| 1. |
- Forsell, Charlotte, et al.
(author)
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Genetic association to the amyloid plaque associated protein gene COL25A1 in Alzheimer's disease
- 2010
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In: Neurobiology of Aging. - Fayetteville, N.Y. : Ankho International. - 0197-4580 .- 1558-1497. ; 31:3, s. 409-415
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Journal article (peer-reviewed)abstract
- The COL25A1 gene, located in 4q25, encodes the CLAC protein, which has been implicated in Alzheimer's disease (AD) pathogenesis. CLAC was originally identified in amyloid preparations from AD brain and has been shown to be associated with amyloid plaques, inhibition of Abeta-fibril elongation and increased protease resistance of Abeta-fibrils through direct binding to Abeta. These biochemical data as well as the genomic location of the COL25A1 gene in chromosome 4q25 where we previously have reported a weak linkage-signal in Swedish AD families encouraged us to perform a case-control association study of two LD blocks in COL25A1 using 817 AD cases and 364 controls. The LD blocks cover a putative Abeta-binding motif and the variable 3' end of the gene. The analyses indicated association to three of eight analysed SNPs. We found further support for the association by replication in a Swedish population-based longitudinal sample set (n=926). Thus, in addition to the biochemical data, there is now genetic evidence of association between COL25A1 and risk for Alzheimer's disease.
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| 2. |
- Fratiglioni, Laura, et al.
(author)
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Prevention of Alzheimer's disease and dementia : Major findings from the Kungsholmen Project
- 2007
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In: Physiology and Behavior. - : Elsevier. - 0031-9384 .- 1873-507X. ; 92:1-2, s. 98-104
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Journal article (peer-reviewed)abstract
- The aging of the population is a worldwide phenomenon, and studying age-related diseases has become a relevant issue from both a scientific and a public health perspective. This review summarises the major findings concerning prevention of Alzheimer's disease (AD) and other dementias from a population-based study, the Kungsholmen Project. The study addresses risk- and protective factors for AD and dementia from a lifetime perspective: at birth, during childhood, in adult life, and in old age. Although many aspects of the dementias are still unclear, some risk factors have been identified and interesting hypotheses have been suggested for other putative risk or protective factors. At the moment it is also possible to delineate some preventative strategies for dementia.
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| 3. |
- Handels, Ron L. H., et al.
(author)
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Natural Progression Model of Cognition and Physical Functioning among People with Mild Cognitive Impairment and Alzheimer's Disease
- 2013
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 37:2, s. 357-365
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Journal article (peer-reviewed)abstract
- Background: Empirical models of the natural history of Alzheimer's disease (AD) may help to evaluate new interventions for AD. Objective: We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases. Methods: Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged >= 75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models. Results: Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender. Conclusion: Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD.
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| 4. |
- Huang, Wenyong, et al.
(author)
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APOE Genotype, Family History of Dementia, and Alzheimer Disease Risk : A 6-Year Follow-up Study
- 2004
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In: Archives of Neurology. - : American Medical Association. - 0003-9942 .- 1538-3687. ; 61:12, s. 1930-1934
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Journal article (peer-reviewed)abstract
- Background Both family aggregation and apolipoprotein E (APOE) ε4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear.Objective To explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOE genotypes.Design Community-based cohort study.Setting The Kungsholmen district of Stockholm, Sweden.Participants A total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.Main Outcome Measures Risk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders.Results Subjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE ε4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the ε4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non–ε4 carriers.Conclusions Family history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE ε4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE ε4 allele.The role of both family history of dementia and the apolipoprotein E (APOE) gene in the development of Alzheimer disease (AD) has been extensively investigated. There is strong evidence to suggest that APOE ε4 allele carriers, as well as subjects with a family history of dementia, have an increased risk of AD.Familial aggregation and genetic risk factors appear to be most influential in AD at relatively early ages.However, there are reports supporting an effect of both familial aggregation and APOE ε4 even in late-onset AD,although a lower effect in comparison with early-onset cases has been detected.It is hypothesized that APOE ε4 allele might explain the association between family history of dementia and AD. Previous studies have tried to evaluate this hypothesis, but to what extent familial aggregation is due to the association between the ε4 allele and AD remains equivocal. Some studies indicated that ε4-positive patients with AD tended to have a higher rate of family history of dementia than ε4-negative patients. Conversely, patients with family history of AD are also more likely to carry the ε4 allele than patients without family history.Other studies, however, showed that the APOE ε4 allele was not related to familial aggregation of AD.Most previous analyses have been hospital-based case-control studies. Because of ascertainment bias and severe truncation of data, these studies might overestimate the effects of family history and APOE ε4 allele, especially in very old people. Only a small-scale prospective study has examined both family history of dementia and APOE ε4 allele in relation to AD risk among people 75 years or older.In a previous study within the Kungsholmen Project, a strong familial aggregation was detected among prevalent cases of late-onset AD, but the contribution of the APOE ε4 allele was not considered. In the present study, we examined the 6-year follow-up data from the same project to explore whether the risk of dementia and AD due to a positive family history is explained by APOE genotypes.
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| 7. |
- Keller, Lina, et al.
(author)
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The Obesity Related Gene, FTO, Interacts with APOE and is Associated with Alzheimer's Disease Risk : A Prospective Cohort Study
- 2011
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 23:3, s. 461-469
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Journal article (peer-reviewed)abstract
- The FTO gene has been shown to have a small but robust effect on body mass index (BMI) and to increase the risk for diabetes. Both high BMI and diabetes are vascular risk factors that might play a role in the development of Alzheimer's disease (AD) and dementia. Thus, our aim was to explore the impact of FTO on AD and dementia risk. Nine years of follow-up data was gathered from the Kungsholmen project, a prospective population-based study on 1,003 persons without dementia. Cox-regression models were used to assess the relative risks of developing AD and dementia (DSM-III-R criteria) according to FTO genotypes (rs9939609), taking into account APOE, physical inactivity, BMI, diabetes, and cardiovascular disease (CVD). Compared to carriers of the FTO TT-genotype, AA-carriers had a higher risk for AD (RR 1.58, 95% CI: 1.11-2.24) and for dementia (RR 1.48, 95% CI: 1.09-2.02) after adjustment for age, gender, education, and APOE genotype. This effect remained after additional adjustment for physical inactivity, BMI, diabetes, and CVD. An interaction between FTO and APOE was found, with increased risk for dementia for those carrying both FTO AA and APOE epsilon 4. Importantly, the effect of the AA-genotype on dementia/AD risk seems to act mostly through the interaction with APOE epsilon 4. Our findings suggest that the FTO AA-genotype increases the risk for dementia, and in particular AD, independently of physical inactivity, BMI, diabetes, and CVD measured at baseline. Our results are in line with the recently reported association between FTO and reduced brain volume in cognitively healthy subjects.
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| 8. |
- Mangialasche, Francesca, et al.
(author)
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High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in advanced age
- 2010
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In: Journal of Alzheimer's disease : JAD. - Amsterdam, Washington : IOS Press. - 1875-8908. ; 58:3, s. 131-140
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Journal article (peer-reviewed)abstract
- In this study we investigated the association between plasma levels of eight forms of vitamin E and incidence of Alzheimer's disease (AD) among oldest-old individuals in a population-based setting. A dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (alpha-, beta-, gamma, and delta-tocopherol; alpha-, beta-, gamma-, and delta-tocotrienol) were measured at baseline. Vitamin E forms-AD association was analyzed with Cox proportional hazard model after adjustment for several potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total vitamin E in the highest tertile had a reduced risk of developing AD in comparison to persons in the lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32-0.94) for total tocopherols, 0.46 (0.23-0.92) for total tocotrienols, and 0.55 (0.32-0.94) for total vitamin E. When considering each vitamin E form, the risk of developing AD was reduced only in association with high plasma levels of beta-tocopherol (HR: 0.62, 95% CI 0.39-0.99), whereas alpha-tocopherol, alpha- tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model [HR (95% CI): alpha-tocopherol: 0.72 (0.48-1.09); alpha-tocotrienol: 0.70 (0.44-1.11); beta-tocotrienol: 0.69 (0.45-1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is currently debated.
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| 9. |
- Paillard-Borg, Stéphanie, et al.
(author)
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An active lifestyle postpones dementia onset by more than one year in very old adults
- 2012
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 52, s. 216-216
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Journal article (peer-reviewed)abstract
- The purpose of this study was to test the hypothesis that an active lifestyle delays age at dementia onset. This study included 388 incident dementia cases (DSM-III-R criteria) that developed over a 9-year follow-up period among 1,375 baseline dementia-free community dwellers with good cognitive function (MMSE > 23) (mean age = 81.2) from the Kungsholmen Project. An active lifestyle was defined as participation in mental, physical, or social activity. We used linear regression models to estimate influence of baseline active lifestyle on age at onset of incident dementia and general linear models to estimate mean age at dementia onset. Age at onset of dementia was significantly older in persons who had higher levels of participation in mental, physical, or social activity (beta: 0.18, 0.29 and 0.23 respectively, p < 0.001 for all the activities) independent of education, medical condition, functional status, and other confounders including APOE. When the three types of activities were integrated into an index, we found that the broader the spectrum of participation in the activities, the later the onset of disease (beta = 0.93, p = 0.01 for participating in two activities, and beta = 1.42, p < 0.001 for three activities). There were 17 months difference in mean age at dementia onset between the inactive group and the most active group. An active lifestyle operates as a protective factor for dementia by delaying the clinical onset of the disease. These findings highlight the relevance of encouraging old adults to have active lifestyles, which could have a great impact on public health.
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| 10. |
- Qiu, Chengxuan, et al.
(author)
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Decline in blood pressure over time and risk of dementia : a longitudinal study from the Kungsholmen project
- 2004
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In: Stroke. - : American Stroke Association. - 0039-2499 .- 1524-4628. ; 35:8, s. 1810-1815
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Journal article (peer-reviewed)abstract
- Background and Purpose—Low blood pressure has been related to an increased risk of dementia. We sought to verify blood pressure variations before and after a dementia diagnosis and to relate blood pressure decline to subsequent Alzheimer disease and dementia.Methods—A community dementia-free cohort aged _75 years (n_947) underwent follow-up examinations twice over a period of 6 years to detect dementia cases (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised [DSM-III-R] criteria, n_304). Blood pressure variation before and after dementia diagnosis was verified with linear mixed-effects models. Using the dementia-free cohort identified at first follow-up (n_719), the association between blood pressure decline from baseline to first follow-up and subsequent risk of dementia was examined.Results—Blood pressure markedly decreased over 3 years before dementia diagnosis and afterward, whereas no substantial decline was present 3 to 6 years before the diagnosis. However, among subjects with baseline systolic pressure _160 mm Hg, systolic pressure decline _15 mm Hg occurring 3 to 6 years before diagnosis was associated with relative risks (95% CI) of 3.1 (1.3 to 7.0) for Alzheimer disease and 3.1 (1.5 to 6.3) for dementia. There was a dose–response relationship between systolic pressure decline and dementia risk in subjects with vascular disease.Conclusions—Blood pressure starts to decrease only 3 years before dementia diagnosis and continues to decline afterward. A greater decline in systolic pressure occurring 3 to 6 years before diagnosis is associated with an increased risk of dementia only in older people with already low blood pressure or affected by vascular disorders.
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