result. Our findings suggest that maternal vitamin B-12 may not have an important effect on offspring cognitive ability. However, further examination of this issue is warranted.</p> </div

The effect of the p21^cip1 genotype on beta-actin expression.

<p>The graph shows the amount of beta-actin detected per cell expressed as a percentage change relative to the empty vector negative control. Beta-actin expression was determined by Acumen Cytometry with beta-actin immunostaining: with the total amount of beta-actin detected divided by the total number of cells in the sample. The cells were not double stained for p21^cip1 protein, so we were unable to differentiate the p21^cip1 positive population (transfected cells) from the p21^cip1 negative population (non-transfected cells). X-axis: EV NC: Empty vector negative control; com p21: cells transfected with common p21^cip1; var p21: cells transfected with variant p21^cip1. The y-axis represents the percentage change in beta-actin expression per cell relative to the EV NC. The top of the bars represent the mean. The error bars represent the SEM.</p

The ratio of p21^cip1 protein to mRNA in the cells transfected with the different variants of p21^cip1.

<p>The p21^cip1 protein and mRNA results were normalised to the equivalent value for beta-actin.</p><p>The ratio of p21^cip1 protein to mRNA in the cells transfected with the different variants of p21^cip1.</p