Education as a moderator of middle-age cardiovascular risk factor-old-age cognition relationships: testing cognitive reserve hypothesis in epidemiological study.

BACKGROUND: higher educational attainment and less midlife cardiovascular risk factors are related to better old-age cognition. Whether education moderates the association between cardiovascular risk factors and late-life cognition is not known. We studied if higher education provides resilience against the deteriorative effects of higher middle-age body mass index (BMI) and a combination of midlife cardiovascular risk factors on old-age cognition. METHODS: the study population is the older Finnish Twin Cohort (n = 4,051, mean age [standard deviation, SD] = 45.5 years [6.5]). Cardiovascular risk factors and education were studied at baseline with questionnaires in 1975, 1981 and/or 1990 (participation rates of 89, 84 and 77%, respectively). Cognition was evaluated with telephone interviews (participation rate 67%, mean age [SD] =73.4 [2.9] years, mean follow-up [SD] = 27.8 [6.0] years) in 1999-2017. We studied the main and interactive effects of education and BMI/dementia risk score on late-life cognition with linear regression analysis. The study design was formulated before the pre-defined analyses. RESULTS: years of education moderated the association between BMI with old-age cognition (among less educated persons, BMI-cognition association was stronger [B = -0.24 points per BMI unit, 95% CI -0.31, -0.18] than among more educated persons [B = -0.06 points per BMI unit, 95% CI -0.16, 0.03], Pinteraction < 0.01). There was a similar moderating effect of education on dementia risk score consisting of cardiovascular risk factors (P < 0.001). CONCLUSIONS: our results support the cognitive reserve hypothesis. Those with higher education may tolerate the deteriorative effects of midlife cardiovascular risk factors on old-age cognition better than those with lower education.

Physical activity as a protective factor for dementia and Alzheimer's disease: systematic review, meta-analysis and quality assessment of cohort and case-control studies.

OBJECTIVE: Physical activity (PA) is associated with a decreased incidence of dementia, but much of the evidence comes from short follow-ups prone to reverse causation. This meta-analysis investigates the effect of study length on the association. DESIGN: A systematic review and meta-analysis. Pooled effect sizes, dose-response analysis and funnel plots were used to synthesise the results. DATA SOURCES: CINAHL (last search 19 October 2021), PsycInfo, Scopus, PubMed, Web of Science (21 October 2021) and SPORTDiscus (26 October 2021). ELIGIBILITY CRITERIA: Studies of adults with a prospective follow-up of at least 1 year, a valid cognitive measure or cohort in mid-life at baseline and an estimate of the association between baseline PA and follow-up all-cause dementia, Alzheimer's disease or vascular dementia were included (n=58). RESULTS: PA was associated with a decreased risk of all-cause dementia (pooled relative risk 0.80, 95% CI 0.77 to 0.84, n=257 983), Alzheimer's disease (0.86, 95% CI 0.80 to 0.93, n=128 261) and vascular dementia (0.79, 95% CI 0.66 to 0.95, n=33 870), even in longer follow-ups (≥20 years) for all-cause dementia and Alzheimer's disease. Neither baseline age, follow-up length nor study quality significantly moderated the associations. Dose-response meta-analyses revealed significant linear, spline and quadratic trends within estimates for all-cause dementia incidence, but only a significant spline trend for Alzheimer's disease. Funnel plots showed possible publication bias for all-cause dementia and Alzheimer's disease. CONCLUSION: PA was associated with lower incidence of all-cause dementia and Alzheimer's disease, even in longer follow-ups, supporting PA as a modifiable protective lifestyle factor, even after reducing the effects of reverse causation.

Middle-age dementia risk scores and old-age cognition: a quasi-experimental population-based twin study with over 20-year follow-up.

BACKGROUND: Middle-age risk scores predict cognitive impairment, but it is not known if these associations are evident when controlling for shared genetic and environmental factors. Using two risk scores, self-report educational-occupational score and Cardiovascular Risk Factors, Aging and Dementia (CAIDE), we investigated if twins with higher middle-age dementia risk have poorer old-age cognition compared with their co-twins with lower risk. METHODS: We used a population-based older Finnish Twin Cohort study with middle-age questionnaire data (n=15 169, mean age=52.0 years, SD=11.8) and old-age cognition measured via telephone interview (mean age=74.1, SD=4.1, n=4302). Between-family and within-family linear regression analyses were performed. RESULTS: In between-family analyses (N=2359), higher educational-occupational score was related to better cognition (B=0.76, 95% CI 0.69 to 0.83) and higher CAIDE score was associated with poorer cognition (B=-0.73, 95% CI -0.82 to -0.65). Within twin-pair differences in educational-occupational score were significantly related to within twin-pair differences in cognition in dizygotic (DZ) pairs (B=0.78, 95% CI 0.25 to 1.31; N=338) but not in monozygotic (MZ) pairs (B=0.12, 95% CI -0.44 to 0.68; N=221). Within twin-pair differences in CAIDE score were not related to within twin-pair differences in cognition: DZ B=-0.38 (95% CI -0.90 to 0.14, N=343) and MZ B=-0.05 (95% CI -0.59 to 0.49; N=226). CONCLUSION: Middle-age dementia risk scores predicted old-age cognition, but within twin-pair analyses gave little support for associations independent of shared environmental and genetic factors. Understanding genetic underpinnings of risk score-cognition associations is important for early detection of dementia and designing intervention trials.

The Older Finnish Twin Cohort - 45 Years of Follow-up.

The older Finnish Twin Cohort (FTC) was established in 1974. The baseline survey was in 1975, with two follow-up health surveys in 1981 and 1990. The fourth wave of assessments was done in three parts, with a questionnaire study of twins born during 1945-1957 in 2011-2012, while older twins were interviewed and screened for dementia in two time periods, between 1999 and 2007 for twins born before 1938 and between 2013 and 2017 for twins born in 1938-1944. The content of these wave 4 assessments is described and some initial results are described. In addition, we have invited twin-pairs, based on response to the cohortwide surveys, to participate in detailed in-person studies; these are described briefly together with key results. We also review other projects based on the older FTC and provide information on the biobanking of biosamples and related phenotypes.

Physical Activity and Cognitive Decline Among Older Adults: A Systematic Review and Meta-Analysis.

Importance: Physical activity is associated with the risk for cognitive decline, but much of the evidence in this domain comes from studies with short follow-ups, which is prone to reverse causation bias. Objective: To examine how length of follow-up, baseline age, physical activity amount, and study quality modify the longitudinal associations of physical activity with cognition. Data Sources: Observational studies of adults with a prospective follow-up of at least 1 year, a valid baseline cognitive measure or midlife cohort, and an estimate of the association of baseline physical activity and follow-up cognition were sought from PsycInfo, Scopus, CINAHL, Web of Science, SPORTDiscus, and PubMed, with the final search conducted on November 2, 2022. Study Selection: Two independent researchers screened titles with abstracts and full-text reports. Data Extraction and Synthesis: Two reviewers independently assessed study quality and extracted data. Pooled estimates of association were calculated with random-effects meta-analyses. An extensive set of moderators, funnel plots, and scatter plots of physical activity amount were examined. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: Pooled estimates of the associations between physical activity and global cognition, as well as specific cognitive domains, were examined. Results: A total of 104 studies with 341 471 participants were assessed. Analysis of binary outcomes included 45 studies with 102 452 individuals, analysis of follow-up global cognition included 14 studies with 41 045 individuals, and analysis of change in global cognition included 25 studies with 67 463 individuals. Physical activity was associated with a decreased incidence of cognitive impairment or decline after correction for funnel plot asymmetry (pooled risk ratio, 0.97; 95% CI, 0.97-0.99), but there was no significant association in follow-ups longer than 10 years. Physical activity was associated with follow-up global cognition (standardized regression coefficient, 0.03; 95% CI, 0.02-0.03) and change in global cognition (standardized regression coefficient, 0.01; 95% CI, 0.01 to 0.02) from trim-and-fill analyses, with no clear dose-response or moderation by follow-up length, baseline age, study quality or adjustment for baseline cognition. The specific cognitive domains associated with physical activity were episodic memory (standardized regression coefficient, 0.03; 95% CI, 0.02-0.04) and verbal fluency (standardized regression coefficient, 0.05; 95% CI, 0.03-0.08). Conclusions and Relevance: In this meta-analysis of the association of physical activity with cognitive decline, physical activity was associated with better late-life cognition, but the association was weak. However, even a weak association is important from a population health perspective.

TWINGEN: protocol for an observational clinical biobank recall and biomarker cohort study to identify Finnish individuals with high risk of Alzheimer's disease.

INTRODUCTION: A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among THL Biobank donors according to TWINGEN study criteria. METHODS AND ANALYSIS: A multi-centre study (n=800) to obtain blood-based biomarkers, telephone-administered and web-based memory and cognitive parameters, questionnaire information on lifestyle, health and psychological factors, and accelerometer data for measures of physical activity, sedentary behaviour and sleep. A subcohort is being asked to participate in an in-person neuropsychological assessment (n=200) and wear an Oura ring (n=50). All participants in the TWINGEN study have genome-wide genotyping data and up to 48 years of follow-up data from the population-based older Finnish Twin Cohort (FTC) study of the University of Helsinki. The data collected in TWINGEN will be returned to THL Biobank from where it can later be requested for other biobank studies such as FinnGen that supported TWINGEN. ETHICS AND DISSEMINATION: This recall study consists of FTC/THL Biobank/FinnGen participants whose data were acquired in accordance with the Finnish Biobank Act. The recruitment protocols followed the biobank protocols approved by Finnish Medicines Agency. The TWINGEN study plan was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (number 16831/2022). THL Biobank approved the research plan with the permission no: THLBB2022_83.

Accelerometer-measured physical activity and sedentary behavior in nonagenarians: Associations with self-reported physical activity, anthropometric, sociodemographic, health and cognitive characteristics.

BACKGROUND: Research on device-based physical activity in the oldest-old adults is scarce. We examined accelerometer-measured physical activity and sedentary behavior in nonagenarians. We also investigated how the accelerometer characteristics associate with nonagenarians' self-reported physical activity, anthropometric, sociodemographic, health and cognitive characteristics. METHODS: Nonagenarians from a population-based cohort study (N = 38, mean age 91.2) used accelerometers during the waking hours for seven days. They also participated in a health survey and cognitive telephone interview. The Wald test and Pearson and polyserial correlations were used to analyze the data. RESULTS: The participants' average day consisted of 2931 steps, 11 minutes of moderate-to-vigorous physical activity and 13.6 hours of sedentary time. Physical activity bouts less than 3 minutes per day and sedentary time bouts of 20-60 minutes per day were the most common. No sex differences were found. Many accelerometer-measured and self-reported physical activity characteristics correlated positively (correlations ≥0.34, p-values <0.05). The low levels of many accelerometer-measured physical activity characteristics associated with low education (correlations ≥0.25, p-values <0.05), dizziness (correlations ≤-0.42, p-values <0.01) and fear of falling (correlations ≤-0.45, p-values <0.01). Fear of falling was also associated with accelerometer-measured sedentary behavior characteristics (correlations -0.42 or ≥0.43). CONCLUSIONS: Nonagenarians were mostly sedentary and low in physical activity, but individual variability existed. Accelerometer-measured and self-reported physical activity had a good consistency. Education, dizziness and fear of falling were consistently related to accelerometer-measured characteristics in nonagenarians.

TWINGEN - protocol for an observational clinical biobank recall and biomarker study to identify individuals with high risk of Alzheimer's disease.

Introduction: A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among Finnish biobank donors according to TWINGEN study criteria. Methods and analysis: A multi-center study (n=800) to obtain blood-based biomarkers, telephone-administered and web-based memory and cognitive parameters, questionnaire information on lifestyle, health and psychological factors, and accelerometer data for measures of physical activity, sedentary behavior and sleep. A sub-cohort are being asked to participate in an in-person neuropsychological assessment (n=200) and wear an Oura ring (n=50). All participants in the TWINGEN study have genome-wide genotyping data and up to 48 years of follow-up data from the population-based older Finnish Twin Cohort (FTC) study of the University of Helsinki. TWINGEN data will be transferred to Finnish Institute of Health and Welfare (THL) biobank and we aim to further to transfer it to the FinnGen study where it will be combined with health registry data for prediction of AD. Ethics and dissemination: This recall study consists of FTC/THL/FinnGen participants whose data were acquired in accordance with the Finnish Biobank Act. The recruitment protocols followed the biobank protocols approved by Finnish Medicines Agency. The TWINGEN study plan was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (number 16831/2022). THL Biobank approved the research plan with the permission no: THLBB2022_83.

Twin studies on the association of physical activity with cognitive and cerebral outcomes.

Regular physical activity (PA) offers positive effects on the human body. However, the effects of PA on cognition and in the brain are less clear. In this paper, we narratively review the relationship of PA with cognition and dementia, first from general perspective and then through genetically informed studies on the topic. Then we move on to imaging studies on exercise and brain anatomy first by presenting an overall picture of the topic and then discussing brain imaging studies addressing PA and brain structure in twins in more detailed way. Regarding PA and cognition or dementia, genetically informed studies are uncommon, even though the relationship between PA and cognitive ageing has been extensively studied. It is challenging to find twin pairs discordant for PA and dementia. Concerning brain imaging studies, among PA discordant young adult twin pairs, the more active co-twins showed larger gray matter volumes in striatal, prefrontal, and hippocampal regions and in electrophysiological studies automatic deviance-detection processes differed in brain regions involved with sensorimotor, visual and memory functions.

Chronic diseases and objectively monitored physical activity profile among aged individuals - a cross-sectional twin cohort study.

INTRODUCTION: High physical activity (PA) at old age indicates good functional capacity enabling independent living. We investigated how different disease conditions are associated with measured PA indicators in old women and men, and whether they recognize this association. MATERIALS AND METHODS: This cross-sectional twin cohort study in Finland comprised 779 individuals (276 complete twin pairs, including 117 monozygotic pairs), who participated in hip-worn accelerometer monitoring of PA and responded to questions on diseases and mobility limitations at mean age of 73 (range 71-75). RESULTS: Of the participants, 23.2% reported having a disease restricting mobility. With sex and age in the regression model, the reported disease restricting mobility explained 11.8% of the variation in moderate-to-vigorous PA (MVPA) and 10.4% of the variation in daily steps. Adding stepwise other self-reported diseases and body mass index to the model increased the explanatory power for MVPA up to 18.5% and 25.5%, and for daily steps up to 16.0% and 20.7%, respectively. In the co-twin control analysis the PA differences were smaller in disease-discordant monozygotic than dizygotic pairs. CONCLUSIONS: Chronic disease conditions are associated with low PA, which individuals may not always recognize. Shared genetic factors may explain part of the associations. Key messages Among community-dwelling older men and women one-fourth of the variation in objectively measured moderate-to-vigorous physical activity is accounted for by age, sex, body mass index and self-reported diseases. Occurrence of chronic diseases is associated with low physical activity and individuals do not always recognize this. Healthcare professionals should pay attention to the low physical activity and mobility of individuals with chronic disease conditions before these result in limitations in independent living.

Long-term leisure-time physical activity and other health habits as predictors of objectively monitored late-life physical activity - A 40-year twin study.

Moderate-to-vigorous physical activity (MVPA) in old age is an important indicator of good health and functional capacity enabling independent living. In our prospective twin cohort study with 616 individuals we investigated whether long-term physical activity assessed three times, in 1975, 1982 and 1990 (mean age 48 years in 1990), and other self-reported health habits predict objectively measured MVPA measured with a hip-worn triaxial accelerometer (at least 10 hours per day for at least 4 days) 25 years later (mean age of 73 years). Low leisure-time physical activity at younger age, higher relative weight, smoking, low socioeconomic status, and health problems predicted low MVPA in old age in individual-based analyses (altogether explaining 20.3% of the variation in MVPA). However, quantitative trait modeling indicated that shared genetic factors explained 82% of the correlation between baseline and follow-up physical activity. Pairwise analyses within monozygotic twin pairs showed that only baseline smoking was a statistically significant predictor of later-life MVPA. The results imply that younger-age physical activity is associated with later-life MVPA, but shared genetic factors underlies this association. Of the other predictors mid-life smoking predicted less physical activity at older age independent of genetic factors.

Objectively measured physical activity profile and cognition in Finnish elderly twins.

INTRODUCTION: We studied whether objectively measured physical activity (PA) and sedentary behavior (SB) are associated with cognition in Finnish elderly twins. METHODS: This cross-sectional study comprised twins born in Finland from 1940 to 1944 in the Older Finnish Twin Cohort (mean age, 72.9 years; 726 persons). From 2014 to 2016, cognition was assessed with a validated telephonic interview, whereas PA was measured with a waist-worn accelerometer. RESULTS: In between-family models, SB and light physical activity had significant linear associations with cognition after adjusting for age, sex, wearing time, education level, body mass index, and living condition (SB: ß-estimate, -0.21 [95% confidence intervals, -0.42 to -0.003]; light physical activity: ß-estimate, 0.30 [95% confidence intervals, 0.02-0.58]). In within-family models, there were no significant linear associations between objectively measured PA and cognition. DISCUSSION: Objectively measured light physical activity and SB are associated with cognition in Finnish twins in their seventies, but the associations were attributable to genetic and environmental selection.

Midlife Physical Activity and Cognition Later in Life: A Prospective Twin Study.

BACKGROUND: Physical activity has been associated with a reduced risk of cognitive decline but the nature of this association remains obscure. OBJECTIVE: To study associations between midlife physical activity and cognition in old age for a prospective cohort of Finnish twins. METHODS: Physical activity in the Finnish Twin Cohort was assessed using questionnaire responses collected in 1975 and 1981. After a mean follow-up of 25.1 years, the subjects' (n = 3050; mean age 74.2; range 66-97) cognition was evaluated with a validated telephone interview. Both participation in vigorous physical activity, and the volume of physical activity, divided into quintiles, were used as predictors of cognitive impairment. Metrics collected by TELE were used to categorize participants as: cognitively impaired, suffering mild cognitive impairment, or cognitively healthy. RESULTS: Participation in vigorous physical activity compared to non-participation for both 1975 and 1981 was associated with a lower risk of cognitive impairment in individual-based analyses (fully adjusted OR 0.50, 95% CI 0.35-0.73). Pairwise analyses yielded similar but statistically non-significant associations. In terms of the volume of physical activity, the most active quintile of individuals (OR 0.69, 95% CI 0.46-1.04) had a reduced risk of cognitive decline compared with the most sedentary quintile in the fully adjusted model although no clear dose-response was found. CONCLUSION: Vigorous midlife physical activity was associated with less cognitive impairment but without a clear dose-response association between the volume of physical activity and cognition.

Physical activity and dementia: long-term follow-up study of adult twins.

INTRODUCTION: Physical activity is associated with a decreased occurrence of dementia. In twins, we investigated the effect of persistent physical activity in adulthood on mortality due to dementia. MATERIALS AND METHODS: Physical activity was queried in 1975 and 1981 from the members of the older Finnish Twin Cohort (n = 21,791), who were aged 24-60 years at the end of 1981. The subjects were divided into three categories according to the persistence of their vigorous physical activity. Dementia deaths were followed up to the end of 2011. RESULTS: During the 29-year follow-up, 353 subjects died of dementia. In individual-based analyses the age- and sex-adjusted hazard ratio (HR) was 0.65 (95% CI 0.43-0.98) for subjects partaking in vigorous physical activities in both 1975 and 1981 compared to those who were inactive in both years. No significant change was observed after adjusting for potential confounding factors. The corresponding HR for within-pair comparisons of the less active twin versus the more active co-twin was 0.48 (95% CI 0.17-1.32). The results for analyses of the volume of physical activity were inconclusive. CONCLUSIONS: Persistent vigorous leisure-time physical activity protects from dementia, and the effect appears to remain after taking into account childhood environment.