Eeva-Liisa Helkala

Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease

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 Alzheimers 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.

Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study

Objective: To evaluate the impact of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of mild cognitive impairment (MCI) and to investigate the prevalence of MCI in elderly Finnish population, applying the MCI criteria devised by the Mayo Clinic Alzheimer’s Disease Research Center. Background: MCI has been considered as a predictor of AD. Vascular risk factors may be important in the development of cognitive impairment and AD. However, the role of vascular risk factors in MCI and the prevalence of MCI still remain virtually unknown. Methods: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1,449 subjects aged 65 to 79 years were reexamined in 1998. Results: Eighty-two subjects, 6.1% of the population (average age, 72 years) met the criteria for MCI. Midlife elevated serum cholesterol level (≥6.5 mmol/L) was a significant risk factor for MCI (OR, 1.9; 95% CI, 1.2 to 3.0, adjusted for age and body mass index); the effect of systolic blood pressure approached significance. Conclusion: Data point to a role for midlife vascular risk factors in the development of MCI in late life.

Apolipoprotein E 4 Allele, Elevated Midlife Total Cholesterol Level, and High Midlife Systolic Blood Pressure Are Independent Risk Factors for Late-Life Alzheimer Disease

Context Apolipoprotein E (apoE) 4 allele, elevated total cholesterol level, and hypertension are risk factors for late-life Alzheimer disease. Are these risk factors independent, or do the effects of apoE polymorphism on cholesterol metabolism mediate the association between apoE and Alzheimer disease? Contribution In this long-term, prospective population-based study, apoE, elevated total cholesterol level, and elevated systolic hypertension increased the risk for Alzheimer disease in an independent and additive manner. Implications The mechanism by which apoE polymorphism contributes to the development of Alzheimer disease appears different than the mechanism that mediates its effect on cholesterol level. Some risk factors for Alzheimer disease (dyslipidemia and systolic hypertension) are potentially treatable, while others (apoE) are not. The Editors Alzheimer disease is a disease of complex origin, and the exact pathogenic mechanisms remain unknown. Several environmental and genetic factors have been implicated in the development of Alzheimer disease. Two lines of research have recently shown an association between serum total cholesterol level and development of the disease. First, two independent, prospective population-based studies have reported an association between elevated midlife total cholesterol levels and late-life Alzheimer disease (1, 2). Second, two recent studies have shown a reduced rate of the disease in persons who used statins to reduce their blood total cholesterol level (3, 4). To date, only the apolipoprotein E (apoE) 4 allele, which is involved in cholesterol metabolism, has been established as a significant genetic risk factor for Alzheimer disease in the general population (5). Whether the associations of elevated level of serum total cholesterol and apoE polymorphism with Alzheimer disease are independent or interrelated is unknown. Earlier cross-sectional and short follow-up studies yielded conflicting results on the putative relationship among apoE, total cholesterol level, and Alzheimer disease (6-8). Although long-term prospective studies may be better suited for resolving this issue, only two such studies have been reported to date. The first study found that elevated serum total cholesterol level was a risk factor for Alzheimer disease, independent of the apoE 4 allele; however, the association between the apoE 4 allele and Alzheimer disease became weaker after adjustment for serum total cholesterol level (1). Thus, the authors of that study concluded that some of the effect of the apoE 4 allele on the risk for Alzheimer disease might be mediated through elevated levels of serum total cholesterol. In contrast, another prospective study suggested that the presence of the apoE 4 allele may increase the risk for Alzheimer disease, independent of its effect on dyslipidemia and atherogenesis (9). Few prospective studies have suggested that elevated blood pressure earlier in life could increase the risk for Alzheimer disease (2, 10, 11). Although the association between apoE and blood pressure appears to be vague, some studies have reported excess cognitive decline in persons with hypertension who have the apoE 4 allele (12, 13). Moreover, atherosclerosis, which can result from an elevated total cholesterol level or blood pressure, has been studied in relation to Alzheimer disease and apoE polymorphism, also with conflicting results (14, 15). Alzheimer disease is becoming an increasingly serious public health problem. Interventions that could delay disease onset could therefore have a major public health impact. The number of patients with Alzheimer disease is projected to quadruple over the next 50 years, and interventions that would postpone the onset of clinical Alzheimer disease by 5 years would decrease the prevalence of the disease by 50% (16). Alzheimer disease might be prevented by use of interventions for modifiable vascular risk factors. However, the relative importance and putative interactions between vascular risk factors and the apoE polymorphism in the development of Alzheimer disease in the general population remain to be established. We have previously reported that elevated total cholesterol level and systolic blood pressure during midlife increased the risk for Alzheimer disease (2). We recently determined the apoE genotypes in this sample and have therefore been able to study the putative relationship among the apoE 4 allele, midlife total cholesterol level, and midlife blood pressure in the development of Alzheimer disease in a prospective, population-based study setting. Methods Participants The participants in this study were derived from four separate, independent population-based samples studied within the framework of the North Karelia Project and the Finnish part of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (FINMONICA) studies in 1972, 1977, 1982, and 1987 (17, 18). (The survey methods were carefully standardized and followed the World Health Organization protocol for the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease [MONICA] study [17].) The participation rates in these surveys were high, ranging from 82% to 92%. For the current study, we targeted past participants who were still alive at the end of 1997; 65 to 79 years of age; and who lived in or near Kuopio or Joensuu, Finland (n = 2293). We invited a random sample of 2000 persons within this group to a reexamination in 1998. Altogether, 1449 persons (72.5% of the invited sample) participated. The mean follow-up (SD) was 21.0 4.9 years (range, 11 to 26 years). (The duration of follow-up was 26 years for 34.9% of the current study sample, 21 years for 38.1%, 16 years for 15.6%, and 11 years for 11.4%.) The ethics committees of the University of Kuopio and the Kuopio University Hospital, Kuopio, Finland, approved the study protocol. All participants provided written informed consent. Midlife Visit The study protocol is described in detail elsewhere (19). In brief, the survey included a self-administered questionnaire on sociodemographic characteristics; health-related behaviors, including smoking habits and alcohol consumption; and medical history, including cerebrovascular and cardiovascular events and conditions diagnosed by a physician. Height and weight were measured. Blood pressure was measured from the right arm after the participants had been seated for 5 minutes. For most of the current study sample, only a single blood pressure measurement had been recorded in the initial survey. (In the 1972 survey, blood pressure was recorded once; for 186 of 531 participants in the 1977 survey and for all participants in the subsequent surveys, blood pressure was recorded twice.) Venous blood specimens were taken to determine serum total cholesterol levels. Serum total cholesterol level was determined in 1972 and 1977 from frozen serum samples by using the Liebermann-Burchard method; in 1982 and 1987, total cholesterol level in fresh serum samples was measured by using an enzymatic method (CHOD-PAP Monotest, Boehringer, Mannheim, Germany). The enzymatic assay yielded values that were 2.4% lower than those measured by the Liebermann-Burchard method; thus, we corrected the values for total cholesterol level from the 1972 and 1977 surveys accordingly. All cholesterol levels were determined at the same central laboratory, and the laboratory data were standardized against those of national and international reference laboratories. Reexamination in 1998 During the reexamination, the survey methods followed the standards of the previous surveys in all aspects. Cognitive impairment and dementia were diagnosed in three phases: a screening phase, a clinical phase, and a differential diagnostic phase. Cases of dementia were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (20); Alzheimer disease was diagnosed according to the criteria of the U.S. National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association (21). In addition, mild cognitive impairments were diagnosed by using the criteria proposed by the Mayo Clinic Alzheimers Disease Research Center (22). Blood leukocyte samples were analyzed to determine apoE genotype. To extract DNA, we used a standard phenol-chloroform technique; apoE genotypes were analyzed by polymerase chain reaction and HhaI digestion, as described previously (23). Statistical Analyses We analyzed the data using SPSS software for Windows, version 9.0 (SPSS Inc., Chicago, Illinois). We performed a chi-square test to compare the frequency of the apoE allele between controls and participants with Alzheimer disease. We studied the association between the apoE 4 allele and Alzheimer disease by using logistic regression analyses. We present these results as odds ratios with 95% CIs. From model 1, we determined univariate odds ratios. To study whether the apoE 4 allele was associated with Alzheimer disease, independent of midlife hypercholesterolemia and elevated systolic blood pressure, we included the variables of apoE genotype (4 carriers or noncarriers), total cholesterol level, and systolic blood pressure (according to categories) in the second model (model 2). In model 2, we also adjusted for the additional variables of age, history of myocardial infarction (yes or no), history of cerebrovascular symptoms (yes or no), education (years of formal education), sex, smoking status (current smoker, former smoker, or nonsmoker), and alcohol consumption (none, <10 g/d, 10 to 30 g/d, or >30 g/d). Midlife values for serum total cholesterol were classified as high ( 6.5 mmol/L [ 251 mg/dL]) or normal (<6.5 mmol/L [<251 mg/dL]). Midlife blood pressure was classified according to the following groups: normal (<140 mm Hg), borderline (140 to 159 mm Hg), or high ( 160 mm Hg) for systolic blood pressur

Hippocampus and entorhinal cortex in mild cognitive impairment and early AD

Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimers disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control > MCI > AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.

Hippocampal volumes in Alzheimer's disease, Parkinson's disease with and without dementia, and in vascular dementia An MRI study

Hippocampal atrophy detected by volumetric MRI is a sensitive feature of early Alzheimers disease (AD), but there are no studies evaluating hippocampal atrophy by MR volumetry in other dementing diseases. We therefore compared hippocampal volumes in a total of 113 subjects: 50 patients with mild to moderate AD, 9 patients with vascular dementia (VaD), 12 patients with idiopathic Parkinsons disease (PD) without dementia, 8 patients with PD and dementia (PDD), and 34 elderly control subjects. Thin, coronal, contiguous images were obtained by a 1.5-T MR imager. All patient groups had significantly smaller volumes of the hippocampus compared with the control group. In the PDD group, the absolute volumes were even smaller than in the AD group. In the PD group, the volumes were diminished to a lesser but significant extent. The volumes in the VaD group varied: of nine patients, two had no atrophy, three had unilateral, and four had bilateral atrophy. We postulate that hippocampal atrophy does not seem to be a specific phenomenon of dementia in AD but also occurs in VaD and PDD, and even in PD when no dementia is present. However, coexistence of AD pathology in our PD and VaD patients cannot be ruled out. Further studies with access to neuropathologic data are needed.

Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study.

Abstract Objective: To determine the association between features of the insulin resistance syndrome and Alzheimers disease. Design: Cross sectional population based study. Subjects: 980 people aged 69 to 78 (349 men, 631 women). Setting: Population of Kuopio, eastern Finland. Main outcome measures: Presence of features of the insulin resistance syndrome and diagnosis of Alzheimers disease by detailed neurological and neuropsychological evaluation. Results: 46 (4.7%) subjects were classified as having probable or possible Alzheimers disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1.29), low level of education (0.82; 0.72 to 0.93), low total cholesterol concentration (0.77; 0.59 to 1.00), high systolic blood pressure (1.01; 1.00 to 1.03), high fasting and 2 hour plasma glucose concentrations (1.11; 1.01 to 1.23 and 1.08; 1.03 to 1.13, respectively), high fasting and 2 hour insulin concentrations (1.05; 1.02 to 1.08 and 1.003; 1.00 to 1.01, respectively), and abnormal glucose tolerance (1.86; 1.23 to 2.80) were significantly associated with Alzheimers disease. In multivariate analysis including apolipoprotein E4 phenotype, age, education, systolic blood pressure, total cholesterol concentration, fasting glucose concentration, and insulin concentration, apolipoprotein E4 phenotype, age, education, total cholesterol, and insulin were significantly associated with Alzheimers disease. In 532 non-diabetic subjects without the e4 allele hyperinsulinaemia was associated with an increased risk for Alzheimers disease (prevalence of disease 7.5% v 1.4% in normoinsulinaemic subjects, P=0.0004). In contrast, in the 228 with the e4 allele hyperinsulinaemia had no effect on the risk of disease (7.0% v 7.1%, respectively). Conclusion: Features of the insulin resistance syndrome are associated with Alzheimers disease independently of apolipoprotein E4 phenotype. Key messages Apolipoprotein E4 phenotype is a risk factor for Alzheimers disease Other risk factors for Alzheimers disease are not well documented in previous studies In this study, hyperinsulinaemia and other features of the insulin resistance syndrome were associated with Alzheimers disease Insulin resistance is affected by modifications in lifestyle, so the risk of Alzheimers disease might be reducible by the same measures

MRI of the Hippocampus in Alzheimer’s Disease: Sensitivity, Specificity, and Analysis of the Incorrectly Classified Subjects

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimers disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer's disease: Correlation with memory functions

SummaryWe studied the usefulness of measuring volumes of the hippocampus, amygdala and frontal lobes with coronal magnetic resonance imaging (MRI) scans in the diagnosis of early Alzheimers disease (AD). We examined 32 patients diagnosed according to the NINCDS-ADRDA criteria of probable AD and 16 age-matched healthy cognitively normal controls. The AD patients had mild dementia with a mean score of 22.8 in the Mini-Mental Status Examination (MMSE). We used a 1.5T magnetic resonance imager and normalized the volumes for brain area. The AD patients had significantly smaller volumes of the right and the left hippocampus (−38%) (ANOVA, p<0.001) and the left frontal lobe (−16%, p<0.05) compared to controls. The reductions in volumes of the right frontal lobe (−13%), the right amygdala (−14%) or the left amygdala (−18%) were not statistically significant. In the discriminant function analysis which included the volumes of the hippocampus, amygdala, and the frontal lobes and age, the volumes of the left and right hippocampus, the left and right frontal lobe, and the right amygdala entered the model and we could correctly classify 92% of the subjects into AD and control groups (Chi-square 42.6, df 5, p<0.0001). By using the volumes of the hippocampus, the frontal lobes or the amygdala on their alone, the correct classification was achieved in 88%, 65% and 58% of the subjects, respectively. In addition, in AD patients the volumes of the left hippocampus correlated significantly with the MMSE score and with immediate and delayed verbal memory; the smaller the volume the more impaired was their performance. Our data indicate that measurements of volumes of the hippocampus might be useful in diagnosis of early AD.

Association of metabolic syndrome with Alzheimer disease: a population-based study.

Objective: To assess the association of metabolic syndrome (MetS) with Alzheimer disease (AD). Methods: The authors derived subjects from a population-based study of 980 randomly selected elderly subjects. After exclusion of all non-Alzheimer dementia cases, the final study population included 959 subjects (337 men and 622 women) aged 69 to 78 years. The presence of MetS was defined according to the National Cholesterol Education Program (Adult Treatment Panel III) criteria, and the diagnosis of AD was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimers Disease and Related Disorders Association. Results: Of the study subjects, 418 (43.6%) had MetS. Probable or possible AD was diagnosed in 45 subjects (4.7%). AD was more frequently detected in subjects with MetS than in subjects without MetS (7.2 vs 2.8%; p < 0.001). The prevalence of AD was higher in women with MetS vs women without the syndrome (8.3 vs 1.9%; p < 0.001), but in men with MetS, the prevalence of AD was not increased (3.8 vs 3.9%; p = 0.994). In univariate logistic regression analysis, MetS was significantly associated with AD (odds ratio [OR] 2.71; 95% CI 1.44 to 5.10). In multivariate logistic regression analysis including also apolipoprotein E4 phenotype, education, age, and total cholesterol, MetS was significantly associated with AD (OR 2.46; 95% CI 1.27 to 4.78). If only nondiabetic subjects were included in the multivariate analysis, MetS was still significantly associated with AD (OR 3.26; 95% CI 1.45 to 7.27). Conclusion: Metabolic syndrome is associated with Alzheimer disease in elderly subjects.

Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study.

Abstract Objective To evaluate the relation between midlife alcohol consumption and mild cognitive impairment and dementia in old age, and the possible modification of this relation by apolipoprotein E. Design Prospective, population based study. Setting Populations of Kuopio and Joensuu, eastern Finland. Participants Of 1464 men and women aged 65-79 years randomly selected from population based samples studied in 1972 or 1977, 1018 (70%) were re-examined in 1998 (after an average follow up of 23 years). Main outcome measures Mild cognitive impairment and dementia in old age. Results Participants who drank no alcohol at midlife and those who drank alcohol frequently were both twice as likely to have mild cognitive impairment in old age as those participants who drank alcohol infrequently. The risk of dementia related to alcohol drinking was modified by the presence of the apolipoprotein e4 allele. The carriers of apolipoprotein e4 had an increased risk of dementia with increasing alcohol consumption: compared with non-carriers who never drank, the odds ratio for carriers who never drank was 0.6, for infrequent drinkers it was 2.3, and for frequent drinkers was 3.6 (the overall interaction term “drinking frequency*apolipoprotein e4” was significant (P = 0.04), as were the interactions “infrequent drinking*apolipoprotein e4” (P = 0.02) and “frequent drinking*apolipoprotein e4” (P = 0.03)). Non-carriers of apolipoprotein e4 had similar odds ratios for dementia irrespective of alcohol consumption. Conclusion Alcohol drinking in middle age showed a U shaped relation with risk of mild cognitive impairment in old age. Risk of dementia increased with increasing alcohol consumption only in those individuals carrying the apolipoprotein e4 allele.