Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

The chronology of hemoconcentration and hemodilution associated with changes in posture, and the reliability of venous hematocrit (Hct), hemoglobin (Hb), and plasma proteins (PP) as indicators in evaluating changes in plasma volume were determined in seven male subjects. Red cell mass was also measured by the CO method at the termination of the erect and supine positions. Movement to and from supine and erect positions produced consistent, rapid, and progressive changes in Hct, Hb, and PP. Thirty-five minutes in a supine position resulted in a 440-ml expansion of plasma volume. Resumption of the standing position resulted in an increase of 10.3 and 10.8% for Hct and Hb, respectively, and an increase in PP of 20.8%. A fluid efflux of 593 ml reduced blood and plasma volume by 9.5 and 16.2%, respectively. Red cell mass was unaffected by changes in posture. The significance of these postures on the reported alterations in plasma volumes consequent to the imposition of stresses on man are discussed.

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To delineate age- and gender-related differences in physiological responses to cold exposure, men and women between the ages of 20 and 29 yr and 51 and 72 yr, wearing minimal clothing, were exposed at rest for 2 h to 28, 20, 15, and 10 degrees C room temperatures with 40% relative humidity. During the coldest exposure, the rates of increase in metabolic rate (W X m-2 or ml X kg lean body mass-1 X min-1 were similar for all groups. However, older women (n = 7) may have benefited from a larger (P less than 0.05) early metabolic (M) increase (40% within 15 min) than young men (18%) (n = 10), young women (5%) (n = 10), or older men (5%) (n = 10). A similar rapid M response in older women occurred during the 15 degrees C exposure. During all cold exposures, older women maintained constant rectal temperature (Tre) and young women maintained Tre only during the 20 degrees C exposures, whereas Tre of the men declined during all cold exposures (P less than 0.01). Changes in Tre and mean skin temperature (Ts) during cold exposure were largely related to body fat, although age and surface area/mass modified the changes in men. The data suggest that older men are more susceptible to cold ambients than younger people, since they did not prevent a further decline in their initially relatively low Tre. Despite greater insulation from body fat, the older women maintained a constant Tre at greater metabolic cost than men or younger women.