Neuropsychiatric symptoms and functional status in Alzheimer's disease and vascular dementia patients.

Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.

Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α for the treatment of asthma.

Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (7 nM) and was able to inhibit prostaglandin (PG)D(2) and cysteinyl leukotriene release from anti-IgE-stimulated human lung mast cells (0.29 and 0.45 nM, respectively). In a mixed human lung cell population, PF-5212372 was able to inhibit ionomycin-stimulated release of leukotriene B(4), thromboxane A(2), and PGD(2) (2.6, 2.6, and 4.0 nM, respectively) but was significantly less effective against PGE(2) release (>301 nM; p < 0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h after being washed off. In a sheep model of allergic inflammation, inhalation of PF-5212372 significantly inhibited late-phase bronchoconstriction (78% inhibition; p < 0.001) and airway hyper-responsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD(2) release (0.78 nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchi induced by AMP. PF5212372 significantly inhibited AMP-induced contraction of human bronchi (81% inhibition; p < 0.001); this finding, together with the ability of this drug to be effective in a wide range of preclinical asthma models, suggests that inhibition of cPLA(2)α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.

Pharmacological characterization of adenosine receptors on isolated human bronchi.

Adenosine induces airways obstruction in subjects with asthma, but the receptor subtype responsible remains unknown. The objectives of this study were to determine the pharmacological profile of adenosine receptor subtypes mediating contraction and to investigate the mechanism in normal and passively sensitized human airway tissues. Contraction of bronchial rings isolated from resected lung tissue of patients with lung carcinoma was measured in response to nonselective adenosine receptor agonists, 5-AMP and 5'-(N-Ethylcarboxamido)adenosine, and A(1) receptor agonist, N(6)-cyclopentyladenosine, in the absence and presence of selective adenosine receptor antagonists. Pharmacological antagonists, chemical ablation of airway sensory nerves using capsaicin, and passive sensitization of tissue with serum from subjects with atopy and asthma was used to investigate the mechanism of contraction. Human bronchial tissue contracted in a concentration-dependent manner to adenosine agonists that showed a rank order of activity of A(1) > A(2B) >> A2(A) = A3. The maximum contractile response to N(6)-cyclopentyladenosine (231.0 ± 23.8 mg) was significantly reduced in tissues chemically treated with capsaicin to desensitize sensory nerves (desensitized: 101.6 ± 15.2 mg; P < 0.05). Passive sensitization significantly augmented the contraction induced by adenosine A(1) receptor activation (sensitized: 389.7 ± 52.8 mg versus nonsensitized; P < 0.05), which was linked to the release of leukotrienes, and not histamine (MK571: 25.5 ± 1.7 mg; epinastine 260.0 ± 22.2 mg versus control; P < 0.05). This study provides evidence for a role for adenosine A(1) receptors in eliciting human airway smooth muscle constriction, which, in part, is mediated by the action of capsaicin sensitive sensory nerves.

Epithelium integrity is crucial for the relaxant activity of brain natriuretic peptide in human isolated bronchi.

BACKGROUND AND PURPOSE Brain natriuretic peptide (BNP) plays an important role in several biological functions, including bronchial relaxation. Here, we have investigated the role of BNP and its cognate receptors in human bronchial tone. EXPERIMENTAL APPROACH Effects of BNP on responses to carbachol and histamine were evaluated in non-sensitized, passively sensitized, epithelium-intact or denuded isolated bronchi and in the presence of methoctramine, N(ω) -nitro-L-arginine methyl ester (L-NAME) and aminoguanidine. Natriuretic peptide receptors (NPRs) were investigated by immunohistochemistry, RT-PCR and real-time PCR. Release of NO and acetylcholine from bronchial tissues and cultured BEAS-2B bronchial epithelial cells was also investigated. KEY RESULTS BNP reduced contractions mediated by carbachol and histamine, with decreased E(max) (carbachol: 22.7 ± 4.7%; histamine: 59.3 ± 1.8%) and increased EC(50) (carbachol: control 3.33 ± 0.88 µM, BNP 100 ± 52.9 µM; histamine: control 16.7 ± 1.7 µM, BNP 90 ± 30.6 µM); BNP was ineffective in epithelium-denuded bronchi. Among NPRs, only atrial NPR (NPR1) transcripts were detected in bronchial tissue. Bronchial NPR1 immunoreactivity was detected in epithelium and inflammatory cells but faint or absent in airway smooth muscle cells. NPR1 transcripts in bronchi increased after incubation with BNP, but not after sensitization. Methoctramine and quinine abolished BNP-induced relaxant activity. The latter was associated with increased bronchial mRNA for NO synthase and NO release, inhibited by L-NAME and aminoguanidine. In vitro, BNP increased acetylcholine release from bronchial epithelial cells, whereas NO release was unchanged. CONCLUSIONS AND IMPLICATIONS Epithelial cells mediate the BNP-induced relaxant activity in human isolated bronchi.

Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi.

BACKGROUND: Equine obstructive pulmonary disease, also known as heaves or recurrent airway obstruction (RAO) is a common equine pulmonary disease with some similarities to human asthma and COPD, which represents a major cause of morbidity and loss of lung performance. Salbutamol has been widely used for the treatment of human airway diseases and has usually been prepared as the racemic form of the drug. However, recently the R-enantiomer of salbutamol has been introduced into clinical practice in the treatment of asthma in humans and this has been suggested to be an improvement on the racemic form of the drug; therefore thus the S-enantiomer has been demonstrated to have adverse effects in the lung and thus using the R-enantiomer may improve the therapeutic ratio. However, little is known about the properties of the R- and S-enantiomers of salbutamol in equine airways and the present study has evaluated the relaxant effects of racemic ß(2)-agonists in comparison with the R- and S-enantiomers in isolated equine isolated bronchi, as well as the bronchoprotective effects of these drugs on cholinergic and histaminergic pathway. METHODS: We have studied the effects of the R- and S-enantiomers of salbutamol on bronchi isolated from RAO-affected or unaffected horses. The first study assayed the relaxant effects of R- and S-salbutamol on isolated bronchial rings contracted with carbachol or histamine at a sub-maximal concentration (EC70). A second study evaluated the effects of R- and S-salbutamol on semi-logarithmic cumulative concentration-response curves induced by carbachol or histamine. Specific software was used to calculate statistical significance and the appropriate sigmoidal curve-fitting model. RESULTS: Neither enantiomers of salbutamol caused a relaxant effect on the sub-maximal plateau contractile effects of carbachol; in fact, both R- and S-salbutamol induced a slight, but significant contraction (P ≤ 0.05) compared to the controls. In contrast, R-salbutamol induced a significant relaxation of bronchi pre-contracted with histamine (RAO-unaffected: 92.06% ± 2.00; RAO-affected 100.20 ± 3.99; P ≤ 0.01). S-salbutamol induced a weak relaxation (RAO-unaffected: 15.81% ± 5.65; RAO-affected 12.36 ± 5.15) when compared to that induced by papaverine. The incubation with either R- or S-salbutamol shifted rightward (P ≤ 0.001) the carbachol contraction curve in RAO-unaffected bronchi, but not in RAO-affected bronchi, compared to control tissues. R-salbutamol induced a reduction in E(max) values (C: 9.07 gr ± 0.68; R-salb.: 6.36 gr ± 0.21; P ≤ 0.01) in normal bronchi. On the contrary it reduced the histamine potency in RAO-affected bronchi (EC50 7.10 µM ± 0.35, P < 0.001). The incubation with S-salbutamol shifted leftward the histamine concentration curve in both normal bronchi (C: 7.00 µM ± 0.29; S-salb.: 2.25 µM ± 0.19; P ≤ 0.001) and bronchi from RAO-affected horses (C: 2.80 µM ± 0.26; S-salb.: 1.50 µM ± 0.80; P ≤ 0.05). CONCLUSION: Our studies have demonstrated that S-salbutamol elicited a modest increase in contraction of equine airway smooth muscle induced by carbachol and induced a significant hyperresponsiveness to histamine. These results confirm the ability of the S-enantiomer of salbutamol to potentiate the contractile effect of certain spasmogens on airway smooth muscle. Such an adverse effect would be determined in the airways of horses with RAO and suggest that if salbutamol is to be used in the treatment of symptoms of RAO in horses, the R-enantiomer, rather than the racemic mixture should be considered.

Angiotensin-converting enzyme (ACE) genotypes and disability in hospitalized older patients.

The association between angiotensin-converting enzyme (ACE) genotypes and functional decline in older adults remains controversial. To assess if ACE gene variations influences functional abilities at older age, the present study explored the association between the common ACE insertion/deletion (I/D) polymorphism and disability measured with activities of daily living (ADL) in hospitalized older patients. We analyzed the frequency of the ACE genotypes (I/I, I/D, and D/D) in a population of 2,128 hospitalized older patients divided according to presence or absence of ADL disability. Logistic regression analysis adjusted for possible confounding factors, identified an association between the I/I genotype with ADL disability (OR=1.54, 95% CI 1.04-2.29). This association was significant in men (OR=2.01, 95% CI 1.07-3.78), but not in women (OR=1.36, 95% CI 0.82-2.25). These results suggested a possible role of the ACE polymorphism as a genetic marker for ADL disability in hospitalized older patients.

Immunomodulatory impact of a synbiotic in T(h)1 and T(h)2 models of infection.

BACKGROUND AND METHODS: The immunomodulatory activity of a synbiotic combination containing three bacterial strains (Lactobacillus helveticus R0052, Bifidobacterium longum subsp. infantis R0033 and Bifidobacterium bifidum R0071) and short-chain fructooligosaccharide was examined in two distinct infectious rat models. In the T(h)1 model, Wistar rats were administered the synbiotic combination for 2 weeks prior to challenge with a single oral dose of enterotoxigenic Escherichia coli or vehicle. In the T(h)2 model, pretreated rats were challenged with a single subcutaneous dose of hook worm, Nippostrongylus brasiliensis. Blood samples were collected 3 hours or 4 days postchallenge and serum levels of pro- and anti-inflammatory cytokines were measured. RESULTS: Significant reductions in pro-inflammatory cytokines interleukin (IL)-1α, IL-1ß, IL-6, and tumour necrosis factor (TNF)-α were observed in both models suggesting a single, unifying mode of action on an upstream regulator. The N. brasiliensis study also compared the effect of the individual strains to synbiotic. For most of cytokines the combination appeared to average the effect of the individual strains with the exception of IL-4 and IL-10 where there was apparent synergy for the combination. Furthermore, the cytokine response varied by strain. CONCLUSIONS: It was concluded that this synbiotic combination of these three microbes could be beneficial in both T(h)1 and T(h)2 diseases.

Apolipoprotein E-related all-cause mortality in hospitalized elderly patients.

The most common apolipoprotein E (APOE) allelic variation is implicated in many age-related diseases and human longevity with controversial findings. We investigated the effect of APOE gene polymorphism on all-cause mortality in elderly patients taking into consideration the functional disability, cognitive impairment, malnutrition, and the occurrence of common age-related diseases. APOE genotypes were determined in 2,124 geriatric hospitalized patients (46.5% men and 53.5% women; mean age, 78.2 +/- 7.1 years; range, 65-100 years). At hospital admission, all patients underwent a comprehensive geriatric assessment to evaluate functional disability, cognitive status, nutritional status, and comorbidity. The main and secondary diagnoses at hospital discharge were also recorded. Mortality status was evaluated in all patients after a maximum follow-up of 5 years (range, from 1.26 to 5.23 years; median, 2.86 years). During the study period, 671 patients died (32.0%). At hospital admission, these patients showed a significant higher prevalence of cardiovascular diseases (56.3% vs 53.4%; p = 0.007), neoplasias (32.3% vs 13.7%; p < 0.001), and lower prevalence of neurodegenerative diseases (17.7% vs 20.7%; p < 0.001) than survived patients. Moreover, they also showed an higher prevalence of disability (52.0% vs 25.6%; p < 0.001), cognitive impairment (31.0% vs 18.8%; p < 0.001), and malnutrition (74.0% vs 46.1%; p < 0.001) than survived patients. In the overall study population, the APOE epsilon2 allele was significantly associated to neurodegenerative diseases (odds ratio = 0.59; 95% confidence interval (CI), 0.37-0.94). No significant association between the APOE polymorphism and disability, malnutrition, co-morbidity status, and with all-cause mortality was observed. In patients with cardiovascular diseases, however, a decreased risk of all-cause mortality was found in the epsilon2 allele carriers (hazard ratio = 0.56; 95% CI, 0.36-0.88). In this population, APOE allele variants might play a role on cardiovascular disease-related mortality.

Energy expenditure and impact of bronchodilators in COPD patients.

28 Consecutive COPD patients performed four 6-minute walking tests (6-MWTs) in 2 different days before and 2, 4 and 6h after the inhalation of formoterol 12microg or tiotropium 18microg, respectively. Physical activity during each 6-MWT was assessed by the SenseWear Armband. At each time also spirometry was performed. Both formoterol and tiotropium induced a significantly sustained bronchodilation and influenced hyperinflation. Formoterol significantly increased distance walked in 6min at 2h and at 4h, whereas tiotropium significantly increased it at all time points. There was a trend to an increase in calories and metabolic equivalents of task (METs) after formoterol and a decrease after tiotropium, but changes were not statistically significant. Total energy expenditure for each 6-MWT was not changed by formoterol, but decreased in significant manner 6h after the inhalation of tiotropium. Active energy expenditure at physical activity level of more than 3 METs decreased significantly after tiotropium at each 6-MWT, but not after formoterol. We did not find any significant correlation between the changes in lung function and those of parameters recorded with SenseWear Armband. Our study seems to indicate that tiotropium, but not formoterol, is able to reduce energy expenditure in COPD patients, although both drugs elicit significant bronchodilation and are able to increase the distance walked in 6min.

Arformoterol tartrate in the treatment of COPD.

Some basic scientific data suggest that (S)-enantiomers of beta(2)-agonists have different and sometimes opposing effects to (R)-enantiomers. These data may explain the paradoxical response of the airways to the repeated, chronic administration of racemic beta(2)-agonists. Therefore, it is possible that the use of (R)-enantiomers of beta(2)-agonists may be an alternative option to reduce the risks of long-term administration of inhaled long-acting agents. Arformoterol is the (R,R)-enantiomer of formoterol. It is currently available for use as a nebulized solution of arformoterol tartrate and is approved in the USA for twice-daily administration in patients with chronic obstructive pulmonary disease (COPD). Clinical trials in COPD patients have demonstrated that arformoterol is as effective in improving lung function and symptoms as other available long-acting inhaled beta(2)-agonists. Moreover, its safety for long-term administration has been documented in this population. These findings indicate that arformoterol is an effective option for patients with COPD who could benefit from sustained bronchodilation delivered through nebulization, and can be an alternative for patients who cannot use conventional inhaler devices, including metered-dose inhalers or dry-powder devices.

Roflumilast in chronic obstructive pulmonary disease: evidence from large trials.

IMPORTANCE OF THE FIELD: Chronic inflammation plays a central role in chronic obstructive pulmonary disease (COPD). Suppression of the inflammatory response is a logical approach to the treatment of COPD. Corticosteroids are highly effective as an anti-inflammatory treatment, but patients with COPD are poorly responsive to these drugs. The phosphodiesterase (PDE)-4 isoenzyme is a major therapeutic target in COPD because its inhibition increases intracellular cAMP concentrations, which ultimately results in reduction of cellular inflammatory activity. At present roflumilast is the most advanced PDE-4 inhibitor undergoing clinical trials for COPD. AREAS COVERED IN THIS REVIEW: In this paper, we describe the importance of roflumilast as an anti-inflammatory drug and critically review the results of four large trials with roflumilast in COPD (NCT00297102, NCT00297115, NCT00313209, NCT00424268). WHAT THE READER WILL GAIN: An unbiased description of trials that have explored the therapeutic effects of roflumilast in COPD. TAKE HOME MESSAGE: At the moment, roflumilast should only be considered as a second-line treatment, and the exact indication remains to be determined. Apparently, it should be reserved for patients who have frequent exacerbations despite treatment with inhaled bronchodilators. However, considering the high risk of adverse events induced by this drug, the published evidence seems to indicate limiting its use to the treatment of patients suffering from very severe COPD.

Novel bronchodilators in asthma.

PURPOSE OF REVIEW: Because of the central role of bronchodilators in the treatment of asthma, in recent years there has been a renewed interest in the field and now once-daily bronchodilators are in development in an attempt to simplify their use. RECENT FINDINGS: A variety of beta2-agonists with long half-lives, also called ultra long-acting beta2-agonists (ultra-LABAs; indacaterol, carmoterol, milveterol, GSK-642444, BI-1744-CL, LAS-100977, and PF-00610355) are currently under development with the hopes of achieving once-daily dosing. Between them, indacaterol, GSK-642444, and carmoterol are at a more advanced stage of development. Also several novel inhaled long-acting antimuscarinic agents are currently being developed, but their role in the treatment of asthma is limited. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is considered the first-line approach for treating patients suffering from asthma, some novel once-daily combinations of LABAs and ICSs are under development. SUMMARY: Bronchodilators are central in the symptomatic management of asthma. It is likely that the once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes in patients with asthma. In any case, as a LABA in combination with an ICS continues to be the most effective asthma treatment, once-daily combinations of ultra-LABAs and ICSs will be central in the treatment of asthmatic patients in the next years.

Association of apolipoprotein E and angiotensin converting enzyme gene polymorphisms with the multidimensional impairment in older patients.

The role of the apolipoprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy-Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of epsilon4 allele and the ACE D/D genotype was observed. The APOE epsilon4(+) and ACE D/D genotypes were associated with severe MPI grade (APOE epsilon4(+), odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20-2.67; ACE D/D, OR = 1.42, 95% CI 1.05-1.92). The combined APOE epsilon4(+) and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75-4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive.

Survival in Alzheimer's disease is shorter in women carrying heterozygosity at codon 129 of the PRNP gene and no APOE epsilon 4 allele.

We assessed the role of the APOE genotype and prion protein polymorphism at codon 129 in predicting the clinical duration of 92 neuropathologically confirmed sporadic Alzheimer's disease patients. Analyses of survival showed that the absence of the APOE epsilon 4 allele in heterozygous codon 129 PRNP carriers is a negative predictor of survival. When this subgroup of patients was stratified by sex, the effect of APOE was observed in women, but not in men.

Targeting systemic inflammation: novel therapies for the treatment of chronic obstructive pulmonary disease.

The increasing evidence that inflammation in the lungs leads to the structural changes observed in chronic obstructive pulmonary disease, whereas extrapulmonary symptoms and comorbidities may be systemic manifestations of these inflammatory processes, highlights an urgent need to discover novel, effective anti-inflammatory treatments for this disease. Some studies are suggesting that, by decreasing dynamic hyperinflation, bronchodilators might reduce systemic inflammation; inhaled corticosteroids and their combination with long-acting beta2-agonists might contribute to this goal. Even so, the opinion that suppression of the inflammatory response might improve systemic complications is stimulating a search for novel anti-inflammatory therapies. Many drugs include those that inhibit the recruitment and activation of inflammatory cells and/or antagonise their products. However, many of these therapeutic strategies are not specific for neutrophilic inflammation because they affect other cell types, thus, it is difficult to interpret whether any clinical benefit observed is a result of a reduction in airway neutrophils. In any case, there is some evidence that drugs used to treat a co-morbid condition, such as statins, angiotensin converting enzyme (ACE) inhibitors and angiontensin II type 1 (AT1) receptor blockers as well as glycosaminoglycans and peroxisome proliferator-activated receptor (PPAR) agonists, might benefit chronic obstructive pulmonary disease patients because they deal with the extrapulmonary, systemic component of chronic obstructive pulmonary disease.

Lack of association between genetic variants in the mannose-binding lectin 2 (MBL2) gene and HPV infection.

Genetic variants in the immunomodulatory gene mannose-binding lectin 2 (MBL2), were associated with risk, severity, and frequency of viral infections. In a case-control setting, we investigated the association of MBL2 functional polymorphisms with Human Papillomas Virus (HPV) infection. No differences between cases (HPV(+)) and controls (HPV(-)) were found in the distribution of each single genotypes or allele. Haplotype analysis did not show any difference between HPV+ and HPV(-) groups.

Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy.

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity.