Alzheimer Disease: Tuomilehto J

Kivipelto M, Laakso MP, Tuomilehto J, Nissinen A, Soininen H. · Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. · CNS Drugs. · Pubmed #12056919 No free full text.

Abstract: This paper focuses on hypertension and hypercholesterolaemia as risk factors for Alzheimer's disease and, as such, subjects for prevention. The long-term, prospective, population-based studies regarding the relationship between hypertension or hypercholesterolaemia and Alzheimer's disease, and the clinical studies regarding the association between antihypertensive or lipid-lowering medications and the risk of Alzheimer's disease, are reviewed. These studies provide evidence to suggest that elevated blood pressure and cholesterol levels earlier in life may have an important role in the development and expression of late-life Alzheimer's disease. Based on these data, we propose that proper, early interventions aimed at reducing these cardiovascular risk factors may have an impact on the future incidence and prevalence of Alzheimer's disease.

Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Stockholm, Sweden. · Lancet Neurol. · Pubmed #16239176 No free full text.

Abstract: BACKGROUND: Physical activity may help maintain cognitive function and decrease dementia risk, but epidemiological findings remain controversial. The aim of our study was to investigate the association between leisure-time physical activity at midlife and the subsequent development of dementia and Alzheimer's disease (AD). METHODS: Participants were randomly selected from the survivors of a population-based cohort previously surveyed in 1972, 1977, 1982, or 1987. 1449 persons (72.5%) age 65-79 years participated in the re-examination in 1998 (mean follow-up, 21 years). 117 persons had dementia and 76 had AD. Multiple logistic regression methods were used to analyse the association between leisure-time physical activity and dementia or AD. FINDINGS: Leisure-time physical activity at midlife at least twice a week was associated with a reduced risk of dementia and AD (odds ratio [OR] 0.48 [95% CI 0.25-0.91] and 0.38 [0.17-0.85], respectively), even after adjustments for age, sex, education, follow-up time, locomotor disorders, APOE genotype, vascular disorders, smoking, and alcohol drinking. The associations were more pronounced among the APOE epsilon4 carriers. INTERPRETATION: Leisure-time physical activity at midlife is associated with a decreased risk of dementia and AD later in life. Regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals.

Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T, Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Birkenhäger WH, Anonymous00263. · Department of Geriatrics, Hôpital Broca, CHU Cochin, University of Paris V, 54-56 rue Pascal, 75013 Paris, France. · Arch Intern Med. · Pubmed #12374512 links to  free full text

Abstract: BACKGROUND: After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation. OBJECTIVE: To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia. METHODS: Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs. RESULTS: Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33). CONCLUSION: The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

Kivipelto M, Rovio S, Ngandu T, Kåreholt I, Eskelinen M, Winblad B, Hachinski V, Cedazo-Minguez A, Soininen H, Tuomilehto J, Nissinen A. · Aging Research Center, NVS, Karolinska Institutet, Stockholm, Sweden. · J Cell Mol Med. · Pubmed #18318693 No free full text.

Abstract: The risk of dementia and Alzheimer's disease (AD) probably results from an interaction between genetic and environmental factors. The aim of this study was to investigate the effects and putative interactions between the apoE epsilon4 allele and lifestyle related risk factors for dementia and AD. Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982 or 1987. After an average follow-up of 21 years, 1449 individuals (72.5%) aged 65-79 years were re-examined in 1998. The apoE epsilon4 allele was an independent risk factor for dementia/AD even after adjustments for sociodemographic, lifestyle and vascular factors (odds ratio [OR]=2.83, 95% confidence interval [CI]=1.61-4.97). Physical inactivity, alcohol drinking and smoking increased the risk of dementia/AD particularly among the apoE epsilon4 carriers. Furthermore, low-moderate intake of polyunsaturated, and moderate-high intake of saturated fats were associated with an increased risk of dementia/AD more pronouncedly among apoE epsilon4 carriers. Composite effect of the lifestyle factors was particularly seen among the epsilon4 carriers (OR=11.42, 95% CI=1.94-67.07 in the 4th quartile). Physical inactivity, dietary fat intake, alcohol drinking and smoking at midlife are associated with the risk of dementia and AD, especially among the apoE epsilon4 carriers. The apoE epsilon4 carriers may be more vulnerable to environmental factors, and thus, lifestyle interventions may greatly modify dementia risk particularly among the genetically susceptible individuals.

Ngandu T, von Strauss E, Helkala EL, Winblad B, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. · Aging Research Center, Karolinska Institutet, Gävlegatan 16, 11330 Stockholm, Sweden. · Neurology. · Pubmed #17909157 No free full text.

Abstract: BACKGROUND: Low education seems to be associated with an increased risk of dementia and Alzheimer disease (AD). People with low education have unhealthier lifestyles and more cardiovascular risk factors, but it is unclear how this affects the association between education and dementia. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals (72%) aged 65 to 79 participated in a re-examination in 1998. RESULTS: Compared to individuals with formal education of 5 years or less, those with 6 to 8 years of education had OR of 0.57 (95% CI 0.29 to 1.13), and those with 9 years of education or more had OR of 0.16 (95% CI 0.06 to 0.41) for dementia. The corresponding ORs for AD were 0.49 (0.24 to 1.00) and 0.15 (0.05 to 0.40). The associations remained unchanged after adjustments for several demographic, socioeconomic, vascular, and lifestyle characteristics. The results were similar among both men and women. ApoE4 did not modify the association, but the risk of dementia and AD was very low among ApoE4 noncarriers with high education. CONCLUSIONS: The association between low education and dementia is probably not explained by the unhealthy lifestyles of the less educated compared with higher educated persons. Higher educated persons may have a greater cognitive reserve that can postpone the clinical manifestation of dementia. Unhealthy lifestyles may independently contribute to the depletion of this reserve or directly influence the underlying pathologic processes.

Rovio S, Kåreholt I, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M. · Aging Research Center, NVS, Karolinska Institutet, Stockholm, Sweden. · Int J Geriatr Psychiatry. · Pubmed #17721898 No free full text.

Abstract: BACKGROUND: Leisure-time physical activity has been related with a reduced risk of dementia and Alzheimer's disease (AD). The effects of occupational and commuting physical activity (physical activity at work and on the way to work) on cognitive health are still unclear. This study aimed to clarify the association between work-related physical activity and dementia/AD. METHODS: 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 re-examination in 1998. RESULTS: Neither occupational [Odds Ratio (OR) 1.45; 95% Confidence Intervals (CI) 0.66-3.17] nor commuting physical activity (OR 0.46; 95% CI 0.10-2.17) were associated with the risk of dementia or AD after adjustments for age, sex, education, follow-up time, locomotor symptoms, main occupation during life, income at midlife, leisure-time physical activity, other subtype of work-related physical activity, ApoE genotype, vascular disorders and the smoking status. There were also no interactions between work-related physical activity and the ApoE epsilon4 genotype, leisure-time physical activity or sex. CONCLUSIONS: In this study, work-related physical activity was not found to be sufficient to protect against dementia and AD later in life. The lack of effect might be partly due to a residual confounding. Nevertheless, physical activity during leisure-time may be beneficial even for people who are physically active at work or when commuting.

Solomon A, Kåreholt I, Ngandu T, Winblad B, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. · Department of Neuroscience and Neurology, University of Kuopio, Finland. · Neurology. · Pubmed #17339582 No free full text.

Abstract: BACKGROUND: Longitudinal studies have shown that high serum total cholesterol (TC) at midlife is a risk factor for dementia/Alzheimer disease. The significance of TC later in life is unclear. OBJECTIVE: To investigate changes in serum TC from midlife to late life and their relationship with late-life cognition. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia study were derived from random, population-based samples previously studied in a survey in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals aged 65 to 79 were reexamined in 1998. RESULTS: Serum TC levels decreased in most individuals. High midlife TC represented a risk factor for more severe cognitive impairment later in life, and the values were significantly different between the control, mild cognitive impairment, and dementia groups. There were no significant differences in serum TC at reexamination. A moderate decrease in serum TC from midlife to late life (0.5 to 2 mmol/L) was significantly associated with the risk of a more impaired late-life cognitive status, even after adjusting for age, follow-up time, sex, years of formal education, midlife cholesterol, changes in body mass index, APOE epsilon4 genotype, history of myocardial infarction/stroke/diabetes, and lipid-lowering treatment. CONCLUSIONS: The relationship between serum total cholesterol (TC) and dementia seems to be bidirectional. High midlife serum TC is a risk factor for subsequent dementia/Alzheimer disease, but decreasing serum TC after midlife may reflect ongoing disease processes and may represent a risk marker for late-life cognitive impairment.

Laitinen MH, Ngandu T, Rovio S, Helkala EL, Uusitalo U, Viitanen M, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Stockholm, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #16710090 No free full text.

Abstract: BACKGROUND: Lifestyle and vascular factors have been linked to dementia and Alzheimer's disease (AD), but the role of dietary fats in the development of dementia is less clear. METHODS: Participants were derived from random, population-based samples initially studied in midlife (1972, 1977, 1982, or 1987). Fat intake from spreads and milk products was assessed using a structured questionnaire and an interview. After an average follow-up of 21 years, a total of 1,449 (73%) individuals aged 65-80 years participated in the re-examination in 1998. Altogether 117 persons had dementia. RESULTS: Moderate intake of polyunsaturated fats at midlife decreased the risk of dementia even after adjustment for demographic variables, other subtypes of fats, vascular risk factors and disorders, and apolipoprotein E (ApoE) genotype (OR 0.40, CI 0.17-0.94 for the 2nd quartile vs. 1st quartile), whereas saturated fat intake was associated with an increased risk (OR 2.45, CI 1.10-5.47 for the 2nd quartile). The associations were seen only among the ApoE epsilon4 carriers. CONCLUSIONS: Moderate intake of unsaturated fats at midlife is protective, whereas a moderate intake of saturated fats may increase the risk of dementia and AD, especially among ApoE epsilon4 carriers. Thus, dietary interventions may potentially modify the risk of dementia, particularly among genetically susceptible individuals.

Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Stockholm, Sweden. · Arch Neurol. · Pubmed #16216938 links to  free full text

Abstract: 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.

Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H. · University of Kuopio, Department of Neuroscience and Neurology, PO Box 1627, 70211 Kuopio, Finland. · Ann Intern Med. · Pubmed #12160362 links to  free full text

Abstract: BACKGROUND: Presence of the apolipoprotein E (apoE) epsilon4 allele, which is involved in cholesterol metabolism, is the most important genetic risk factor for Alzheimer disease. Elevated midlife values for total cholesterol level and blood pressure have been implicated recently as risk factors for Alzheimer disease. OBJECTIVE: To study the relative importance and the putative relationship among the apoE epsilon4 allele, midlife total cholesterol level, and midlife blood pressure as risk factors for late-life Alzheimer disease. DESIGN: Prospective population-based study. SETTING: Kuopio and Joensuu, eastern Finland. PARTICIPANTS: Participants were derived from random population surveys from 1972, 1977, 1982, and 1987. A total of 1449 persons (73%), 65 to 79 years of age, participated in the reexamination in 1998 (mean follow-up, 21 years). MEASUREMENTS: Midlife blood pressure and total cholesterol level, apoE genotype, and development of Alzheimer disease during follow-up. RESULTS: The apoE epsilon4 allele was an independent risk factor for Alzheimer disease, even after adjustment for midlife vascular risk factors and other confounders (odds ratio, 2.1 [95% CI, 1.1 to 4.1]). Similarly, elevated midlife values for serum total cholesterol level (odds ratio, 2.8 [CI, 1.2 to 6.7]) and systolic blood pressure (odds ratio, 2.6 [CI, 1.1 to 6.6]) were independent risk factors for Alzheimer disease, even after adjustment for apoE genotype and other confounding factors. CONCLUSIONS: The association between the apoE epsilon4 allele and Alzheimer disease does not seem to be mediated by vascular factors. The apoE epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for Alzheimer disease. The risk for Alzheimer disease from treatable factors--elevated total cholesterol level and blood pressure--appears to be greater than that from the apoE epsilon4 allele.

Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. · Department of Neuroscience and Neurology, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. · BMJ. · Pubmed #11408299 links to  free full text

Abstract: OBJECTIVE: To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life. DESIGN: Prospective, population based study. SETTING: Populations of Kuopio and Joensuu, eastern Finland. PARTICIPANTS: Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65-79 took part in the re-examination in 1998. MAIN OUTCOME MEASURES: Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life. RESULTS: People with raised systolic blood pressure (>/=160 mm Hg) or high serum cholesterol concentration (>/=6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease. CONCLUSION: Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.