Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk.

We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

Sequence variation in SORL1 and dementia risk in Swedes.

The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid beta-amyloid(1-42), tau levels, or age at onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best odds ratio = 1.097; 95% confidence interval = 1.038-1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct linkage disequilibrium blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.

Stability of genetic influences on pulmonary function in a longitudinal study of octogenarian twins.

Using data from the first four waves of the OCTO-Twin study (twins 80 + years), the present study investigated the stability and change of genetic and environmental contributions to pulmonary function. Using a genetic simplex model, variance in peak expiratory flow (PEF) at each wave was decomposed into additive genetic and nonshared (specific) environmental factors. Additionally, this analysis distinguished the source of these influences, either from previous waves (transmissions) or from novel influences at each wave (innovations). At each time point (except wave 1), the genetic variance was due to genetic transmissions from prior time points. Conversely, the specific environmental variance in PEF at each time point was mainly due to environmental innovations. These results imply that genetic factors contribute to the stability of pulmonary function over time whereas environmental factors contribute to its change.

Discharged after stroke - important factors for health-related quality of life.

AIMS: This study examines different correlates to health-related quality (HRQoL) of life after discharge in patients with stroke. BACKGROUND: HRQoL is an important aspect of life after suffering a stroke. Previous research has revealed several variables associated with poststroke quality of life, including age, gender, depression, fatigue, length of hospital stay, functional status and amount of social participation. However, the time span after stroke varies greatly in the different studies. Although the multiple factors that contribute to short-term postdischarge HRQoL have potential importance for discharge planning, to our knowledge, these factors have not been systematically investigated during the earlier days following discharge. DESIGN: Cross-sectional study. METHODS: The sample consisted of 188 consecutively included individuals (mean age 74 years, 56% men) from a stroke unit in southern Sweden. The interviews were performed two to three weeks after discharge and included use of the SF-36, the Center for Epidemiological Studies Depression Scale, the Barthel Index, the Frenchay Activities Index, performance of interests and survey of patients' perceived participation in discharge planning. Multiple linear regression analysis was conducted to identify variables associated with HRQoL. RESULTS: Multiple regression analyses with the eight scales of SF-36 as dependent variables revealed eight models, one for each scale, which were statistically significant. Depressive symptoms were associated with lower HRQoL. Ability to perform personal and social activities, interests, younger age, education (elementary school) and shorter hospital stay were related to higher HRQoL. Patients' perceived participation in discharge planning was both positively and negatively associated with HRQoL. CONCLUSIONS: Several variables were related to good HRQoL two to three weeks post-discharge, particularly fewer depressive symptoms, participation in social activities such as outdoor activities and performance of interests. RELEVANCE TO CLINICAL PRACTICE: These results can be used to design needs assessment forms of discharge planning to promote adaptation and recovery after stroke.

End-of-life care in the oldest old.

OBJECTIVE: The aim of this study was to describe the last year of life of a sample of the oldest old, focusing on care trajectories, health, social networks, and function in daily life activities. METHOD: Data originated from the NONA study, a longitudinal study of 193 individuals among the oldest old living in a Swedish municipality. During this longitudinal study, 109 participants died. Approximately one month after their death, a relative was asked to participate in a telephone interview concerning their relative's last year of life. One hundred two relatives agreed to participate. RESULTS: Most of the elderly in this sample of the oldest old (74.5%) died at an institution and the relatives were mostly satisfied with the end-of-life care. The oldest old relatives estimated that the health steadily declined during the last year of life, and that there was a decline in performing of daily life activities. They also estimated that those dying in institutions had fewer social contacts than those dying in a hospital or at home. SIGNIFICANCE OF RESULTS: Care at end of life for the oldest old is challenged by problems with progressive declines in ability to perform activities of daily living and health. The findings also highlight the need to support social networks at eldercare institutions.

A survey of ABCA1 sequence variation confirms association with dementia.

We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.

Heritabilities for fifteen routine biochemical values: findings in 215 Swedish twin pairs 82 years of age or older.

OBJECTIVE: The aim of the present study was to calculate the overall heritability of some routine biochemical analyses. Furthermore, as genetic and environmental influences might differ across various segments, genetic impact in the highest and lowest thirds of the distributions was estimated. METHODS: Ninety-six monozygotic and 120 dizygotic same-sex twin pairs aged 82 and older were tested. Structural equation modelling was used to estimate the genetic and environmental influences on serum levels of albumin, calcium, total cholesterol, HDL-cholesterol, GGT, potassium, sodium, creatinine, urea, urate, cobalamin, folate, homocysteine, free thyroxine and thyroid stimulating hormone (TSH). RESULTS: Additive genetic influence of between 66% and 28% of the variance was accounted for all values except creatinine, for which the genetic influence was marginal. The highest influence was found for homocysteine, cobalamin, folate and HDL-cholesterol. Genetic influence for the tests was mainly in congruence with previous findings in younger samples. When limited to the highest and lowest thirds of distribution, there were substantial differences in the proportion of genetic influence for some tests. CONCLUSION: For the majority of biochemical tests, the magnitude of genetic influence is considerable. Heritability estimates, however, should be considered in a broad context, with age, gender, morbidity and medication taken into account. Notably, for many test values, the genetic impact may differ considerably between the highest and the lowest range of the distribution.

Patients' perceptions of their participation in discharge planning after acute stroke.

AIMS AND OBJECTIVES: To describe stroke patients' perceptions of their participation in the discharge planning process and identify correlates of perceived participation. BACKGROUND: Patients have the right to participate in discharge planning, but earlier research has shown that they are often dissatisfied with the information they receive and their involvement in goal-setting during discharge planning. DESIGN: Cross-sectional study. METHODS: The sample consisted of 188 persons (mean age 74 years, SD 11.2) with acute stroke who were admitted to a stroke unit at a hospital in southern Sweden during 2003-2005. Data was collected by face-to-face interviews 2-3 weeks after discharge using the 'Patients' Questionnaire on Participation in Discharge Planning'. This instrument measures perceived participation in discharge planning in three subscales: P-Information, P-Medical Treatment, P-Goals and Needs. RESULTS: The percentage of patients who perceived that they had participated in discharge planning was as follows: 72-90% according to P-Information, 29-38% according to P-Medical Treatment and 15-47% according to P-Goals and NEEDS: Age, education and performance of activities of daily living were significantly related to perceived participation as measured by different subscales. CONCLUSIONS: Most of the patients perceived that they received information, but fewer perceived participation in the planning of medical treatment and needs of care/service/rehabilitation and goal-setting. Professionals need to pay more attention to patients in different subgroups to facilitate their participation in discharge planning. Relevance to clinical practice. To facilitate and increase patients' participation in discharge planning, methods should be implemented for goal-setting and identifying patients' needs. Methods that foster patient participation may improve goal-orientated care, services and rehabilitation after discharge.

Discharge planning of stroke patients: the relatives' perceptions of participation.

AIMS: To describe relatives' perceived participation in discharge planning for patients with stroke and identify correlates to perceived participation. BACKGROUND: Stroke affects both patients and their relatives and previous research shows that relatives were often dissatisfied with their perceived involvement in discharge planning and the information they get. DESIGN: Prospective cross-sectional study. METHODS: The study comprised 152 consecutively enrolled relatives (mean age = 60.8 years) of acute stroke patients admitted to a stroke unit in southern Sweden during 2003-2005. Data were collected through interviews 2-3 weeks after discharge using 'Relative's Questionnaire about Participation in Discharge planning'. This instrument measures perceived participation in three subscales: R-Information-Illness, R-Information-Care/support, and R-Goals and Needs. The Overall Rating of Relative's Perceived Participation in Discharge Planning was measured by a visual analogue scale (VAS) (1-10 score). RESULTS: Among the relatives, 56-68% reported positively according to R-Information-Illness, but 46-53% perceived that they did not receive any information about care/medication/rehabilitation/support. About 80% perceived no participation at all in goals and needs. The mean value of the VAS was 3.89 (SD 3.40) score. Regression analyses revealed that longer stay at hospital, patients with higher education, and relatives of female patients and female relatives were associated with relatives' perceptions of higher participation in discharge planning. CONCLUSIONS: Relatives perceived that they needed more information and knowledge about stroke and care/medication/rehabilitation/support. They also needed to be more involved in goal-setting and in identifying patient needs. Professionals should take into consideration these associated variables to improve relatives' perceived participation. RELEVANCE TO CLINICAL PRACTICE: Clinicians should give more attention to the altered situation of stroke patients' relatives when planning for continuing care and when setting postdischarge goals for the patients. The professionals need to develop strategies to involve relatives in sharing information, goal-setting and needs assessment in discharge planning.

The pattern of cognitive symptoms predicts time to dementia onset.

BACKGROUND: Few studies have examined whether cognitive symptom patterns differ by age and length of time before dementia onset. Our objective was to investigate whether different patterns of cognitive symptoms at ages 70, 75, and 79 years predict short-term (< or =5 years) and long-term (>5 years) dementia onset. METHODS: A representative sample of 382 nondemented 70-year-olds from Gothenburg, Sweden was examined periodically up to age 90 years. Information on dementia in those lost to follow-up was obtained from medical records. Cognitive assessments at ages 70, 75, and 79 years included psychiatric and psychometric examinations. Four patterns of cognitive performance were examined in relation to dementia onset: (1) unimpaired cognition, (2) isolated low memory, (3) low non-memory, and (4) global low cognitive performance. RESULTS: Short-term onset was predicted by global low performance at ages 70, 75, and 79 years and by low non-memory performance at ages 70 and 75. Isolated low memory was not a short-term predictor at any examination, but it predicted long-term onset at ages 70 and 75 years. CONCLUSIONS: A global pattern of low cognitive performance predicts short-term but not long-term onset of dementia, whereas isolated low memory performance predicts dementia only in the long-term. Our findings also suggest that preclinical symptoms of dementia might differ by age.

Health, functional capacity, formal care, and survival in the oldest old: a longitudinal study.

There are surprisingly few longitudinal studies of the oldest old, but these studies are of high importance because the number of oldest old continues to increase in most countries and because of the uniqueness in this population. The aims of this study were to investigate how health, activities of daily living (ADL), and use of care change over time in the oldest old and to seek how differences in health and ADL affect survival of the oldest old. The study was longitudinal in design, and the participants were interviewed by trained nurses. A group of 300 persons was randomly selected from three age-groups; 86, 90, and 94. For the first phase, in 1999, 157 persons could and wanted to participate; from these 98 persons continued to participate in the second phase and 62 in the third. Repeated measures (general linear model=GLM) from the oldest old showed a decline in objective health and ADL with increasing age, but subjective health remained positive and stable. The use of formal help increased with age, and once the oldest old entered the old-age care system, it was rare that they returned to independent living. Analysis using a Cox regression model showed that health and ADL significantly predicted survival, but age did not.

Role of genes and environments for explaining Alzheimer disease.

CONTEXT: Twin studies using selected samples have shown high heritability for Alzheimer disease (AD). OBJECTIVE: To evaluate genetic and environmental influences on AD in a fully ascertained population of older twins, including like- and unlike-sex pairs. DESIGN: Five-group quantitative genetic model: male monozygotic twins, female monozygotic twins, male dizygotic twins, female dizygotic twins, and unlike-sex twins. SETTING AND PARTICIPANTS: All twins in the Swedish Twin Registry aged 65 years and older. The study included 11,884 twin pairs, among whom were 392 pairs in which 1 or both members had AD. MAIN OUTCOME MEASURES: All individuals were screened for cognitive dysfunction. Suspected cases of dementia and their co-twins received complete clinical diagnostic evaluations for AD. Estimates of heritability, shared environmental influences, and nonshared environmental influences, adjusting for age, were derived from the twin data. RESULTS: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantly greater in dizygotic than in monozygotic pairs, suggesting genetic influences on timing of the disease. CONCLUSIONS: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset.

Accounting for the relationship between low education and dementia: a twin study.

We evaluated whether the association between low education and greater risk of dementia is explained by genetic influences, using three different types of analyses. The HARMONY study (Swedish for "health" (Hälsa), "genes" (ARv), "environment" (Miljö), "and" (Och), and "new" (NY)) includes members of the Swedish Twin Registry who were aged 65 and older and alive in 1998, and who were screened and clinically assessed for dementia. There were 394 cases with dementia and 7786 unrelated controls. Analyses included co-twin control, tests for association between education and a measured genotype, and bivariate twin modeling. Low education was a significant risk factor for dementia both in case-control analyses (odds ratio=1.77, 95% confidence interval 1.38 to 2.28) and co-twin control analyses with monozygotic twin pairs (odds ratio=3.17, 95% confidence interval 1.26 to 7.93). Apolipoprotein E genotype was not associated with education and did not account for the relationship between education and dementia. Bivariate twin modeling showed that the association between education and dementia was not mediated by genetic influences in common between education and dementia. The association was mediated by shared environmental influences that were related to both dementia and to education. Low education is confirmed as a risk factor for dementia. Findings from three different analytic approaches showed that genetic influences did not explain this association.

Genotype-environment interactions: cognitive aging and social factors.

The possibility of genotype-environment interaction for memory performance and change was examined in 150 monozygotic (MZ) twin pairs from the Swedish Adoption Twin Study of Aging (SATSA). We used an MZ twin pair difference approach to examine the possibility that genotype was associated with intrapair variability and thus suggestive of genotype-nonshared environment interactions. Multiple 'variability genes' were found for longitudinal change in a semantic memory task including candidates coding for apolipoprotein E (APOE) and estrogen receptor alpha (ESR1) as well as serotonin candidates (HTR2A and 5HTT). One candidate also related to variability in change in episodic memory (5HTT). Of the significant associations observed, generally results indicated that MZ pairs who carry putative risk alleles were less variable than noncarriers, suggesting that noncarriers may be more sensitive to environmental contexts. We sought to 'contextualize' the possible nonshared environmental influences for found gene-environment (G x E) effects by considering intrapair differences in measured social and stress factors, including social support, life events and depressive symptoms. Results suggested that nonshared environmental influences associated with depressive symptoms may moderate the G x E relationship observed for ESR1 and APOE and longitudinal semantic memory change whereby noncarriers of putative risk alleles may be relatively more sensitive to depressionevoking environmental contexts than carriers of the risk allele. Thus, the contexts that facilitate or reduce depressive symptoms may affect semantic memory resiliency dependent on genotype. Further work ought to consider larger sample sizes as well as consider additional social and contextual factors.

Effects of repeated testing in a longitudinal age-homogeneous study of cognitive aging.

Estimates of gains related to repeated test exposure (retest effects) and within-person cognitive changes are confounded in most longitudinal studies because of the nonindependent time structures underlying both processes. Recently developed statistical approaches rely on between-person age differences to estimate effects of repeated testing. This study, however, demonstrates how retest effects can be evaluated at the group level in an age-homogeneous population-based study by use of a sampling-based design approach in which level and change of cognitive performance of previous participants, measured at ages 70, 75, 79, 81, 85, 88, 90, 92, 95, 97, and 99 years, were compared with performances of survivors of a representative sample identified and drawn from the same original population cohort but invited for the first time at age 85 with subsequent measurements at ages 88, 90, 92, 95, 97, and 99. The comparisons revealed a trend toward retest effects on two out of five cognitive measurements. The study demonstrates how a design-based approach can provide valuable insights into continuous learning processes embedded in population average aging trajectories that are not confounded with cohort and mortality-related selective attrition.

Satisfaction with present life predicts survival in octogenarians.

We examined the effect of life satisfaction on survival over 10 years among 80-year-old and older same-sex twins of whom 320 individuals responded to the Life Satisfaction Index Z questionnaire in connection with the OCTO-Twin study. We treated participants as individuals in semiparametric Cox regression mixed-effects models (frailty) by adjusting the similarity of mortality risk within twin pairs by modeling it as a random variable. An exploratory factor analysis yielded three factors: Zest and Mood represented satisfaction with present life and Congruence represented satisfaction with past life. Those in the lowest quartile of factors of satisfaction with present life had an almost twofold risk for mortality compared with those in the highest quartile, even after adjustment for multiple confounders. Satisfaction with past life satisfaction showed no association with mortality.

Sex differences after all those years? Heritability of cognitive abilities in old age.

We investigated sex differences in genetic and environmental effects on cognitive abilities among older adult twins. We drew participants from the Swedish Twin Registry; our sample included 647 twin pairs. Our cognitive measures included Synonyms, Block Design, Digit Span, Thurstone's Picture Memory, Symbol Digit, and general cognitive ability tests. Higher age was related to lower performance in all cognitive measures, except synonyms. For digit span forward, symbol digit, and general cognitive ability tasks, there was a Sex x Age interaction, with greater deficits in the performance of women compared with those of men at higher ages. We found no sex-specific genetic influences. In other words, the same genetic effects were operating for men and women. Furthermore, the magnitude of genetic effect was similar for men and women.

Potentially modifiable risk factors for dementia in identical twins.

BACKGROUND: The purpose of this study was to test nongenetic factors that might explain discordance for dementia in monozygotic twin pairs. Risk factors included education, engaged lifestyle in midlife, and early life circumstances indexed by tooth loss, short adult height, and parental social class. METHODS: Data are from the HARMONY study, including members of the Swedish Twin Registry age 65 and older and alive in 1998, who were screened and assessed clinically for dementia. Analyses included a case-control design to evaluate the risk factors and a co-twin control design that permits testing nongenetic risk factors while controlling for genetic influences. Case-control analyses included 310 dementia cases and 3,063 nondemented controls. There were 106 monozygotic twin pairs discordant for dementia. Risk factors were assessed independently by the Swedish Twin Registry three decades previously. RESULTS: Case-control findings showed that history of tooth loss before age 35 and low educational attainment were significant risk factors for Alzheimer's disease, with short adult height also contributing to risk for total dementia. In co-twin control analyses, only history of tooth loss before age 35 was a significant risk factor for Alzheimer's disease, whereas low educational attainment also contributed to risk for total dementia and lack of physical exercise to risk for non-Alzheimer's dementias. CONCLUSIONS: Potentially modifiable risk factors from early and midlife, with a cumulative detrimental effect on the brain, contribute to risk of dementia. Based on the association with tooth loss, further investigation of inflammatory load as a risk factor for Alzheimer's disease is warranted.

Complete ascertainment of dementia in the Swedish Twin Registry: the HARMONY study.

The purpose of this report is to describe the Study of Dementia in Swedish Twins (known as HARMONY), including procedures for complete ascertainment of all cases of Alzheimer's disease (AD) and other dementias in 14,435 individuals aged 65 and older from the national Swedish twin registry. Telephone cognitive screening identified 11.5% as positive for cognitive dysfunction. Clinical diagnoses were completed for 1557 individuals, including individuals who screened positive, their twin partners, and a sample of normal controls. Estimated prevalence of dementia ranged from 1.4% for age 65-69 to 29.2% for age 90 and older. Concordance rates for Alzheimer's disease were 59% for monozygotic twins, 32% for like-sexed, and 24% for unlike-sexed dizygotic twins. Among monozygotic twins where both twins had Alzheimer's disease, the within pair difference in age of onset ranged from both becoming demented in the same year to 7 years difference in onset.

Quantitative genetic analysis of latent growth curve models of cognitive abilities in adulthood.

Though many cognitive abilities exhibit marked decline over the adult years, individual differences in rates of change have been observed. In the current study, biometrical latent growth models were used to examine sources of variability for ability level (intercept) and change (linear and quadratic effects) for verbal, fluid, memory, and perceptual speed abilities in the Swedish Adoption/Twin Study of Aging. Genetic influences were more important for ability level at age 65 and quadratic change than for linear slope at age 65. Expected variance components indicated decreasing genetic and increasing nonshared environmental variation over age. Exceptions included one verbal and two memory measures that showed increasing genetic and nonshared environmental variance. The present findings provide support for theories of the increasing influence of the environment with age on cognitive abilities.