Measuring selection in contemporary human populations.

Are humans currently evolving? This question can be answered using data on lifetime reproductive success, multiple traits and genetic variation and covariation in those traits. Such data are available in existing long-term, multigeneration studies - both clinical and epidemiological - but they have not yet been widely used to address contemporary human evolution. Here we review methods to predict evolutionary change and attempts to measure selection and inheritance in humans. We also assemble examples of long-term studies in which additional measurements of evolution could be made. The evidence strongly suggests that we are evolving and that our nature is dynamic, not static.

Colloquium papers: Natural selection in a contemporary human population.

Our aims were to demonstrate that natural selection is operating on contemporary humans, predict future evolutionary change for specific traits with medical significance, and show that for some traits we can make short-term predictions about our future evolution. To do so, we measured the strength of selection, estimated genetic variation and covariation, and predicted the response to selection for women in the Framingham Heart Study, a project of the National Heart, Lung, and Blood Institute and Boston University that began in 1948. We found that natural selection is acting to cause slow, gradual evolutionary change. The descendants of these women are predicted to be on average slightly shorter and stouter, to have lower total cholesterol levels and systolic blood pressure, to have their first child earlier, and to reach menopause later than they would in the absence of evolution. Selection is tending to lengthen the reproductive period at both ends. To better understand and predict such changes, the design of planned large, long-term, multicohort studies should include input from evolutionary biologists.

Constraints on the coevolution of contemporary human males and females.

Because autosomal genes in sexually reproducing organisms spend on average half their time in each sex, and because the traits that they influence encounter different selection pressures in males and females, the evolutionary responses of one sex are constrained by processes occurring in the other sex. Although intralocus sexual conflict can restrict sexes from reaching their phenotypic optima, no direct evidence currently supports its operation in humans. Here, we show that the pattern of multivariate selection acting on human height, weight, blood pressure and glucose, total cholesterol, and age at first birth differs significantly between males and females, and that the angles between male and female linear (77.8 ± 20.5°) and nonlinear (99.1 ± 25.9°) selection gradients were closer to orthogonal than zero, confirming the presence of sexually antagonistic selection. We also found evidence for intralocus sexual conflict demonstrated by significant changes in the predicted male and female responses to selection of individual traits when cross-sex genetic covariances were included and a significant reduction in the angle between male- and female-predicted responses when cross-sex covariances were included (16.9 ± 15.7°), compared with when they were excluded (87.9 ± 31.6°). We conclude that intralocus sexual conflict constrains the joint evolutionary responses of the two sexes in a contemporary human population.

Exercise and cognition: results from the National Long Term Care Survey.

BACKGROUND: Age remains a robust risk factor for Alzheimer's disease as well as other dementias. Therefore, the aging of the population in the United States will result in dramatic increases in the prevalence of dementia if preventative interventions are not identified. The aim of this study was to examine potential associations between exercise and lowering the risk of cognitive impairment. METHODS: National Long Term Care Survey data were used. Level of exercise participation was measured at baseline (1994) and cognitive impairment status was measured at baseline and 5- and 10-year follow-up. Linear regression was performed, controlling for age, sex, education, baseline score on cognitive test, diabetes, and hypertension. RESULTS: At 10-year follow-up, the number of different types of exercises performed was inversely associated with the onset of cognitive impairment (P = .002) as was the number of exercise sessions lasting at least 20 minutes (P = .007). CONCLUSION: Study results from National Long Term Care Survey data provide evidence supporting the potential for exercise to lower the risk of dementia.

Rate of decline in Alzheimer disease measured by a Dementia Severity Rating Scale.

OBJECTIVE: To measure clinically relevant change in Alzheimer disease (AD) using a family member-completed Dementia Severity Rating Scale (DSRS) questionnaire. BACKGROUND: Measuring rate of change provides important clinical information. Most neuropsychologic scores change nonlinearly, complicating their use as a predictor of change throughout the illness. METHODS: DSRS and Mini Mental State scores were prospectively collected on 702 patients with AD from first evaluation until they became too impaired to return to clinic. RESULTS: DSRS score increased an average of 4.48 points/y [95% confidence interval (CI): 4.14-4.82] throughout the entire range of severity. In contrast, the Mini Mental State declined an average of 2.15 points/y (95% CI: 1.85-2.46) during the first 2 years, accelerated to 3.83 points/y (95% CI: 3.28-4.38) during the subsequent 3 years, and then slowed to an annual decline of 1.63 points during the last 2 years (95% CI: 0.21-3.05). A younger age of symptom onset was associated with an increased rate of DSRS change (P=0.03). CONCLUSIONS: The DSRS provides a clinical measure of functional impairment in AD that increases about 4.48 points/y from the earliest symptomatic stage until patients become too severely impaired to return to clinic.

Differences in the association between apolipoprotein E genotype and mortality across populations.

BACKGROUND: The gene for apolipoprotein-E (APOE) has three common alleles (epsilon2, epsilon3, and epsilon4) that have been shown to be associated with differences in the risk of death in persons older than 60 years in European populations. However, previous research suggests that they may not be associated with mortality in African Americans, and the evidence in Asians is mixed. It is now possible to examine the effects of these genotypes on mortality in African American, Chinese, Japanese, and Korean populations. METHODS: The analysis is based on two types of published data: genotype by age and mortality by genotype. Demographic synthesis uses a multistate model to combine data from these case-control and cohort studies to provide maximum likelihood estimates of the relative risks of death. RESULTS: In general, the APOE epsilon2 allele is associated with 5%-10% lower mortality than the epsilon3/3 genotype. The epsilon4/4 allele is generally associated with a moderately high relative risk of death. The epsilon3/4 genotype is associated with 22% excess risk in Europeans and U.S. whites and with about 35% in Chinese. However, there is no evidence of excess risk with epsilon3/4 among African Americans and little excess risk among Japanese and Koreans. The relationship between genotype and mortality is consistent within these ethnic groups. For example, the estimates of R(3/4) for Japanese in Japan and Hawaii are both low, and the estimates for Chinese in Taiwan and Shanghai are relatively high. CONCLUSIONS: . The relationship between APOE genotype and mortality differs across population groups but shows little evidence of variation within groups.

Measuring selection in human populations using the growth rate per generation.

Estimates of the speed of evolution between generations depend on the association between individual traits and a measure of fitness. The two most frequently used measures of fitness are the net reproduction rate and the 1-year growth factor implied by the fertility and mortality rates. Results based on the two lead to very different results. The reason is that the 1-year growth factor is not a measure of change between generations. Therefore, studies of changes between generations should use the amount of growth over the length of a generation. This is especially important for studies of human populations because of the long length of generation. In addition, estimates based on a single year's growth are overly sensitive to data on individuals who fail to reproduce. The effects of using a generational measure are demonstrated using data from Kenya and Ukraine. These results demonstrate that using a 1-year growth rate to measure fitness leads to estimates that understate the rate at which evolution changes the characteristics of a human population.

Earlier onset of Alzheimer disease symptoms in latino individuals compared with anglo individuals.

BACKGROUND: Latino individuals are the largest minority group and the fastest growing population group in the United States, yet there are few studies comparing the clinical features of Alzheimer disease (AD) in this population with those found in Anglo (white non-Latino) patients. OBJECTIVE: To compare the age at AD symptom onset in Latino and Anglo individuals. DESIGN: Cross-sectional assessment using standardized methods to collect and compare age at AD symptom onset, demographic variables, and medical variables. SETTING: Five National Institute on Aging-sponsored Alzheimer's Disease Centers with experience evaluating Spanish-speaking individuals. PATIENTS: We evaluated 119 Latino and 55 Anglo patients who had a diagnosis of AD. MAIN OUTCOME MEASURE: Age at symptom onset. RESULTS: After adjusting for center, sex, and years of education, Latino patients had a mean age at symptom onset 6.8 years earlier (95% confidence interval, 3.5-10.3 years earlier) than Anglo patients. CONCLUSIONS: An earlier age at symptom onset suggests that US mainland Latino individuals may experience an increased burden of AD compared with Anglo individuals. The basis for the younger age at symptom onset remains obscure.

Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?

BACKGROUND: Tau and beta-amyloid (Abeta) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific pathology, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects. OBJECTIVES: To correlate antemortem cerebrospinal fluid (CSF) tau and Abeta levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Abeta. DESIGN: Prospective study. SETTING: Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects. MAIN OUTCOME MEASURES: Correlation of CSF tau and Abeta with final diagnosis. RESULTS: Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Abeta42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL). CONCLUSIONS: Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean +/- 2 SDs of the cognitively normal cohort.

The APOE gene and differences in life expectancy in Europe.

Common alleles of the apolipoprotein-E gene (APOE) are associated with different risks of ischemic heart disease, Alzheimer's disease, and other chronic conditions in European populations. Also, the APOE allele frequencies vary widely among European countries. We estimated the proportion of differences in mortality and differences in life span that are attributable to differences in APOE allele frequencies in Europe. Mortality rates by age, sex, and APOE genotype for six countries (Denmark, Finland, France, Italy, the Netherlands, and Sweden) were used to standardize mortality rates to the allele frequencies in Italy. Differences in APOE allele frequencies explain 12%-17% of the variation among these countries in mortality in people older than 65 years and 1%-2% of the variation in life span in those older than 65 years. Differences by genotype in mortality in people older than 15 years account for about 3.5% of the genetic contribution to the variation in life span in Denmark.

The Impact of Exercise, Cognitive Activities, and Socialization on Cognitive Function: Results From the National Long-Term Care Survey.

Currently, there are no effective treatments for Alzheimer's disease and related disorders and age continues to be a robust risk factor. Thus, population aging in the United States may have catastrophic results if interventions are not found and implemented. This study examines possible associations between cognitive impairment and exercise, cognitive activities, and socialization. Cognitive activities, socialization, and exercise were assessed at baseline, and cognitive function was measured at baseline, 5-year, and 10-year follow-up. Controlling for baseline cognitive function, age, sex, education, diabetes, and hypertension, linear regression was performed. Engagement in cognitive activities was inversely associated with the onset of cognitive impairment at 5-year follow-up but was no longer significant at 10-year follow-up. Exercise was associated with a lower risk of cognitive impairment at 10-year follow-up but was not significant at 5-year follow-up. Associations with socialization were not statistically significant at either follow-up.

A multistate model of the genetic risk of Alzheimer's disease.

The risk of Alzheimer's disease (AD) increases rapidly with age. It is not clear whether this increase continues at the very oldest ages. A slowing of the rate of increase in risk could result from heterogeneity associated with genetic or other risk factors. This study models explicitly the effect of heterogeneity of risk on the age pattern of incidence of AD. The model is fitted to published data from five prevalence studies and nine studies of AD risk by genotype for the apolipoprotein-E (APOE) gene. The model suggests that the prevalence of AD among white males at age 100 is 41.5%. Heterogeneity in the risk of AD causes the incidence rate to level off at about 11.7% per year at age 102. Some of the heterogeneity of risk is due to differences by APOE genotype. The model estimates that at age 80, the epsilon3/4 genotype is associated with an incidence rate 3.40 times that of those with the epsilon3/3 genotype. The epsilon4/4 genotype is associated with a relative risk of 9.4. Carriers of the epsilon2 allele have a risk that is only 43% of the risk among the epsilon3/3. There is substantial variation in risk associated with unobserved risk factors. Within each APOE genotype, the coefficient of variation of risk is about 1.09. In addition, the model estimates that about 0.20% of the population carries genes that cause AD at very early ages, through mechanisms that are not associated with the APOE genotype.

Mortality differences by APOE genotype estimated from demographic synthesis.

The 4 allele of apolipoprotein E (APOE) is associated with increased risk of two major causes of death in low-mortality populations: ischemic heart disease and Alzheimer's disease. It is less common among centenarians than at younger ages. Therefore, it is likely that it is associated with excess risk of death. This article extends demographic models that estimate relative mortality risks from changes in gene frequencies with age. The resulting demographic synthesis combines gene frequencies with data on mortality by genotype from cohort studies. The model was applied to data from Denmark, Finland, France, Italy, Sweden, and the United States. Near age 50, the 3/4 genotype is associated with a risk of death of 1.34 times that of the 3/3 (95% CI 1.18-1.67). The relative risk for 4/4 is the square of the relative risk for 3/4, 1.81. The 2/3 genotype is protective with a relative risk of 0.84 (0.68-0.93) near age 50. These relative risks move toward 1.0 at the oldest ages and APOE genotype is associated with little variation in mortality over age 100. There are no significant differences in the relative risks by sex. There is little evidence of differences within Europe in the effects of APOE. This approach can be generalized to combine data on genetic risk factors for disease from a wide variety of study designs and sample characteristics.