A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Different sodium requirements for 86Rb efflux and for growth hormone and prolactin secretion from bovine anterior pituitary cells.

The sodium dependence of growth hormone and prolactin secretion and of 86Rb efflux from bovine anterior pituitary cells in response to acetylcholine and TRH was examined. Decreasing the external sodium concentration prevented the increases in the rates of 86Rb efflux and of growth hormone secretion caused by acetylcholine, or by TRH in the presence of IBMX. The growth hormone secretory response was less sensitive to sodium removal than was 86Rb efflux. However, even complete removal of extracellular sodium did not affect TRH-induced prolactin secretion. Ouabain and low extracellular potassium, which inhibit the sodium pump and increase intracellular sodium, prolonged the secretion of growth hormone in response to acetylcholine, but TRH-induced prolactin secretion was not affected. Inhibition of the sodium pump speeded the decline in the 86Rb efflux rate following stimulation by both acetylcholine and TRH. The results suggest that a sodium-dependent step is necessary for the efflux of 86Rb and for growth hormone secretion but not for prolactin secretion. The possible relationship between 86Rb efflux and hormone secretion from lactotrophs and somatotrophs is discussed.

Inhibition by dopamine of 86Rb efflux and hormone secretion from bovine anterior pituitary cells perifused in the presence of acetylcholine or TRH.

The effects of dopamine (10(-5) M) on growth hormone and prolactin secretion and the fractional rate of 86Rb efflux were investigated using perifused bovine pituitary cells. Dopamine decreased the control efflux rate, prevented the rise caused by thyroliberin (10(-7) M) in the presence of 3-isobutyl-1-methylxanthine (10(-4) M) and greatly decreased the rise caused by acetylcholine (2.5 x 10(-5) M). Under these conditions it inhibited the prolactin secretion but it had no effect on growth hormone secretion induced by either treatment. Dopamine receptors in lactotrophs are therefore coupled to secretion and potassium permeability, but if somatotrophs contain dopamine receptors they are coupled only to K+ efflux.