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Eric B Larson

Publications and source records attributed to Eric B Larson.

At least 19 recordsLinked to original sources
PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-&#x3b2; 42 (A&#x3b2;42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF A&#x3b2;42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In A&#x3b2;42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p&#x2009;=&#x2009;0.04) and rs13115400 near LINC00290 (p&#x2009;=&#x2009;0.002). These loci showed stronger associations among females (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.03, p&#x2009;=&#x2009;4.25&#x2009;&#xd7;&#x2009;10-8; &#x3b2;&#x2009;=&#x2009;0.03, p&#x2009;=&#x2009;3.97&#x2009;&#xd7;&#x2009;10-8) than males (&#x3b2;&#x2009;=&#x2009;-&#xa0;0.02, p&#x2009;=&#x2009;0.009; &#x3b2;&#x2009;=&#x2009;0.01, p&#x2009;=&#x2009;0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values&#x2009;<&#x2009;0.02) but not males (p&#x2009;>&#x2009;0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p&#x2009;=&#x2009;0.004), driven by a stronger association among females (&#x3b2;&#x2009;=&#x2009;0.05, p&#x2009;=&#x2009;4.57&#x2009;&#xd7;&#x2009;10-10) compared to males (&#x3b2;&#x2009;=&#x2009;0.02, p&#x2009;=&#x2009;0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale&#x2009;=&#x2009;0.047; pmale&#x2009;=&#x2009;0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p&#x2009;=&#x2009;0.006; CLDN16 p&#x2009;=&#x2009;0.002) but not males (p&#x2009;&#x2265;&#x2009;0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 &#xd7; 10(-9), joint analysis P (P(J)) = 1.7 &#xd7; 10(-9); stages 1, 2 and 3, P(M) = 8.2 &#xd7; 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 &#xd7; 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 &#xd7; 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 &#xd7; 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 &#xd7; 10(-10), P(J) = 5.2 &#xd7; 10(-11)), CLU (rs1532278; P(M) = 8.3 &#xd7; 10(-8), P(J) = 1.9 &#xd7; 10(-8)), BIN1 (rs7561528; P(M) = 4.0 &#xd7; 10(-14), P(J) = 5.2 &#xd7; 10(-14)) and PICALM (rs561655; P(M) = 7.0 &#xd7; 10(-11), P(J) = 1.0 &#xd7; 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Performance-based physical function and future dementia in older people.

BACKGROUND: The association of physical function with progression to dementia has not been well investigated. We aimed to determine whether physical function is associated with incident dementia and Alzheimer disease (AD). METHODS: We performed a prospective cohort study of 2288 persons 65 years and older without dementia. Patients were enrolled from 1994 to 1996 and followed up through October 2003. Main outcome measures included incident dementia and AD. RESULTS: During follow-up 319 participants developed dementia (221 had AD). The age-specific incidence rate of dementia was 53.1 per 1000 person-years for participants who scored lower on a performance-based physical function test at baseline (< or = 10 points) compared with 17.4 per 1000 person-years for those who scored higher (> 10 points). A 1-point lower performance-based physical function score was associated with an increased risk of dementia (hazard ratio, 1.08; 95% confidence interval, 1.03-1.13; P < .001), an increased risk of AD (hazard ratio, 1.06; 95% confidence interval, 1.01-1.12; P = .01), and an increased rate of decline in the Cognitive Ability Screening Instrument scores (0.11 point per year; 95% confidence interval, 0.08-0.14; P < .001) after adjusting for age, sex, years of education, baseline cognitive function, APOE epsilon4 allele, family history of AD, depression, coronary heart disease, and cerebrovascular disease. CONCLUSIONS: Lower levels of physical performance were associated with an increased risk of dementia and AD. The study suggests that poor physical function may precede the onset of dementia and AD and higher levels of physical function may be associated with a delayed onset.

Aged↗
PubMed2006

Esterified estrogen and conjugated equine estrogen and the risk of incident myocardial infarction and stroke.

BACKGROUND: Clinical trials of conjugated equine estrogen (CEE) or estradiol vs placebo in postmenopausal women have found no effect or an elevated risk of myocardial infarction (MI) and stroke. The association of these end points with the use of esterified estrogen (EE) is unknown. METHODS: We examined the risk of MI and stroke associated with current use of CEE, use of EE, or nonuse of hormones in a population-based case-control study in a health maintenance organization. Cases were all postmenopausal women with an incident MI (n = 1644) or stroke (n = 1080). Controls (n = 4205) consisted of a random sample of postmenopausal women without MI or stroke. Current use of postmenopausal hormones was assessed using a computerized pharmacy database. RESULTS: There was no difference in risk of MI or stroke associated with current use of CEE or EE compared with nonuse or for current use of CEE compared with EE. In analyses restricted to hormone users, there was a suggestion of higher ischemic stroke risk associated with CEE alone (without progestin) compared with EE alone (odds ratio, 1.57; 95% confidence interval, 0.98-2.53). There was also a suggestion that when initiated in the previous 6 months, CEE was associated with a higher risk of MI than EE (odds ratio, 2.33; 95% confidence interval, 0.93-5.82). CONCLUSION: Further study may be warranted of the effects of EE on the risk of cardiovascular end points.

Adult↗
PubMed2006

Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older.

BACKGROUND: Alzheimer disease and other dementing disorders are major sources of morbidity and mortality in aging societies. Proven strategies to delay onset or reduce risk for dementing disorders would be greatly beneficial. OBJECTIVE: To determine whether regular exercise is associated with a reduced risk for dementia and Alzheimer disease. DESIGN: Prospective cohort study. SETTING: Group Health Cooperative, Seattle, Washington. PARTICIPANTS: 1740 persons older than age 65 years without cognitive impairment who scored above the 25th percentile on the Cognitive Ability Screening Instrument (CASI) in the Adult Changes in Thought study and who were followed biennially to identify incident dementia. MEASUREMENTS: Baseline measurements, including exercise frequency, cognitive function, physical function, depression, health conditions, lifestyle characteristics, and other potential risk factors for dementia (for example, apolipoprotein E epsilon4); biennial assessment for dementia. RESULTS: During a mean follow-up of 6.2 years (SD, 2.0), 158 participants developed dementia (107 developed Alzheimer disease). The incidence rate of dementia was 13.0 per 1000 person-years for participants who exercised 3 or more times per week compared with 19.7 per 1000 person-years for those who exercised fewer than 3 times per week. The age- and sex-adjusted hazard ratio of dementia was 0.62 (95% CI, 0.44 to 0.86; P = 0.004). The interaction between exercise and performance-based physical function was statistically significant (P = 0.013). The risk reduction associated with exercise was greater in those with lower performance levels. Similar results were observed in analyses restricted to participants with incident Alzheimer disease. LIMITATIONS: Exercise was measured by self-reported frequency. The study population had a relatively high proportion of regular exercisers at baseline. CONCLUSION: These results suggest that regular exercise is associated with a delay in onset of dementia and Alzheimer disease, further supporting its value for elderly persons.

Age of Onset↗
PubMed2006

Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease.

BACKGROUND: Functional polymorphisms in tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) can affect immune response, inflammation, tissue injury, and possibly the susceptibility to Alzheimer disease (AD). OBJECTIVE: To evaluate the association between promoter region polymorphisms in the TNF-alpha and IL-10 genes and risk of late-onset AD in older white subjects. DESIGN: Community-based case-control study. SETTING: Group Health Cooperative of Puget Sound. PARTICIPANTS: White subjects (n = 265) meeting criteria for probable or definite AD (cases) and white control subjects (n = 347) (controls). MAIN OUTCOME MEASURES: Genotyping results for TNF-alpha, IL-10, and apolipoprotein E (APOE) genotyping. RESULTS: The TNF-alpha -863 A allele was associated with reduced odds of developing AD, and the test for trend suggested that having 2 copies of the A allele further reduces the risk (odds ratios [C/C, reference], 0.66 for C/A and 0.58 for A/A; P = .04). Because of linkage disequilibrium in the TNF-alpha region, we constructed promoter region haplotypes as defined by single nucleotide polymorphisms at positions -863 and -308. Based on knowledge of TNF-alpha protein production, we ordered the haplotypes based on apparent increasing transcriptional activity. After adjusting for age, education, and the presence of the APOE epsilon4 genotype, the test for trend showed increasing odds of AD with increasing transcriptional activity (P = .02). The IL-10 -1082 and IL-10 -592 allele and genotype frequencies were not significantly different between cases and controls. CONCLUSION: Variation in the TNF-alpha promoter region, or possibly polymorphisms in nearby genes, could affect cerebral inflammatory response and the risk of late-onset AD.

Age of Onset↗
PubMed2006

Fruit and vegetable juices and Alzheimer's disease: the Kame Project.

BACKGROUND: Growing evidence suggests that oxidative damage caused by the beta-amyloid peptide in the pathogenesis of Alzheimer's disease may be hydrogen peroxide mediated. Many polyphenols, the most abundant dietary antioxidants, possess stronger neuroprotection against hydrogen peroxide than antioxidant vitamins. METHODS: We tested whether consumption of fruit and vegetable juices, containing a high concentration of polyphenols, decreases the risk of incident probable Alzheimer's disease in the Kame Project cohort, a population-based prospective study of 1836 Japanese Americans in King County, Washington, who were dementia-free at baseline (1992-1994) and were followed through 2001. RESULTS: After adjustment for potential confounders, the hazard ratio for probable Alzheimer's disease was 0.24 (95% confidence interval [CI], 0.09-0.61) comparing subjects who drank juices at least 3 times per week with those who drank less often than once per week with a hazard ratio of 0.84 (95% CI, 0.31-2.29) for those drinking juices 1 to 2 times per week (P for trend < .01). This inverse association tended to be more pronounced among those with an apolipoprotein Eepsilon-4 allele and those who were not physically active. Conversely, no association was observed for dietary intake of vitamins E, C, or beta-carotene or tea consumption. CONCLUSIONS: Fruit and vegetable juices may play an important role in delaying the onset of Alzheimer's disease, particularly among those who are at high risk for the disease. These results may lead to a new avenue of inquiry in the prevention of Alzheimer's disease.

Aged↗
PubMed2006

Longitudinal change in positive affect in community-dwelling older persons.

OBJECTIVES: To determine whether positive affect, defined as emotional contentment and happiness, remains stable in late life and to identify predictors of longitudinal change in positive affect. DESIGN: Longitudinal observational study. SETTING: Community. PARTICIPANTS: Six hundred sixty-three individuals aged 70 and older without disability at baseline and free of chronically depressed mood. MEASUREMENTS: Positive affect, social network, social activity, chronic health conditions, activities of daily living, instrumental activities of daily living (IADLs), cognitive functioning, and negative affect measured over 54 months, at 18-month intervals, up to four times. RESULTS: Positive affect remained relatively stable over 4.5 years of follow-up. Higher average levels of social activity and lower levels of negative affect were associated with higher positive affect. An increase of 1 point in negative affect (on a 7-point scale) was associated with a 0.23-point concurrent decrease in positive affect (on a 5-point scale). Needing help in an additional IADL was associated with a decrease in positive affect of 0.04 points. A greater number of chronic conditions at enrollment was associated with lower positive affect. CONCLUSION: Positive affect is directly correlated with social involvement and inversely correlated with negative affect, IADL functioning, and comorbidity. Positive affect was mostly related to factors that do not change over time, although it showed some sensitivity to short- and long-term changes in physical health and functioning.

Activities of Daily Living↗
PubMed2006

Predicting lewy body pathology in a community-based sample with clinical diagnosis of Alzheimer's disease.

Accurate antemortem prediction of Lewy body pathology in patients with dementia is problematic. This study generates a model that better predicts Lewy body pathology in community-based patients with clinical Alzheimer's disease. Lewy body pathology was detected in 80 of 152 participants (52.6%) with an initial diagnosis of probable Alzheimer's disease. In a stepwise logistic regression model, female gender, lower education, being married, bradykinesia, hallucinations, and absence of irritability predicted the greatest likelihood of Lewy body pathology. The predictive model correctly diagnosed Lewy body pathology with an estimated sensitivity of 75%, specificity of 68%, and accuracy of 72%; the area under the receiver operating characteristic curve was 0.75. In a community-based autopsy sample, this predictive model confirmed parkinsonism and hallucinations as important predictors of Lewy body pathology in patients with clinical Alzheimer's disease. The model also identified other demographic and clinical characteristics that might enhance the prediction of Lewy body pathology.

Aged↗
PubMed2005

Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors.

BACKGROUND: Functional status limitations may be associated with both an increased risk of death and a decreased likelihood of influenza vaccination, and so may confound the association of influenza vaccination and risk of all cause mortality in seniors. METHODS: We conducted a nested case-control study of persons >or=65 years of age that included 252 cases who died during an influenza season and 576 age-matched controls. We identified functional limitations by medical record review, and compared the effect of adjustment for those factors with that of adjustment for disease covariates defined by diagnosis codes, using methods reported by previous influenza vaccine effectiveness studies, on the association of influenza vaccination and risk of death. RESULTS: Functional limitations, such as requiring assistance for bathing, were highly prevalent in cases, even in the subgroup defined as free of comorbidity by diagnosis code criteria, and were associated with a decreased likelihood of vaccination among controls. Adjustment for functional limitations resulted in an estimate of the relative risk of death in vaccinated persons compared with unvaccinated persons that was closer to the null [odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.47-1.06] than the unadjusted estimate (OR, 0.59; 95% CI, 0.41-0.83). In contrast, adjustment for diagnosis code covariates moved the estimate further from the null (OR, 0.45; 95% CI, 0.30-0.68). CONCLUSIONS: Functional limitations appear to be important confounders of the association of vaccination and risk of death, while adjustment for diagnosis code covariates did not control for a healthy vaccinee bias. Further research is needed on methods to reduce the influence of bias in observational studies of influenza vaccine effectiveness.

Activities of Daily Living↗
PubMed2005

Alcohol and cognitive performance: a longitudinal study of older Japanese Americans. The Kame Project.

BACKGROUND: Recent data demonstrate that moderate consumption of alcohol (13-52 grams of ethanol per day) may be beneficial to cognitive functioning among older adults. METHODS: Longitudinal growth curve analyses controlling for baseline age, body mass index (BMI), education/income, migrant status, smoking, history of diagnosed stroke, hypertension, coronary heart disease (CHD), depression, diabetes and stroke (time-varying) were used to examine the relationship between alcohol consumption, gender and cognitive performance over an 8-year follow-up period. The sample included 1624 Japanese American community-dwelling adults aged 65 and older who were cognitively intact at baseline and participated in at least one follow-up examination. Cognitive performance was measured using the Cognitive Abilities Screening Instrument (CASI; 0-100 point scale), a global test of cognitive function. RESULTS: Current consumers (n = 480) scored significantly (p < 0.05) higher on CASI (mean rate of change-1.22 CASI units) over the 8-year follow-up period than past consumers or abstainers (n = 1144; mean rate of change-3.77 CASI units). There was no significant main effect for gender, or an alcohol and gender interaction. CONCLUSIONS: This study provides further support regarding the beneficial effects of moderate alcohol consumption on cognitive performance over time. Observed benefits were not modified by gender. Future studies need to determine whether alcohol preserves cognition directly or whether other factors such as physiology or cultural drinking practices are driving the observed association.

Aged↗
PubMed2005

Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease.

Biochemical characterization of the major detergent-insoluble proteins that comprise hallmark histopathologic lesions initiated the molecular era of Alzheimer's disease (AD) research. Here, we reinvestigated detergent-insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)-mass spectrometry (MS)-MS-based proteomics, we robustly identified 125 proteins in the detergent-insoluble fraction of late-onset AD (LOAD) temporal cortex that included several proteins critical to Abeta production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot. Following multiple analyses, we estimated that these represent ~80% of detergent-insoluble proteins in LOAD detectable by our method. Abeta, tau, and 7 of 8 other newly identified detergent-insoluble proteins were disproportionately increased in temporal cortex from patients with LOAD and AD derived from mutations in PSEN1 and PSEN2; all of these except tau were elevated in individuals with prodromal dementia, while none except Abeta were elevated in aged APPswe mice. These results are consistent with the amyloid hypothesis of AD and extend it to include widespread protein insolubility, not exclusively Abeta insolubility, early in AD pathogenesis even before the onset of clinical dementia.

Alzheimer Disease↗
PubMed2005

Clinical empathy as emotional labor in the patient-physician relationship.

Empathy should characterize all health care professions. Despite advancement in medical technology, the healing relationship between physicians and patients remains essential to quality care. We propose that physicians consider empathy as emotional labor (ie, management of experienced and displayed emotions to present a certain image). Since the publication of Hochschild's The Managed Heart in 1983, researchers in management and organization behavior have been studying emotional labor by service workers, such as flight attendants and bill collectors. In this article, we focus on physicians as professionals who are expected to be empathic caregivers. They engage in such emotional labor through deep acting (ie, generating empathy-consistent emotional and cognitive reactions before and during empathic interactions with the patient, similar to the method-acting tradition used by some stage and screen actors), surface acting (ie, forging empathic behaviors toward the patient, absent of consistent emotional and cognitive reactions), or both. Although deep acting is preferred, physicians may rely on surface acting when immediate emotional and cognitive understanding of patients is impossible. Overall, we contend that physicians are more effective healers--and enjoy more professional satisfaction--when they engage in the process of empathy. We urge physicians first to recognize that their work has an element of emotional labor and, second, to consciously practice deep and surface acting to empathize with their patients. Medical students and residents can benefit from long-term regular training that includes conscious efforts to develop their empathic abilities. This will be valuable for both physicians and patients facing the increasingly fragmented and technological world of modern medicine.

Empathy↗
PubMed2005

Education modifies the effect of apolipoprotein epsilon 4 on cognitive decline.

OBJECTIVES: To assess the influence of education on the association between apolipoprotein E and cognitive change. DESIGN: Prospective cohort. PARTICIPANTS: HMO-based sample of 2168 non-demented community-dwelling elderly followed over 6 years. MEASUREMENTS: Generalized estimating equations were used with the difference between baseline and follow-up cognitive abilities screening instrument (CASI) as the outcome variable. RESULTS: At follow-up, 6% of the sample had a decline of 1.5 S.D. or greater on the CASI. Compared to individuals without an APOE4 allele, individuals with a single APOE4 allele did not have greater CASI decline. By contrast, individuals with two APOE4 alleles experienced greater decline in cognitive performance and the magnitude of that decline decreased as years of educational attainment increased. These relationships held after adjusting for age, gender, ethnicity, depression, diabetes, and history of vascular disease. CONCLUSION: Lower education was associated with steep 4-year cognitive decline for APOE4 homozygotes but not for APOE4 heterozygotes. Potentially modifiable host factors such as education could influence the association of high-risk genotypes and cognitive decline.

Age Factors↗
PubMed2005

Developmental and vascular risk factors for Alzheimer's disease.

To investigate developmental and vascular risk factors for Alzheimer's disease (AD), we examined 90 incident cases of probable AD in a cohort of 1859 individuals followed prospectively for six years. The presence of the APOE-epsilon4 allele was the strongest risk factor, and with increasing survival age, the effect of epsilon4 diminished. Among epsilon4 positives, developmental risk factors such as smaller head circumference (< or =54.4 cm) and having more than four children in the household at age 2-3 were independently associated with incident AD (hazard ratio (HR)=2.6 (95% CI 1.04-6.3) and 3.3 (1.2-9.2), respectively). Among epsilon4 negatives, vascular risk factors were related to AD risk (self-reported diagnoses of transient ischemic attack and diabetes (HR=5.1, 95% CI 1.7-15.5; HR 3.3, 95% CI 1.4-8.1)). These findings indicate that clinical AD is a result of early life as well as later life risk factors, and that genetic predisposition to the disease may modify the constellation of predictors.

Age Factors↗