Biomedical subjects

Laura Fratiglioni

Publications and source records attributed to Laura Fratiglioni.

At least 19 recordsLinked to original sources

PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Journal Article↗

PubMed2006

Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE.

Insulin degrading enzyme (IDE) is one of the principal proteases involved in the degradation of the beta-amyloid peptide, which is the major constituent of senile plaques in Alzheimer's disease (AD) brains. Previous association studies between AD and IDE have produced inconsistent results which may be indicative of a need for larger case-control series to identify what may be a relatively small effect size. Thus, we performed a large association study using four SNPs in the 276-kb haplotype block in and around IDE (IDE_7, IDE_9, IDE_14 and HHEX_23) in a previously unpublished Swedish and a UK case-control series, and combined our data with a previously reported Swedish case-control sample set from Prince et al., 2003. The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE_9 located in the 3'-end of the IDE gene after conservative multiple testing Bonferroni correction (p=0.005). The effect seemed to predominate in male cases. However, we did not observe a globally significant association to haplotypes generated from three "tag" SNPs. These findings indicate a role for IDE in AD, and provide models that may improve chances of further independent replication.

Aged↗

PubMed2006

Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study.

BACKGROUND: Heart failure has been linked to cognitive impairment in several previous studies, but to our knowledge, no investigations have explored the relationship between heart failure and the risk of dementia. We sought to examine the hypothesis that heart failure is a risk factor for dementia and Alzheimer disease. METHODS: A community-based cohort of 1301 individuals 75 years or older and without dementia in Stockholm, Sweden, was examined 3 times over a 9-year period to detect patients with dementia and Alzheimer disease using the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Heart failure was defined according to the guidelines of the Task Force on Heart Failure of the European Society of Cardiology by integrating clinical symptoms and signs with inpatient register entries and use of cardiac medications. Data were analyzed using Cox proportional hazards models with adjustment for major potential confounders. RESULTS: During the 6534 person-years of follow-up (mean, 5.02 years per person), 440 subjects were diagnosed as having dementia, including 333 with Alzheimer disease. At baseline, heart failure was identified in 205 subjects. Heart failure was associated with a multi-adjusted hazard ratio (HR) of 1.84 (95% confidence interval [CI], 1.35-2.51) for dementia and 1.80 (95% CI, 1.25-2.61) for Alzheimer disease. Use of antihypertensive drugs (83% of which are diuretics) seemed to reduce dementia risk due to heart failure (HR, 1.38; 95% CI, 0.99-1.94). Heart failure and low diastolic pressure (< 70 mm Hg) had an additive effect on the risk for dementia (HR, 3.07; 95% CI, 1.67-5.61). CONCLUSIONS: Heart failure is associated with an increased risk of dementia and Alzheimer disease in older adults. Antihypertensive drug therapy may partially counteract the risk effect of heart failure on dementia disorders.

Aged↗

PubMed2006

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.

Age of Onset↗

PubMed2006

Anaemia increases the risk of dementia in cognitively intact elderly.

Although cross-sectional studies found an association between anaemia and dementia, longitudinal studies provided contradictory results. We hypothesize that anaemia might increase the risk of developing dementia because of chronic brain hypo-oxygenation. Using baseline data from a community-based longitudinal study, the Kungsholmen Project, Stockholm, Sweden, we clinically followed 1435 non demented subjects aged 75-95 years for 3 years to detect incident dementia cases (DSM-III-R criteria). Subjects that fulfilled WHO criteria for anaemia, baseline haemoglobin concentration; 130 g/L (men) and 120 g/L (women), had a higher hazard ratios (HR) of developing dementia 3 years later (HR 1.6, 95% CI: 1.1-2.4). In persons with good baseline cognition (MMSE>or=26, n=1139), the association was stronger and still significant after adjustments for conditions potentially related to anaemia and dementia, such as chronic diseases, inflammatory markers, and indicators of nutritional status. The HR was increased even when different haemoglobin cut offs for anaemia definition were used. Thus, anaemia is suggested to be a new potential modifiable risk factor for dementia.

Aged↗

PubMed2006

Personality and risk of cognitive impairment 25 years later.

The authors examined the relationship between personality and cognitive impairment in 4,039 members of the Swedish Twin Registry. Neuroticism and extraversion scores were collected in 1973 at midlife, and cognitive impairment was assessed in the same group 25 years later. Data were analyzed with case-control and co-twin control designs. Greater neuroticism was associated with higher risk of cognitive impairment in the results from case-control, but not from co-twin, analyses. Compared with both extraversion and introversion, moderate extraversion was associated with lower risk of cognitive impairment in both case-control and co-twin designs, as was the combination of high neuroticism and low extraversion. Findings are discussed in the context of theories related to personality, psychological distress, arousal, and cognitive function.

Aged↗

PubMed2006

Cerebrovascular disease, APOE epsilon4 allele and cognitive decline in a cognitively normal population.

OBJECTIVES: To investigate whether cerebrovascular disease (CVD) and apolipoprotein E (APOE) epsilon4 allele were associated with cognitive decline and whether the relationship between CVD and cognitive decline varied by APOE epsilon4 status. METHODS: A total of 809 cognitively normal community-dwelling residents aged >75 years were followed to detect subjects with cognitive decline, defined as follow-up. Mini-mental state examination (MMSE) score was >10% decease of the baseline score. Logistic and multinomial logistic models were developed to estimate odds ratio (OR) and 95% confidence interval (CI) of cognitive decline related to a history of CVD and APOE epsilon4 by taking into account major potential confounders including baseline MMSE score. RESULTS: During the mean 3.5 years of follow-up, 190 subjects experienced cognitive decline. Multi-adjusted ORs (95% CIs) of overall cognitive decline were 2.27 (1.23-4.17) for CVD and 1.69 (1.13-2.54) for APOE epsilon4, but no interaction was detected. Multinomial logistic analysis led to the CVD-related ORs of 1.42 (0.75-2.67) for cognitive decline without progression to dementia and 3.41 (1.55-7.55) for the decline progressing to dementia; similar analysis from a separate model led to adjusted OR of 2.28 (0.88-5.87; p=0.09) for the decline progressing to Alzheimer's disease. The risk effects of CVD on cognitive decline with progression to dementias were statistically significant mainly among individuals without APOE epsilon4 allele. CONCLUSIONS: CVD is a major risk factor for cognitive decline associated with progression to dementia and Alzheimer's disease. There appears no interaction between CVD and APOE epsilon4 on cognitive decline in very old people.

Aged↗

PubMed2006

Heritability of an age-dependent categorical phenotype: cognitive dysfunction.

We investigated the extent to which cognitive dysfunction is shaped by genetic or environmental influences, and whether these factors differ in women and men. All members of the Swedish Twin Registry aged 65 and older were screened by telephone using the TELE, a brief cognitive assessment instrument (Gatz et al., 2002), and the Blessed Dementia Rating Scale (Blessed et al., 1968) from relatives of those who scored poorly on the TELE. Data were available for 4308 pairs where both members responded and 5070 pairs where only one member was alive and participated. To analyze all available data, we used a raw data method extended to ordinal data. As the prevalence of cognitive dysfunction increases with age, we incorporated age-adjusted thresholds. The best fitting model from biometric analyses indicated 35% of the variation in liability to cognitive dysfunction could be explained by heritable influences and the remaining 65% by nonfamilial environmental influences. Differences by gender were not significant. As this is a normative population including cognitively intact individuals, preclinical dementia cases and demented individuals, the relative magnitude of genetic and environmental effects is of particular interest in light of high heritabilities found for dementias such as Alzheimer's disease. The findings emphasize the extent to which research is needed to uncover nonfamilial environmental influences on cognitive dysfunction in later life.

Age of Onset↗

PubMed2005

Global prevalence of dementia: a Delphi consensus study.

BACKGROUND: 100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region. METHODS: 12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality. FINDINGS: Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours. INTERPRETATION: We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.

Aged↗

PubMed2005

Mental, physical and social components in leisure activities equally contribute to decrease dementia risk.

BACKGROUND: There is accumulating evidence in the literature that leisure engagement has a beneficial effect on dementia. Most studies have grouped activities according to whether they were predominantly mental, physical or social. Since many activities contain more than one component, we aimed to verify the effect of all three major components on the dementia risk, as well as their combined effect. METHODS: A mental, social and physical component score was estimated for each activity by the researchers and a sample of elderly persons. The correlation between the ratings of the authors and the means of the elderly subjects' ratings was 0.86. The study population consisted of 776 nondemented subjects, aged 75 years and above, living in Stockholm, Sweden, who were still nondemented after 3 years and were followed for 3 more years to detect incident dementia cases. RESULTS: Multi-adjusted relative risks (RRs) of dementia for subjects with higher mental, physical and social component score sums were 0.71 (95% CI: 0.49-1.03), 0.61 (95% CI: 0.42-0.87) and 0.68 (95% CI: 0.47-0.99), respectively. The most beneficial effect was present for subjects with high scores in all or in two of the components (RR of dementia = 0.53; 95% CI: 0.36-0.78). CONCLUSIONS: These findings suggest that a broad spectrum of activities containing more than one of the components seems to be more beneficial than to be engaged in only one type of activity.

Aged↗

PubMed2005

Cognitive impairment is the major risk factor for development of geriatric syndromes during hospitalization: results from the GIFA study.

OBJECTIVE: To detect the main factors associated with the occurrence of specific geriatric syndromes (namely pressure sores, fecal incontinence, urinary incontinence and falls) in elderly patients during hospitalization. DESIGN: Observational prospective study. SETTING: Eighty-one community and university hospitals throughout Italy. PARTICIPANTS: 13,729 patients aged 65 years and more, consecutively admitted to medical or geriatric acute wards during 20 months in the period between 1991 and 1998. MEASUREMENTS: Occurrence of pressure sores, fecal incontinence, urinary incontinence and falls during the stay in hospital. RESULTS: Pressure sores were already present in 3% of hospitalized subjects, fecal incontinence in 7.3%, while urinary incontinence, evaluated on a subgroup of total population (4,268 subjects), had a prevalence of 22.3%. During hospitalization (mean stay of 15 days), 74 subjects developed new pressure sores, 55 became fecal and 35 urinary incontinent, and 279 subjects had at least one episode of fall. In multivariate analyses, cognitive impairment, advanced age (85+ years), length of stay (more than 3 weeks) and severe disability were the main independent predictors of development of the four geriatric syndromes, with cognitive impairment as the most significant risk factor for all the four outcomes (OR 4.9, 95% CI 2.4-9.9 for pressure sores; OR 6.3, 95% CI 3.0-13.0 for fecal incontinence; OR 5.3, 95% CI 2.3-12.0 for urinary incontinence; OR 1.6, 95% CI 1.2-2.3 for falls). CONCLUSION: Very old people have a significant increased risk of several geriatric syndromes during the stay in hospital, particularly if it is long and they are cognitively impaired. A standardized comprehensive geriatric evaluation at admission could be helpful in detecting all subjects at risk and preventing the development of hospital-acquired geriatric syndromes.

Accidental Falls↗

PubMed2005

Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.

BACKGROUND: Vascular risk factors play a role in the development of dementia, including Alzheimer disease (AD). However, little is known about the effect of body mass index and clustering of vascular risk factors on the development of dementia. OBJECTIVE: To investigate the relation between midlife body mass index and clustering of vascular risk factors and subsequent dementia and AD. DESIGN AND SETTING: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years participated in the reexamination in 1998. MAIN OUTCOME MEASURES: Dementia and AD. RESULTS: Obesity at midlife (body mass index>30 kg/m2) was associated with the risk of dementia and AD even after adjusting for sociodemographic variables (odds ratio [OR], 2.4 [95% confidence interval (CI), 1.2-5.1]). The association was somewhat modified by further adjusting for midlife blood pressure, total cholesterol level, and smoking (OR, 2.1 [95% CI, 1.0-4.6]) and also for apolipoprotein E genotype and history of vascular disorders (OR, 1.9 [95% CI, 0.8-4.6]). Midlife obesity, high total cholesterol level, and high systolic blood pressure were all significant risk factors for dementia with ORs of around 2 for each factor, and they increased the risk additively (OR, 6.2 for the combination). CONCLUSIONS: Obesity at midlife is associated with an increased risk of dementia and AD later in life. Clustering of vascular risk factors increases the risk in an additive manner. The role of weight reduction for the prevention of dementia needs to be further investigated.

Age Factors↗

PubMed2005

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.

Age Factors↗

PubMed2005

Alzheimer's disease and depression: preclinical comorbidity effects on cognitive functioning.

Both Alzheimer's disease (AD) and depression (D) are prevalent disorders in old age and may co-occur in the same individual. The present study examined whether a diagnosis of D in AD has negative effects on cognitive functioning in the preclinical stage of the diseases, as well as at the time when the diagnoses were rendered. Population-based samples of 13 individuals with incident AD and D, 109 incident AD cases without D, and 179 normal older adults were followed over a three-year period. The groups were compared preclinically and at the time of diagnosis on global cognitive functioning using the MMSE total and the specific item scores, as well as the occurrence of depressive symptoms. As expected, there were clear AD-related deficits preclinically, which were exacerbated at follow-up. In addition, there were D-related deficits on three MMSE items (i.e., following commands, reading, and writing). The poorer performance on the three MMSE items was linked to an elevation of depressive symptoms. However, D was not associated with greater decline in cognitive functioning over the three-year follow-up period. Thus, although depressive symptoms may result in slight cognitive deficits in preclinical AD, at the time of the dementia diagnosis these effects may be absorbed by the neurodegenerative process.

Aged↗

PubMed2005

The age-dependent relation of blood pressure to cognitive function and dementia.

The relation of blood pressure with cognitive function and dementia has, in recent years, received much attention from epidemiological research. Some cross-sectional studies have shown an inverse association between blood pressure and the prevalence of dementia and Alzheimer's disease, whereas longitudinal studies yield mixed results that largely depend on the age at which blood pressure is measured and the time interval between blood pressure and outcome assessments. Some studies suggest that midlife high blood pressure is a risk factor for late-life cognitive impairment and dementia, and that low diastolic pressure and very high systolic pressure in older adults may be associated with subsequent development of dementia and Alzheimer's disease. Observational studies and randomised clinical trials provide limited evidence for a protective effect of antihypertensive therapy against dementia and stroke-related cognitive decline. Atherosclerosis resulting from long-standing hypertension, and cerebral hypoperfusion secondary to severe atherosclerosis and to low blood pressure may be major biological pathways linking both high blood pressure in midlife and low blood pressure in late-life to cognitive decline and dementia.

Aged↗

PubMed2005

Performance on neurocognitive tests by co-twins to dementia cases compared to normal control twins.

Nondemented co-twins of twins who were diagnosed as demented were compared to randomly selected members of normal control twin pairs in which both members of the pair were nondemented. Nondemented co-twins included 23 monozygotic and 62 dizygotic twins; there were 27 normal control twins. Both monozygotic and dizygotic nondemented co-twins of dementia cases scored significantly lower than normal control twins on 5 of 10 cognitive tests. Moreover, monozygotic co-twins of dementia cases had a generally lower score profile than dizygotic co-twins of dementia cases did. These findings show that being at greater genetic risk for dementia is reflected in cognitive performance even in the absence of a diagnosis of dementia.

Aged↗

PubMed2005

Longitudinal models of growth and survival applied to the early detection of Alzheimer's disease.

This article explores new statistical methodologies for using longitudinal data in the early prediction of Alzheimer's disease (AD). Specifically, the authors examine some new techniques that allow the joint or "shared" estimation of longitudinal components based on both duration (survival) and quantitative changes (growth curves). These new shared growth-survival parameter models may be used to characterize the declining functions that anticipate the onset of AD. The authors apply these models to data from the Kungsholmen Project, a longitudinal study of aging in Stockholm, Sweden. They examine age-based survival-frailty models for the onset of AD, latent growth-decline curve models for changes in cognition over age, and 3 alternative forms of models for the shared relationships of survival and early cognitive decline. The accuracy and reliability of this approach is considered for a better understanding of the developmental course of AD in these data, including the potential removal of biases due to subject selection.

Adult↗

PubMed2005

[Variability of epidemiological measures in mild cognitive impairment and dementia].

Variability in occurrence estimates is one of the basic features of the epidemiology of dementia and mild cognitive impairment (MCI). This review will cover two levels of variability that affect epidemiological research on dementia and MCI: the conceptual and the operational level. More specifically, it is highlighted how the lack of a precise definition of MCI leads to a greater variability in the occurrence estimates of this condition, when compared to dementia. Variability will decrease only when more precise criteria and aims of the concept "MCI" will be specified.

Aged↗