Closing the gap in Alzheimer's disease research through the Sex | Gender in Neurodegeneration Consortium.
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Letter↗
Biomedical subjects
Miia Kivipelto
Publications and source records attributed to Miia Kivipelto.
Alcohol drinking and cognitive functions: findings from the Cardiovascular Risk Factors Aging and Dementia (CAIDE) Study.
BACKGROUND: Moderate alcohol drinking is suggested to be beneficial for cognitive functions, but the results of previous studies have varied greatly. Little is known about the effects of midlife alcohol drinking on the cognitive functions later in life. METHODS: Participants were derived from random, population-based samples studied in Eastern Finland in 1972, 1977, 1982, or 1987. A total of 1,341 participants were reexamined in 1998, after an average follow-up period of 21 years, at ages 65-79 years. RESULTS: The participants who did not drink alcohol at midlife had a poorer performance in episodic memory, psychomotor speed, and executive function in late life as compared with infrequent and frequent drinkers, adjusted for sociodemographic and vascular factors. Also late-life nondrinkers had poorer psychomotor speed and executive function. These findings were evident especially among nonsmokers. Further, no interactions between apolipoprotein E4 and alcohol or sex and alcohol were found. CONCLUSIONS: Alcohol drinking both at midlife and later is favorably related to the function in several cognitive domains, including episodic memory, psychomotor speed, and executive function, in late life. However, it is not clear whether the association is causal, what is the possible mechanism, and what would be a safe limit of drinking for the best cognitive function.
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MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study.
The concept of mild cognitive impairment (MCI) has been proposed to represent a transitional stage between normal aging and dementia. We studied the predictive value of the MRI-derived volumes of medial temporal lobe (MTL) structures, white matter lesions (WML), neuropsychological tests, and Apolipoprotein E (APOE) genotype on conversion of MCI to dementia and AD. The study included 60 subjects with MCI identified from population cohorts. During the mean follow-up period of 34 months, 13 patients had progressed to dementia (9 to Alzheimer's disease (AD)). In Cox regression analysis the baseline volumes of the right hippocampus, the right entorhinal cortex and CDR sum of boxes predicted the progression of MCI to dementia during the follow-up. In a bivariate analysis, only the baseline volumes of entorhinal cortex predicted conversion of MCI to AD. The Mini-Mental State Examination (MMSE) score at baseline, WML load, or APOE genotype were not significant predictors of progression. The MTL volumetry helps in identifying among the MCI subjects a group, which is at high risk for developing AD.
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Metabolic syndrome and cognitive function: a population-based follow-up study in elderly women.
OBJECTIVE: To test the hypothesis that metabolic syndrome predicts cognitive impairment, and to examine the association of single metabolic risk factors with cognitive functioning. METHODS: We performed a 12-year follow-up study in a population-based sample of 101 women aged 60-70 years at baseline. Metabolic syndrome was defined by the National Cholesterol Education Program criteria (> or =3 out of 5 risk factors). Global cognitive function was measured by the Mini-Mental State Examination both at baseline and follow-up. A detailed neuropsychological evaluation for memory and cognitive speed was performed at follow-up. RESULTS: The prevalence of metabolic syndrome increased from 13% at baseline to 49% at follow-up (p < 0.001). Women with metabolic syndrome at baseline had a 4.27 (95% confidence interval: 1.02-17.90; p = 0.047) times higher risk of poor memory at follow-up after adjustment for age, education and depression. The increasing number of metabolic risk factors was associated with worsening of memory at follow-up (p = 0.034 for linear trend). Women with low baseline levels of high-density lipoprotein (HDL) cholesterol were more likely to have poor memory at follow-up than those with higher HDL levels (p = 0.028). The risk of having poor memory increased by 46.5% (95% confidence interval: 15-66%; p = 0.008) with 1 SD decrease in HDL cholesterol level. CONCLUSION: In elderly women, metabolic syndrome may be an important contributor to worsening of memory, which is an essential part of mild cognitive impairment.
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Rethinking the dementia diagnoses in a population-based study: what is Alzheimer's disease and what is vascular dementia?. A study from the kungsholmen project.
OBJECTIVE: To explore the hypothesis that older adults often are affected by more than one disease, making the differential diagnosis between Alzheimer's disease (AD) and vascular dementia (VaD) difficult. METHODS: Incident dementia cases (n = 308) from a population-based longitudinal study of people 75+ years were investigated. The DSM-III-R criteria were used for the clinical diagnosis of dementia. Data on vascular disorders (hypertension, cerebrovascular and ischemic heart diseases, heart failure, atrial fibrillation, diabetes) as well as type of onset/course of dementia were used retrospectively to reclassify dementias. RESULTS: Only 47% of the AD cases were reclassified as pure AD without any vascular disorder. Among subjects with AD and with a vascular component, cerebrovascular disease was the most common (41%). Only 25% of VaD were reclassified as pure VaD. Further, 26% of the pure AD subjects developed a vascular disorder in the following 3 years. CONCLUSIONS: Both vascular and degenerative mechanisms may often contribute to the expression of dementia among the elderly. Most of the AD cases have vascular involvements, and pure dementia types in very old subjects constitute only a minority of dementia cases.
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Cerebral embolism and Alzheimer's disease.
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Alzheimer Disease↗
The effect of apolipoprotein polymorphism on brain in mild cognitive impairment: a voxel-based morphometric study.
We investigated the effect of apolipoprotein E (ApoE) on the whole brain in 51 individuals with mild cognitive impairment using voxel-based morphometry. Between cases heterozygous for the ApoE epsilon4 (n = 15) and those who were ApoE epsilon4 noncarriers (n = 28), only the right parahippocampal gyrus, with the entorhinal cortex included, reached the level of statistical significance. In cases homozygous for the epsilon4 allele (n = 8) versus noncarriers, the greatest atrophy was located in the right amygdala followed by the right parahippocampal gyrus, the left amygdala and the left medial dorsal thalamic nucleus.
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Are the CSF levels of 24S-hydroxycholesterol a sensitive biomarker for mild cognitive impairment?
There is a need for effective biomarkers showing whether or not a patient with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD) with dementia. At the present three cerebrospinal fluid (CSF) biomarkers are in general use: total tau, phospho-tau and beta-Amyloid. These markers are regarded to have high capacity to differentiate early AD from normal ageing. We have analysed CSF levels of a new marker for neuronal degeneration, 24S-hydroxycholesterol (24OHC) in patients with MCI. For reasons of comparison, we also analysed these levels in patients with AD. There was a significant correlation between CSF levels of 24OHC and total tau (as well as phospho-tau) in both groups of patients. Fifty percent of the patients contemplated for MCI were found to have elevated levels of 24OHC (using a 95th upper percentile set cut-off). All the MCI patients with normal levels of 24OHC had normal levels of the other markers. In patients with AD, the percentages of those with increased levels of 24OHC, tau and phospho tau were similar (55-67%). In this pilot study, we discuss the possibility that 24OHC may be a sensitive test for MCI.
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Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study.
BACKGROUND: Several vascular risk factors are associated with dementia. We sought to develop a simple method for the prediction of the risk of late-life dementia in people of middle age on the basis of their risk profiles. METHODS: Data were used from the population-based CAIDE study, which included 1409 individuals who were studied in midlife and re-examined 20 years later for signs of dementia. Several midlife vascular risk factors were studied to create the scoring tool. The score values were estimated on the basis of beta coefficients and the dementia risk score was the sum of these individual scores (range 0-15). FINDINGS: Occurrence of dementia during the 20 years of follow-up was 4%. Future dementia was significantly predicted by high age (> or = 47 years), low education (< 10 years), hypertension, hypercholesterolaemia, and obesity. The dementia risk score predicted dementia well (area under curve 0.77; 95% CI 0.71-0.83). The risk of dementia according to the categories of the dementia risk score was 1.0% for those with a score of 0-5, 1.9% for a score of 6-7, 4.2% for a score of 8-9, 7.4% for a score of 10-11, and 16.4% for a score of 12-15. When the cut-off of 9 points or more was applied the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98. INTERPRETATION: The dementia risk score is a novel approach for the prediction of dementia risk, but should be validated and further improved to increase its predictive value. This approach highlights the role of vascular factors in the development of dementia and could help to identify individuals who might benefit from intensive lifestyle consultations and pharmacological interventions.
Area Under Curve↗
High cholesterol diet induces tau hyperphosphorylation in apolipoprotein E deficient mice.
We analysed the effects of high cholesterol (HC) intake and reduced apolipoprotein E (apoE) activity on tau phosphorylation and on the activities of the major tau kinases and phosphatases in brains from wild-type and apoE-knockout (apoEKO) mice. We show that HC diet potently induced intraneuronal accumulation of hyperphosphorylated tau in apoEKO mice, as well as upregulation of several tau kinases, without affecting tau phosphatases. Our results suggest an interaction between dietary and genetic factors in the development of tauopathies, which can be relevant in humans, where the apoE4 isoform could have a lack of function as compared to other isoforms.
Animals↗
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↗
Statin therapy in Alzheimer's disease.
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Alzheimer Disease↗
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 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.
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Apolipoprotein E, B vitamins, and cognitive function in older adults.
Recognition of dated and contemporary famous faces, short-term memory, and visuospatial abilities were investigated in adults aged 75 years and older as a function of apolipoprotein E (APOE) genotype, epsilon4 or not epsilon4, and whether participants recorded normal or low levels of B vitamins. No associations between B vitamins and APOE were identified in respect to short-term memory or visuospatial skills, or for contemporary famous faces. However, in respect to the recognition of dated famous faces, deficits in persons carrying the epsilon4 allele who also recorded low vitamin B(12) values were found. The results suggest that the neurological structures and processes supporting face recognition may be vulnerable to the combined influence of the APOE epsilon4 allele and low levels of vitamin B(12). This finding was unrelated to incipient dementia up to 6 years following testing. The results are discussed with reference to the neuroanatomical reserves that epsilon4 carriers may possess.
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Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study.
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.
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Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects.
BACKGROUND: Mild cognitive impairment (MCI) has attracted considerable interest as a potential predictor of Alzheimer's disease (AD). Both the apolipoprotein E (ApoE) epsilon4 allele and vascular factors have been associated with a higher risk for AD, recently they have also been linked to the risk of MCI. OBJECTIVES: To estimate the incidence of MCI among cognitively healthy elderly subjects during a 3-year follow-up, and to evaluate the impact of demographic and vascular factors as well as the ApoE epsilon4 allele on the conversion to MCI. METHODS: At baseline, the cognitive abilities of 806 out of 1,150 eligible subjects (aged 60-76 years) from a population-based sample were examined. Cognitively intact subjects (n = 747) were followed for an average of 3 years. RESULTS: 66 subjects (8.8%) had converted to MCI. The global incidence rate of MCI was 25.94/1,000 person-years. Persons with higher age (OR 1.08, 95% CI 1.01-1.16), ApoE epsilon4 allele carriers (OR 2.04, 95% CI 1.15-3.64) and persons with medicated hypertension (OR 1.86, 95% CI 1.05-3.29) were more likely to convert to MCI than those individuals of lower age and without an ApoE epsilon4 allele or medicated hypertension. Persons with high education (OR 0.79, 95% CI 0.70-0.89) were less likely to convert to MCI than persons with low or no education. In subjects with both the ApoE epsilon4 allele and medicated hypertension, the crude OR for conversion was 3.92 (95% CI 1.81-8.49). In subjects with cardiovascular disease, the crude OR for conversion was 2.13 (95% CI 1.26-3.60). Gender, elevated blood pressure, diabetes or cerebrovascular disease had no significant effect on the conversion to MCI. CONCLUSION: Higher age, the presence of at least one ApoE epsilon4 allele and medicated hypertension are independent risk factors, but high education is a protective factor for MCI. The results suggest that vascular factors may have an important role in the pathogenesis of MCI.
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Serum lipids and hippocampal volume: the link to Alzheimer's disease?
The association between hippocampal volume (as a presumed index of Alzheimer's disease pathology) with serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was studied in 86 elderly subjects with a range of cognitive functions. High-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol or total cholesterol, was associated with hippocampal volume and dementia. This is compatible with protective effects of high-density lipoprotein cholesterol on hippocampal atrophy and Alzheimer's disease.
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