Association of APOE epsilon2/epsilon3/epsilon4 and promoter gene variants with dementia but not cardiovascular mortality in old age.

The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE epsilon4 allele were associated with a 4.1-fold (95% CI, 2.2-7.7) increased risk of dementia as compared to the epsilon3/epsilon3 genotype in old subjects. Moreover, homozygosity for the -219T allele was found to be associated with a 2.4-fold (95% CI, 1.0-5.8) increased risk independently of epsilon2 and epsilon4; the -491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among epsilon4 carriers (RR, 0.6; 95% CI, 0.4-1.0) or -219T homozygous subjects (RR, 1.1; 95% CI, 0.7-1.7), nor did it decrease among -491T homozygous subjects (RR, 1.4; 95% CI, 0.6-3.1). In conclusion, both the APOE epsilon2/epsilon3/epsilon4 and the -219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age.

A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics.

BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.

Geriatric conditions in acutely hospitalized older patients: prevalence and one-year survival and functional decline.

BACKGROUND: To study the prevalence of eighteen geriatric conditions in older patients at admission, their reporting rate in discharge summaries and the impact of these conditions on mortality and functional decline one year after admission. METHOD: A prospective multicenter cohort study conducted between 2006 and 2008 in two tertiary university teaching hospitals and one regional teaching hospital in the Netherlands. Patients of 65 years and older, acutely admitted and hospitalized for at least 48 hours, were invited to participate. Eighteen geriatric conditions were assessed at hospital admission, and outcomes (mortality, functional decline) were assessed one year after admission. RESULTS: 639 patients were included, with a mean age of 78 years. IADL impairment (83%), polypharmacy (61%), mobility difficulty (59%), high levels of primary caregiver burden (53%), and malnutrition (52%) were most prevalent. Except for polypharmacy and cognitive impairment, the reporting rate of the geriatric conditions in discharge summaries was less than 50%. One year after admission, 35% had died and 33% suffered from functional decline. A high Charlson comorbidity index score, presence of malnutrition, high fall risk, presence of delirium and premorbid IADL impairment were associated with mortality and overall poor outcome (mortality or functional decline). Obesity lowered the risk for mortality. CONCLUSION: Geriatric conditions were highly prevalent and associated with poor health outcomes after admission. Early recognition of these conditions in acutely hospitalized older patients and improving the handover to the general practitioner could lead to better health outcomes and reduce the burden of hospital admission for older patients.

Measuring the cost-effectiveness of lipid-lowering drugs in the elderly: the outcomes research and economic analysis components of the PROSPER trial.

Little information exists to quantify the functional status and economic consequences of lipid-lowering therapy in elderly patients. We describe the design of the cost-effectiveness component of the first large, randomized, placebo-controlled trial of lipid-lowering therapy in subjects aged 70 years or older. The PROspective Study of Pravastatin in the Elderly at Risk has randomized 5804 men and women 70-82 years old, with existing vascular disease or related risk factors, to receive 40 mg/d of pravastatin or placebo. The cost-effectiveness study will be based on within-trial observations of differences between the two study arms in rates of myocardial infarction, stroke and related vascular disease outcomes (including vascular dementia). In addition to comparing within-trial clinical outcomes, we will model the projected changes in life expectancy and cardiovascular outcome rates that would be seen with lifelong use of the drug, based on the risk reduction rates seen in the trial as well as baseline observational data from the three countries where the trial is being conducted (Scotland, Ireland and the Netherlands). A state transition (Markov) model will be constructed to estimate the likely states of health, functional status and health care resource utilization (including lipid-lowering drug costs) in a cohort of elderly patients with versus without pravastatin therapy over a series of 1-year cycles until death. In addition, a standard measure of utility (the Health Utilities Index) will be administered to all study subjects to permit calculation of quality-adjusted life-years gained with this regimen. This approach will make it possible to go beyond the calculation of a single endpoint for each subject, and to translate the trial findings into definitions of effectiveness and outcomes that will be relevant to the ongoing debate concerning how best to relate the benefits of such medications to their costs.