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.     

Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a population-based study

Inflammation has been associated with Alzheimer's disease (AD) and dementia. The association between rheumatoid arthritis (RA) or arthritis and dementia/AD has been investigated in several case-control or hospital- and register-based studies with mixed results. This long-term population-based study investigates the association between presence of joint disorders (RA and other joint disorders) in midlife and cognitive status later in life. 1,449 participants were first evaluated in 1972, 1977, 1982, and 1987 and follow-up was performed after 21 years. A self-administered questionnaire including questions on joint disorders was used at both evaluations. Cognitive status (control, mild cognitive impairment, dementia/AD) was assessed at follow-up. The presence of any joint disorder in midlife was significantly associated with a worse cognitive status later in life: OR (95% CI) in an ordinal logistic regression analysis adjusted for age, gender, follow-up time, education, APOEε4, body mass index, smoking, drug treatment, and diabetes was 1.96 (1.17-3.28). For RA only, OR (95% CI) was 2.77 (1.26-6.10). The correlation remained significant for RA when AD was considered instead of dementia OR (95% CI) 2.49 (1.09-5.67). The presence of joint disorders, especially RA, at midlife seems to be associated with a worse cognitive status later in life. Given the chronic inflammatory component of RA, this study suggests that inflammatory mechanisms may have an important role in increasing the risk of cognitive impairment and dementia/AD.     

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.     

Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study

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.     

Work-related physical activity and the risk of dementia and Alzheimer's disease

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.     

APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study

BACKGROUND: Both family aggregation and apolipoprotein E (APOE) epsilon4 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 epsilon4 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 epsilon4 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-epsilon4 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 epsilon4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE epsilon4 allele.     

Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE epsilon4 allele

BACKGROUND: The epsilon4 allele of apolipoprotein E (APOE) and head injury are risk factors for dementia diseases, and may act synergistically to further increase the risk. The aim of this study was to examine the association between mild head injury, APOE and dementia. METHODS: Data were obtained from the Betula prospective population-based study of aging, memory, and health. The study included 543 participants in the age range 40-85 years, free of dementia at baseline, who were followed up within a 5-year interval. Dementia was classified using DSM-IV criteria. Information on previous head injury was obtained through screening of the participants' answers to health questionnaires at baseline and at follow-up. RESULTS: Subjects with head injury but without APOE epsilon4 had no increased risk of dementia. Subjects with APOE epsilon4 had an increased risk and those with both APOE epsilon4 and head injury had the highest risk of dementia (odds ratio = 5.2). CONCLUSIONS: APOE epsilon4 constitutes a risk factor for dementia, mild injury in isolation does not increase the risk, but head injury in combination with the APOE epsilon4 leads to increased risk of dementia.     

APOE genotype,memory test performance,and the risk of Alzheimer's disease in the Canadian Study of Health and Aging

OBJECTIVES: This study examined the relation between two risks for Alzheimer's disease (AD): the apolipoprotein (APOE) epsilon4 allele and poor memory test performance. METHODS: In the Canadian Study of Health and Aging (CSHA), a 5-year longitudinal population-based study that screened and followed over 10,000 participants, 2,914 had an initial clinical assessment and 1,624 had APOE genotype testing. All participants were categorized as having no cognitive impairment, cognitive impairment but no dementia, or dementia at both baseline and follow-up. We examined those (n = 209) with a complete neuropsychological assessment at baseline and no evidence of cognitive impairment who had either APOE epsilon3/epsilon3 or epsilon3/epsilon4 genotypes and who had a clinical consensus diagnosis of either no cognitive impairment or AD at follow-up. Delayed free recall memory was evaluated at CSHA-1 with the Buschke Cued Recall Test (BCRT). RESULTS: The risk of AD at follow-up was increased for participants with an APOE epsilon3/epsilon4 genotype when memory test performance was not considered, but logistic regression demonstrated that a model which also considered baseline memory test performance was more predictive of AD. In the more complete model, reduced BCRT free recall scores were associated with an increased risk of AD, whereas the risk associated with the APOE epsilon3/epsilon4 genotype was no longer significant. CONCLUSIONS: For those with no evidence of cognitive impairment, drawn from a population-based sample of elderly persons, the APOE epsilon3/epsilon4 genotype was only associated with an increased risk of AD after 5 years if their memory test performance was relatively poor at baseline. Regardless of the APOE genotype, and in the absence of clinical evidence of cognitive impairment, reduced scores on a test of delayed free recall at baseline was associated with an increased risk of AD after 5 years.     

APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old

OBJECTIVE: To examine the effect of the epsilon 4 allele on cognitive decline in the oldest old. METHODS: We studied all 601 citizens of the city of Vantaa age 85 years and older in 1991. A total of 553 subjects (92%) took part in the study, which used the Mini-Mental State Examination (MMSE) and assessment of dementia according to the Diagnostic and Statistical Manual of Mental Disorders, third ed., revised (DSM-III-R) criteria. The survivors were re-examined 3 years later. APOE genotype was determined in 510 subjects, representing 83.2% of the original population. RESULTS: Approximately one-half of the subjects (n = 250) died before the follow-up, and 253 subjects (97.3% of the survivors) were re-examined. The occurrence of the APOE epsilon 4 allele did not have any significant effect on survival. Of the 187 previously nondemented subjects, 58 (31%) had developed dementia. The OR for the epsilon 4 carriers to develop dementia was not significant: OR = 1.78; 95% CI = 0.88 to 3.60. In individuals with a follow-up MMSE score (n = 222), the mean decline in the score was 3.1 points. APOE epsilon 4 carrier status did not have a significant effect on the mean MMSE change except in the previously demented subjects, among whom the drop was larger in the APOE epsilon 4 carriers. CONCLUSIONS: The lack of association between APOE epsilon 4 carrier status and mortality, or development of dementia, or cognitive decline in these very elderly people, whether analyzed in the whole population or among the nondemented subjects only, suggests that the APOE epsilon 4 effect in younger subjects is age-dependent, and that it is no longer present in very old age.     

Cerebrovascular disease, APOE epsilon4 allele and cognitive decline in a cognitively normal population

OBJECTIVES: To investigate whether cerebrovascular disease (CVD) and apolipoprotein E (APOE) epsilon4 allele were associated with cognitive decline and whether the relationship between CVD and cognitive decline varied by APOE epsilon4 status. METHODS: A total of 809 cognitively normal community-dwelling residents aged >75 years were followed to detect subjects with cognitive decline, defined as follow-up. Mini-mental state examination (MMSE) score was >10% decease of the baseline score. Logistic and multinomial logistic models were developed to estimate odds ratio (OR) and 95% confidence interval (CI) of cognitive decline related to a history of CVD and APOE epsilon4 by taking into account major potential confounders including baseline MMSE score. RESULTS: During the mean 3.5 years of follow-up, 190 subjects experienced cognitive decline. Multi-adjusted ORs (95% CIs) of overall cognitive decline were 2.27 (1.23-4.17) for CVD and 1.69 (1.13-2.54) for APOE epsilon4, but no interaction was detected. Multinomial logistic analysis led to the CVD-related ORs of 1.42 (0.75-2.67) for cognitive decline without progression to dementia and 3.41 (1.55-7.55) for the decline progressing to dementia; similar analysis from a separate model led to adjusted OR of 2.28 (0.88-5.87; p=0.09) for the decline progressing to Alzheimer's disease. The risk effects of CVD on cognitive decline with progression to dementias were statistically significant mainly among individuals without APOE epsilon4 allele. CONCLUSIONS: CVD is a major risk factor for cognitive decline associated with progression to dementia and Alzheimer's disease. There appears no interaction between CVD and APOE epsilon4 on cognitive decline in very old people.     

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.     

Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment

BACKGROUND: In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear. OBJECTIVE: To evaluate the predictive utility of the APOE epsilon4 genotype for conversion to probable Alzheimer disease (AD). DESIGN: Naturalistic, longitudinal study. SETTING: Memory disorders outpatient clinic. PATIENTS: A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. MAIN OUTCOME MEASURES: Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. RESULTS: The APOE epsilon4 allele was present in 25% of patients and 21% of healthy controls. During a mean +/- SD follow-up of 35.2 +/- 24.3 months, 35 of 136 patients converted to AD. APOE epsilon4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE epsilon4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE epsilon4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). CONCLUSIONS: APOE epsilon4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE epsilon4 homozygosity was associated with increased risk of conversion to AD. However, APOE epsilon4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.     

Incidence of dementia in very elderly individuals: a clinical, neuropathological and molecular genetic study

AIMS: To evaluate the effect of medical record use on figures for the incidence of dementia and the effect of apolipoprotein E (APOE) polymorphism on this incidence and neuropathologically defined Alzheimer's disease (AD) in very elderly individuals. METHODS: Cognitive functions were examined in a cohort of 328 (92% of the very elderly people of a town participated in this study) nondemented Finnish elderly individuals 85 years of age or more in 1991. The examination was repeated in survivors in 1994, 1996, 1999 and 2001. Medical notes and social work records were evaluated. All these individuals were genotyped for APOE. Neuropathological analysis of AD-type pathology was performed on 159 of 303 subjects who died during the follow-up. RESULTS: Age group, gender or APOE did not significantly affect the incidence of dementia, which was over 20% higher (85 vs. 69 per 1,000 person-years) if the cognitive status at death was ascertained by medical and social work records than without this evaluation. The APOE upsilon4 allele was highly significantly (p=0.002) and age almost significantly (p=0.06) associated with neuropathological AD in nondemented individuals. CONCLUSIONS: Medical records should be analyzed in studies on the incidence of dementia in very elderly individuals. APOE polymorphism does not affect the incidence of dementia in this age group. However, clinical dementia diagnosis in very elderly individuals does not necessarily correlate well with the presence of neuropathological AD which, even in this age group, is significantly associated with the APOE upsilon4 allele.     

Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study.

OBJECTIVE: Several studies suggest that depression is a risk factor for development of dementia in the elderly. In a study of older depressed individuals, the authors examined both neuroimaging and genetic factors in development of dementia. The authors hypothesized that change in subcortical gray matter and white matter hyperintensity volumes would be associated with development of dementia, as would presence of an apolipoprotein E (APOE) epsilon 4 allele. METHODS: The sample consisted of 161 older depressed subjects without dementia who had magnetic resonance imaging scans at baseline and at two years. Blood samples were also taken to determine APOE genotype. All participants were treated with antidepressants using a guideline-based treatment algorithm. Their cognitive status was evaluated annually. A consensus panel of experts evaluated each case to determine cognitive status and assign a diagnosis. RESULTS: Twenty subjects became demented over the follow-up period (5.4 years on average). Change in white matter hyperintensity volume was significantly associated with development of dementia, especially among non-Alzheimer dementias. There was a trend for change in subcortical gray matter hyperintensity volume to be associated with incident dementia. APOE genotype was not associated with onset of dementia. CONCLUSION: Worsening cerebrovascular disease in older depressed adults is associated with cognitive decline and dementia, particularly of the non-Alzheimer disease type. The association of change in white matter lesion volume and incident dementia among depressed elders extends the vascular depression hypothesis of geriatric depression to include cognitive outcomes of depression in the elderly.     

Vascular risk factors and cognitive disorders

Delaying the onset of dementia by just a few years could have a major impact on the prevalence of the disease at the population level. Vascular risk factors are modifiable and may offer an important opportunity for preventive approaches. Several studies have shown that diabetes, hypertension, obesity, and smoking are associated with an increased risk of cognitive decline and dementia, but other groups have not observed such a relation. Positive associations were observed mainly in studies where risk factors were assessed in midlife, suggesting that age is an important modulator in the relation between vascular risk factors and cognition. The population attributable risk of dementia is particularly high for hypertension. Associations of vascular risk factors with cognitive decline and dementia are probably mediated largely by cerebrovascular disease, including both stroke and covert vascular brain injury, which can have additive or synergistic effects with coexisting neurodegenerative lesions. To date, randomized trials have not convincingly demonstrated that treating vascular risk factors is associated with a reduction in cognitive decline or dementia risk. Of eight randomized trials testing the effect of antihypertensive agents on dementia risk, only one was positive, and another in a subgroup of individuals with recurrent stroke. In most trials, cognition and dementia were secondary outcomes, follow-up was short and treatment was initiated at an older age. No effect on cognitive decline or dementia could be demonstrated for statins and intensive glycemic control. Future areas of investigation could include differential class effects of antihypertensive drugs on cognitive outcomes and identification of high risk individuals as target population for clinical trials initiated in midlife.     

Apolipoprotein E gene polymorphism, total plasma cholesterol level, and Parkinson disease dementia

BACKGROUND: Apolipoprotein E gene (APOE) polymorphism is an important determinant for the development of various cardiovascular and neurodegenerative disorders. There have been conflicting reports of association of APOE polymorphism with dementia in Parkinson disease (PD). OBJECTIVE: To determine the relationship between APOE polymorphisms and plasma cholesterol concentration, and PD with dementia (PDD). DESIGN: Four-year (1999-2002) case-control study. SETTING: Academic medical center with inpatient and outpatient movement disorders services. Patients Consecutive white patients of the same ethnic background with PD. INTERVENTIONS: Strict clinical, neuropsychological, and neuroimaging criteria were used to exclude dementia with Lewy bodies, Alzheimer disease, and vascular dementia. Findings were compared in 2 clinical groups, including 98 patients (47 men and 51 women; mean age, 71 years) with PDD and 100 patients (52 men and 48 women; mean age, 62 years) with PD without dementia. MAIN OUTCOME MEASURES: Analysis of APOE genotypes and allelic frequency (polymerase chain reaction) and plasma cholesterol concentration (enzymatic assay) were evaluated by a clinician blinded to the clinical diagnosis, and findings were compared between the groups with PDD or PD without dementia. Multiple stepwise regression analysis and the Spearman rank correlation coefficient were used to evaluate relationships between dementia and both APOE polymorphism and cholesterol concentration. Statistical significance was set at P<.05. RESULTS: Epsilon4 allele frequencies were similar in PDD and PD without dementia (16.8% vs 19%, respectively). Cholesterol concentration, APOE genotypes, and allelic frequencies did not relate to PDD. CONCLUSIONS: In contrast to Alzheimer disease, when PDD is carefully defined, it is clearly not associated with APOE polymorphisms or with a distinctive plasma cholesterol profile. Ongoing longitudinal follow-up with emphasis on autopsy recruitment will enable further analyses of biochemical alterations underlying PDD.     

Lack of associations between modifiable risk factors and dementia in the very old: findings from the Cambridge City over-75s cohort study

ABSTRACT

Objectives: To investigate the association between modifiable risk and protective factors and severe cognitive impairment and dementia in the very old. Additionally, the present study tests the predictive validity of the ‘LIfestyle for BRAin health’ (LIBRA) score, an index developed to assess an individual's dementia prevention potential.

Method: Two hundred seventy-eight individuals aged 85 years or older from the Cambridge City over-75s cohort study were followed-up until death. Included risk and protective factors were: diabetes, heart disease, hypertension, depression, smoking, low-to-moderate alcohol use, high cognitive activity, and physical inactivity. Incident severe cognitive impairment was based on the Mini-Mental State Examination (score: 0-17) and incident dementia was based on either post-mortem consensus clinical diagnostic assessments or death certificate data. Logistic regressions were used to test whether individual risk and protective factors and the LIBRA score were associated with severe cognitive impairment or dementia after 18 years follow-up.

Results: None of the risk and protective factors or the LIBRA score was significantly associated with increased risk of severe cognitive impairment or dementia. Sensitivity analyses using a larger sample, longer follow-up period, and stricter cut-offs for prevalent cognitive impairment showed similar results.

Conclusion: Associations between well-known midlife risk and protective factors and risk for severe cognitive impairment or dementia might not persist into very old age, in line with suggestions that targeting these factors through lifestyle interventions should start earlier in life.     

The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study

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 ?4. Importantly, the effect of the AA-genotype on dementia/AD risk seems to act mostly through the interaction with APOE ?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.     

The association between APOE and dementia does not seem to be mediated by vascular factors

OBJECTIVE: The effect of APOE on dementia may be mediated through dyslipidemia and atherogenesis through its effect on cholesterol metabolism. The authors investigated this possibility among aged survivors from the UK Medical Research Council Trial of the Treatment of Hypertension in Older Adults. DESIGN: A total of 370 of 657 survivors from an initial cohort of 1,088 recruited into the trial between 1983 and 1985 were traced in 1994 and agreed to be screened for dementia. Blood samples were analyzed for APOE genotype and serum fibrinogen. Cholesterol level, smoking behavior, blood pressure, body mass index, and EKG recordings had been measured at recruitment 10 to 12 years earlier. Odds ratios (ORs) for the association between APOE epsilon4/* and both AD and dementia were estimated and adjusted incrementally for the effect of age and premorbid intelligence, cholesterol, other risk factors for vascular disease, and EKG evidence of cardiovascular disease. RESULTS: The authors diagnosed 24 cases of National Institute of Neurological and Communicative Disorders and Stroke AD from 41 cases of dementia. The crude OR for the association between APOE epsilon4/* and AD was 3.40 (95% CI 1.30 to 8.91). APOE genotype was associated with serum cholesterol level, and there was a nonsignificant trend for an association with smoking behavior. After adjusting for these and all other vascular risk factors and vascular disease variables listed earlier, the OR for the association between APOE epsilon4/* and AD increased to 4.81 (1.60 to 14.4). CONCLUSION: Presence of APOE epsilon4/* seems to increase the risk for dementia and AD independently of its effect on dyslipidemia and atherogenesis.     

Apolipoprotein E epsilon4 allele, temporal lobe atrophy, and white matter lesions in late-life dementias.

OBJECTIVE: To examine the relationship between the apolipoprotein E (APOE) epsilon4 genotype, medial temporal lobe atrophy, and white matter hyperintensities on magnetic resonance imaging in late-life dementias. DESIGN: Structural magnetic resonance imaging study using T2-weighted and proton density-weighted axial scans and T1-weighted coronal scans. SETTING: Community-dwelling population of elderly patients prospectively chosen from a clinical case register of consecutive referrals to old age psychiatry services. SUBJECTS: Twenty-five subjects with Alzheimer disease (by criteria of the National Institute of Neurological and Communication Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; mean age, 77.8 years), 22 subjects with dementia with Lewy bodies (consensus criteria; mean age, 77.2 years), and 24 subjects with vascular dementia (by criteria of the National Institute of Neurological Disorders and Stroke and the Association International pour la Recherche et l'Enseignement en Neurosciences; mean age, 76.9 years) were selected. Subjects were well matched for age, sex, duration of illness, and cognitive function. MAIN OUTCOME MEASURES: The APOE genotype was determined using the polymerase chain reaction method, and medial temporal lobe atrophy and white matter hyperintensities (periventricular and deep white matter) were visually rated using standardized scales. RESULTS: In all subjects with dementia, no significant associations were noted between APOE epsilon4 status and medial temporal lobe atrophy (mean score: 0 epsilon4 = 4.5, 1 epsilon4 = 4.5, and 2 epsilon4 = 4.3; P = .90), periventricular hyperintensities (0 epsilon4 = 3.3, 1 epsilon4 = 3.1, and 2 epsilon4 = 2.9; P = .83), and white matter hyperintensities (0 epsilon4 = 5.3, 1 epsilon4 = 4.9, and 2 epsilon4 = 4.9; P = .79). CONCLUSIONS: The APOE epsilon4 allele does not determine medial temporal lobe atrophy or white matter lesions, as measured by magnetic resonance imaging in patients with Alzheimer disease, vascular dementia, or dementia with Lewy bodies. Although APOE epsilon4 may modify the risk for acquiring dementia, this finding provides further evidence that APOE epsilon4 does not influence pathological processes thereafter.