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Predictors of Dementia: Insulin, Fatty Acids and Vascular Risk Factors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy. (Geriatrik)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Identification of modifiable risk factors for Alzheimer’s disease (AD) is crucial in order to diminish suffering from this devastating disease. The aim of this thesis was to investigate if different aspects of glucose metabolism, insulin, fatty-acid composition or other vascular risk factors predict the future development of AD and dementia.

This thesis is based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, which started in 1970. A total of 2322 men at age 50 were examined with focus on vascular risk factors. The cohort was re-examined at ages 60, 71, 77, 82 and 88. Incident diagnoses of AD, vascular dementia, other dementias and cognitive impairment were assessed in 2005–2010.

The risk of AD was increased in subjects with lower early insulin response measured with both an intravenous glucose tolerance test at 50 years and an oral glucose tolerance test at 71 years of age. The presence of vascular risk factors such as hypertension, obesity, hypercholesterolemia and smoking increased the risk of future vascular dementia but not of AD. Furthermore, saturated fatty acids at midlife were inversely associated with risk of AD. No evidence of a protective effect of omega-3 fatty acids against dementia was found.

The susceptibility allele, APOE ε4, was the strongest individual risk factor. APOE ε4 carriers with vascular risk factors had the greatest risk of developing dementia. Low insulin response was a risk factor for AD mainly in APOE ε4 non-carriers.

Disturbances in insulin and glucose metabolism, vascular risk factors and fatty acids are linked differentially to the pathogenesis of AD and vascular dementia. These observations should be considered when future clinical approaches are planned to prevent and postpone the onset of dementia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 734
Keyword [en]
dementia, Alzheimer’s disease, vascular dementia, insulin secretion, diabetes, fatty acids, epidemiology, vascular risk factors
National Category
Clinical Medicine
Research subject
Geriatrics
Identifiers
URN: urn:nbn:se:uu:diva-164528ISBN: 978-91-554-8248-0 (print)OAI: oai:DiVA.org:uu-164528DiVA: diva2:468449
Public defence
2012-02-15, Enghoffssalen, Akademiska sjukhuset ing 50 bv, Uppsala, 13:00 (English)
Opponent
Supervisors
Projects
ULSAM
Available from: 2012-01-23 Created: 2011-12-20 Last updated: 2012-01-24
List of papers
1. Impaired insulin secretion increases the risk of Alzheimer disease
Open this publication in new window or tab >>Impaired insulin secretion increases the risk of Alzheimer disease
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2008 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 14, 1046-47 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia. METHODS: The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models. RESULTS: A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10-1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE epsilon4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05-2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment. CONCLUSIONS: In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16349 (URN)10.1212/01.wnl.0000310646.32212.3a (DOI)000259649100006 ()18401020 (PubMedID)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2017-12-08Bibliographically approved
2. Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men
Open this publication in new window or tab >>Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men
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2009 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 8, 1504-1510 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. METHODS: The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. RESULTS: Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. CONCLUSIONS/INTERPRETATION: In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.

Keyword
Alzheimer's disease, Diabetes, Insulin, Insulin resistance, Vascular dementia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-123412 (URN)10.1007/s00125-009-1393-9 (DOI)000268006200007 ()19455303 (PubMedID)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-12-12Bibliographically approved
3. Serum fatty-acid composition and the risk of Alzheimer’s disease: a longitudinal population based study
Open this publication in new window or tab >>Serum fatty-acid composition and the risk of Alzheimer’s disease: a longitudinal population based study
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2012 (English)In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 66, no 8, 885-890 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND/OBJECTIVES:

It is unknown if a specific fatty-acid composition influences the development of Alzheimer's disease (AD). Nutrition is a possible target for prevention of dementia and especially omega-3-based fatty acids (n-3 FAs) have previously been suggested to be beneficial for cognition. The objective was to ascertain whether serum FAs predicts the risk of incident AD and dementia in a longitudinal population-based cohort.

SUBJECTS/METHODS:

Uppsala Longitudinal Study of Adult Men started in 1970. The proportions of FAs in serum cholesteryl esters were estimated in men (n=2009) who were 50 years old at baseline. During a 35 year follow-up time, 213 men had developed dementia, out of which 91 AD. The associations were analyzed with Cox proportional hazards and logistic regression; adjusted for age, education and vascular risk factors.

RESULTS:

Subjects with a higher proportion of saturated FAs had a decreased risk of AD in crude and multi-adjusted models (hazard ratio for 1-s.d. increase in palmitic acid 0.72; 95% confidence intervals: 0.59-0.89). These associations persisted even in the group of approximately 85-year-old survivors. n-3 FAs FAs were not associated with decreased risk of AD or dementia.

CONCLUSIONS:

In contrast to experimental studies, saturated FAs were inversely associated with risk of AD. No evidence of a protective effect of n-3 FAs against dementia was found. The results remained essentially unchanged if competing risk from mortality was taken into account.

Keyword
fatty acid, alzheimer's disease, dementia
National Category
Medical and Health Sciences
Research subject
Geriatrics
Identifiers
urn:nbn:se:uu:diva-164527 (URN)10.1038/ejcn.2012.63 (DOI)000307236900003 ()22713770 (PubMedID)
Projects
ULSAM
Available from: 2011-12-20 Created: 2011-12-20 Last updated: 2017-12-08
4. Vascular Risk Factors and Dementia: 40-Year Follow-Up of a Population-Based Cohort
Open this publication in new window or tab >>Vascular Risk Factors and Dementia: 40-Year Follow-Up of a Population-Based Cohort
2011 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 31, no 6, 460-466 p.Article in journal (Refereed) Published
Abstract [en]

Aims: Our aim was to evaluate the longitudinal associations of individual and multiple vascular risk factors with the subsequent development of dementia and Alzheimer's disease (AD). Methods: The Uppsala Longitudinal Study of Adult Men started in 1970 when the 2,268 participants were 50 years old. Baseline investigations included determinations of blood pressure, fasting glucose, cholesterol, BMI and smoking status. Over a maximum follow-up of 40 years, 349 participants were diagnosed with dementia, out of which 127 had AD. Analyses were repeated using a re-examination of the cohort at 70 years of age as a baseline. Results: No associations between vascular risk factors and AD were found. For all-type dementia, the association between high systolic blood pressure and dementia was the most consistent. High fasting glucose was associated with increased risk of all-type dementia only when measured at 70 years. Individuals with both an APOE epsilon 4 allele and vascular risk factors had the greatest dementia risk. Conclusion: Vascular risk factors influence the future risk of dementia, in particular vascular and mixed-type rather than AD. The impact of vascular risk factors on dementia in a longitudinal study depends on the age at baseline and the length of follow-up. Copyright

Keyword
Alzheimer's disease, Apolipoprotein epsilon 4, Epidemiology, Glucose, Hypertension, Lipids, Obesity, Smoking, Vascular dementia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-158428 (URN)10.1159/000330020 (DOI)000293835800010 ()21791923 (PubMedID)
Available from: 2011-09-08 Created: 2011-09-07 Last updated: 2017-12-08Bibliographically approved

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