Midlife Fitness Research Articles

Dietary patterns and cardiorespiratory fitness in midlife and subsequent all-cause dementia: findings from the Cooper Center Longitudinal Study

BackgroundIdentifying lifestyle factors that independently or jointly lower dementia risk is a public health priority given the limited treatment options available to patients. In this cohort study, we examined the associations between Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diet adherence and cardiorespiratory fitness (CRF) with later-life dementia, and assessed whether the associations between dietary pattern and dementia are modified by CRF.MethodsData are from 9,095 adults seeking preventive care at the Cooper Clinic (1987–1999) who completed a 3-day dietary record and a maximal exercise test. Alzheimer’s disease and related disorders or senile dementia (i.e., all-cause dementia) was identified from Medicare administrative claims (1999–2019). Illness-death models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between Mediterranean or DASH diet adherence (primary exposure), CRF (secondary exposure), and all-cause dementia, adjusted for demographic and clinical factors. An interaction term was included between diet score and CRF to assess effect modification by CRF.ResultsThe mean age at baseline was 50.6 (standard deviation [SD]: 8.4) years, and a majority of the study sample were men (77.5%) and White (96.4%). 1449 cases of all-cause dementia were identified over a mean follow-up of 9.2 (SD: 5.8) years. Neither Mediterranean nor DASH diet adherence was associated with dementia risk in fully adjusted models (HR per SD of Mediterranean diet score: 1.00, 95% CI: 0.94, 1.05; HR per SD of DASH diet score: 1.02, 95% CI: 0.96, 1.08). However, participants with higher CRF had a decreased hazard of dementia (HR, per metabolic equivalent of task [MET] increase, Mediterranean model: 0.95, 95% CI: 0.92, 0.98; HR, per MET increase, DASH model: 0.96, 95% CI: 0.92, 0.97). No effect modification by CRF was observed in the association between diet and dementia.ConclusionsIn this sample of apparently healthy middle-aged adults seeking preventive care, higher CRF at midlife was associated with a lower risk of all-cause dementia, though adherence to a Mediterranean or DASH diet was not, and CRF did not modify the diet-dementia association. CRF should be emphasized in multimodal interventions for dementia prevention and investigated among diverse samples.

Associations of midlife fitness and obesity profiles with cognitive function

AbstractLow fitness and obesity at midlife are individually associated with later‐life decline in cognition and health. However, the relationship between profiles of midlife fitness and obesity with midlife cognition is unclear and was examined by this study. Participants from the third follow‐up of the Childhood Determinants of Adult Health study (2014–2019; aged 36–49 years) were assessed for obesity (body mass index [BMI]), cardiorespiratory (physical work capacity) and muscular fitness (isometric grip and leg strength), and these factors were entered into a latent profile analysis. Psychomotor‐attention, learning–working memory and global cognition composites were derived from z‐scores of individual CogState battery tests. Linear regression analyses examined associations between profiles of fitness and obesity with cognition, adjusting for age, sex, education, alcohol and smoking. Using data from 617 participants [44.4 ± 2.6 (mean ± SD) years, 52% female], we identified 5 mutually exclusive profiles of obesity and fitness. Relative to those with the lowest fitness and highest BMI (5% of sample), those with a profile of (1) highest muscular fitness and average BMI (9%), (2) average muscular fitness and BMI (61%) and (3) highest cardiorespiratory fitness (CRF) and below average BMI (7%) all exhibited better global cognition [at least 0.44 (0.12, 0.77) SD, 95% CI] and psychomotor‐attention performance [at least 0.59 (0.27, 0.91) SD, 95% CI]. Compared with low fitness and unhealthy BMI levels, possessing average or high muscular and CRF and a healthy BMI in midlife was associated with better cognitive performance. Enhancing fitness and reducing obesity in midlife could contribute to improved cognitive performance in middle age.

Cardiorespiratory fitness in midlife and subsequent incident depression, long-term sickness absence, and disability pension due to depression in 330,247 men and women

ObjectiveSpecific information for whom and when cardiorespiratory fitness (CRF) is associated with depression risk is lacking. We aimed to study the association between adulthood CRF and incident depression, long-term sickness absence, and disability pension due to depression, as well as examine moderation of sex, age, education, and occupation on associations. MethodsA large prospective cohort study follows participants over time with Swedish occupational health screenings data. The study includes 330,247 individuals (aged 16–79 years, 46% women) without a depression diagnosis at baseline. CRF was estimated from a submaximal cycle test. ResultsCRF was associated beneficially from low to higher levels with incident depression and long-term sickness absence due to depression. Further, CRF at high levels (≥46 ml/min/kg) was associated with a decreased risk of receiving disability pension due to depression. The associations remained after adjustment for age and sex, but not lifestyle-related factors and co-morbidity. Participants with moderate and high CRF had 16% and 21%, respectively, lower risk for incident depression, and participants with high CRF had 11% lower risk for long-term sickness absence due to depression. Associations between higher CRF and the outcomes were mainly evident in men, younger participants, and individuals with low education. ConclusionIn a large sample of adults without a depression diagnosis at baseline, higher CRF was shown to be beneficially related to the risk of incident depression and, to some extent, long-term sickness absence due to depression. If causal, targeted interventions focusing on increasing CRF in these sub-groups should be prioritized.

Independent and joint associations of cardiorespiratory fitness and BMI with dementia risk: the Cooper Center Longitudinal Study

ObjectiveThis study aimed to examine the association of midlife fitness and body mass index (BMI) with incident dementia later in life.Design and participantsA cohort study of 6428 individuals (mean age...

Functional connectivity mediates the relationship between cardiorespiratory fitness and stress in midlife.

BackgroundIncreasing evidence suggests that the relation between mental health and physical health is bidirectional and underpinned by complex neural systems. Cardiovascular fitness is a key measure of physical health but its relation to mental health is insufficiently examined. Characterizing the neural mechanisms by which cardiovascular fitness influences mental health could inform the development of strategies to promote mental health and minimize the risk of mental disorders. Methods and resultsThe relation between cardiorespiratory fitness, functional brain connectivity and mental health was studied in 418 healthy middle-aged (aged 40–65 years) adult participants of the Barcelona Brain Health Initiative (BBHI). Higher cardiorespiratory fitness, measured by VO₂ peak, was associated with lower symptoms of anxiety (β = −0.111, p = 0.017) and stress (β = −0.242, p = 0.002) scores, evaluated by the Depression Anxiety and Stress Scale (DASS-21) and its three subscales (stress, anxiety, and depression). Higher within-network functional connectivity of the Default Mode Network (DMN) was associated with higher VO₂ peak (β = 0.195, p = 0.002), and lower stress scores (β = −0.126, p = 0.011). In addition, higher functional connectivity between the Frontoparietal Network (FPN) and Salience Network (SN) was associated with higher VO₂ peak (β = 0.187, p = 0.002), and lower stress scores (β = −0.123, p = 0.016). Both within-DMN [ACME = −0.02 (-0.04,-0.00), p = 0.040] and between FPN-SN [ACME = −0.01 (-0.04,-0.00), p = 0.036] functional connectivity mediated the relationship between cardiorespiratory fitness and stress. ConclusionsThe relationship between the cardiorespiratory fitness and stress in middle-aged adults is mediated by functional connectivity of several intrinsic resting-state networks. These results highlight a potential mechanistic pathway through which higher cardiorespiratory fitness can positively impact brain health in midlife.

Analysis of Cardiorespiratory Fitness in Early Adulthood and Midlife With All-Cause Mortality and Fatal or Nonfatal Cardiovascular Disease

Optimizing cardiovascular fitness is a prevention strategy against premature death and cardiovascular disease (CVD) events. Since this evidence has largely been established in older populations, the importance of cardiorespiratory fitness during earlier periods of adulthood remains unclear. To examine the association of early-adulthood cardiorespiratory fitness and percentage of early-adulthood cardiorespiratory fitness retained during midlife with subsequent risk of all-cause mortality and CVD-related morbidity and mortality overall as well as by sex and race. This retrospective population-based cohort study analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing prospective cohort study conducted at field center clinics in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. Participants in the CARDIA study were aged 18 to 30 years when they completed the baseline graded exercise test protocol in 1985 to 1986 and have since undergone follow-up examinations biannually and every 2 to 5 years. Data were collected through August 31, 2020, and were analyzed in October 2022. Cardiorespiratory fitness was estimated from a symptom-limited, maximal graded exercise test protocol conducted at baseline and at year 7 and year 20 follow-up examinations. All-cause mortality and combined fatal and nonfatal CVD events were obtained since year 20 of follow-up examinations through August 31, 2020. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for each primary exposure with each outcome. A total of 4808 participants (mean [SD] age at baseline, 24.8 [3.7] years; 2670 females [56%]; 2438 Black individuals [51%]) were included in the sample. During 68 751 person-years of follow-up, there were 302 deaths (6.3%) and 274 CVD events (5.7%) since year 20. Every 1-minute increment in cardiorespiratory fitness at baseline was associated with a lower risk of all-cause mortality in females (HR, 0.73; 95% CI, 0.64-0.82) and males (HR, 0.87; 95% CI, 0.80-0.96). Every 5% increment in cardiorespiratory fitness retained through year 20 was associated with a lower risk of all-cause mortality (HR, 0.89; 95% CI, 0.79-0.99), but no evidence of effect modification by race or sex was found. Every 1-minute increment in cardiorespiratory fitness at baseline was associated with a lower risk of fatal or nonfatal CVD (HR, 0.89; 95% CI, 0.82-0.96), and the estimated HR per 5% increment in cardiorespiratory fitness retained throughout midlife was 0.89 (95% CI, 0.78-1.00), with no evidence for interaction by race or sex. This cohort study found that higher early-adulthood cardiorespiratory fitness and greater retention of early-adulthood cardiorespiratory fitness throughout midlife were associated with a lower risk of premature death and CVD events. Additional research is needed to clarify the association of cardiorespiratory fitness timing across the life course with risk of clinical outcomes.

P05-01 Change in cardiorespiratory fitness in midlife and incident hypertension

BackgroundLow cardiorespiratory fitness (CRF) is associated with higher blood pressure and risk of incident hypertension. However, existing literature has mainly investigated CRF at baseline. For HEPA initiatives, it is important to know how change in CRF in midlife associate with incident hypertension, and whether this varies between sexes, age and baseline CRF.Methods91,728 individuals (20-79 years, 48% women, free from hypertension at baseline) from the Swedish workforce who had completed two health profile assessments in a nationwide occupational health service screening between 1986 and 2019 were included. CRF (assessed as VO2max) was estimated using a submaximal cycle test. Change in CRF between the two tests was expressed as % change in absolute CRF (L·min-1) per year and categorized as “maintainers” (-1% to 1% change/year), “decreases” (≥-1% change/year) or “increasers” (≥1% change/year). Incident hypertension was defined as having a blood pressure >140/90 mmHg or diagnosed with hypertension at the second test. Binary logistic regression was used to assess OR (95% CI) for hypertension at the second test between maintainers, decreases and increasers. All analyses were adjusted for sex, age, heart medication, time between tests, education, and change in other lifestyle variables between the two tests (stress, diet, exercise, smoking).ResultsCompared to maintainers (set as reference), OR for decreases was 1.27 (1.18-1.38) and increasers OR 0.99 (0.89-1.09). Isolating midlife participants (40-60 years), OR for decreasers was 1.47 (1.30-1.66) and increasers OR 0.75 (0.64-0.86). Looking at sex differences, male decreasers had OR 1.24 (1.12-1.36) and female decreasers OR 1.36 (1.20-1.56), compared to maintainers, while OR for male and female increasers was 0.93 (0.83-1.03) and 0.97 (0.83-1.13). For participants with low CRF at baseline (<32·kg-1·min-1), OR for decreasers was 1.70 (1.51-1.92) and increasers 1.32 (1.18-1.49). Corresponding ORs in those with high CRF at baseline were 0.90 (0.80-1.02) and 0.43 (0.26-0.71).ConclusionsDecrease in CRF with >1% per year associated with significant higher risk for incident hypertension, while maintaining or increasing CRF had similar risk associations. This was seen in both men and women, different age-groups and baseline level of CRF. Health enhancing promotion strategies to maintain or increase CRF level is highly clinically relevant.

Midlife Cardiorespiratory Fitness and the Development of Peripheral Artery Disease in Later Life.

BackgroundData are sparse on the prospective associations between physical activity and incidence of lower extremity peripheral artery disease (PAD).Methods and ResultsLinking participant data from the CCLS (Cooper Center Longitudinal Study) to Medicare claims files, we studied 19 023 participants with objectively measured midlife cardiorespiratory fitness through maximal effort on the Balke protocol who survived to receive Medicare coverage between 1999 and 2009. The study aimed to determine the association between midlife cardiorespiratory fitness and incident PAD with proportional hazards intensity models, adjusted for age, sex, body mass index, and other covariates, to PAD failure time data. During 121 288 person‐years of Medicare follow‐up, we observed 805 PAD‐related hospitalizations/procedures among 19 023 participants (21% women, median age 50 years). Lower midlife fitness was associated with a higher rate of incident PAD in patients aged 65 years and older (low fit [quintile 1]: 11.4, moderate fit [quintile 2 to 3]: 7.8, and high fit [quintile 4 to 5]: 5.7 per 1000 person years). After multivariable adjustment for common predictors of incident PAD such as age, body mass index, hypertension, and diabetes, these findings persisted. Lower risk for PAD per greater metabolic equivalent task of fitness was observed (hazard ratio [HR], 0.93 [95% CI, 0.90–0.97]; P<0.001). Among a subset of patients with an additional fitness assessment, each 1 metabolic equivalent task increase from baseline fitness was associated with decreased risk of incident PAD (HR, 0.90 [95% CI, 0.82–0.99]; P=0.03).ConclusionsCardiorespiratory fitness in healthy, middle‐aged adults is associated with lower risk of incident PAD in later life, independent of other predictors of incident PAD.

Association of Estimated Cardiorespiratory Fitness in Midlife With Cardiometabolic Outcomes and Mortality

The associations of estimated cardiorespiratory fitness (eCRF) during midlife with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality are not well understood. To examine associations of midlife eCRF with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality. This cohort study included 2962 participants in the Framingham Study Second Generation (conducted between 1979 and 2001). Data were analyzed from January 2020 to June 2020. eCRF was calculated using sex-specific algorithms (including age, body mass index, waist circumference, physical activity, resting heart rate, and smoking) and was categorized as: (1) tertiles of standardized eCRF at examination cycle 7 (1998 to 2001); (2) tertiles of standardized average eCRF between examination cycles 2 and 7 (1979 to 2001); and (3) eCRF trajectories between examination cycles 2 and 7, with the lowest tertile or trajectory (ie, low eCRF) as referent group. Subclinical atherosclerosis (carotid intima-media thickness [CIMT], coronary artery calcium [CAC] score); arterial stiffness (carotid-femoral pulse wave velocity [-1000/CFPWV]); incident hypertension, diabetes, chronic kidney disease (CKD), cardiovascular disease (CVD), and mortality after examination cycle 7. A total of 2962 participants were included in this cohort study (mean [SD] age, 61.5 [9.2] years; 1562 [52.7%] women). The number of events or participants at risk after examination cycle 7 (at a mean follow-up of 15 years) was 728 of 1506 for hypertension, 214 of 2268 for diabetes, 439 of 2343 for CKD, 500 of 2608 for CVD, and 770 of 2962 for mortality. Compared with the low eCRF reference value, high single examination eCRF was associated with lower CFPWV (β [SE], -11.13 [1.33] ms/m) and CIMT (β [SE], -0.12 [0.05] mm), and lower risk of hypertension (hazard ratio [HR], 0.63; 95% CI, 0.46-0.85), diabetes (HR, 0.38; 95% CI, 0.23-0.62), and CVD (HR, 0.71; 95% CI, 0.53-0.95), although it was not associated with CKD or mortality. Similarly, compared with the low eCRF reference, high eCRF trajectories and mean eCRF were associated with lower CFPWV (β [SE], -11.85 [1.89] ms/m and -10.36 [1.54] ms/m), CIMT (β [SE], -0.19 [0.06] mm and -0.15 [0.05] mm), CAC scores (β [SE], -0.67 [0.25] AU and -0.63 [0.20] AU), and lower risk of hypertension (HR, 0.54; 95% CI, 0.34-0.87 and HR, 0.48; 95% CI, 0.34-0.68), diabetes (HR, 0.27; 95% CI, 0.15-0.48 and HR, 0.31; 95% CI, 0.18-0.54), CKD (HR, 0.63; 95% CI, 0.40-0.97 and HR, 0.64; 95% CI, 0.44-0.94), and CVD (HR, 0.46; 95% CI, 0.31-0.68 and HR, 0.43; 95% CI, 0.30-0.60). Compared with the reference value, a high eCRF trajectory was associated with lower risk of mortality (HR, 0.69; 95% CI, 0.50-0.95). In this cohort study, higher midlife eCRF was associated with lower burdens of subclinical atherosclerosis and vascular stiffness, and with a lower risk of hypertension, diabetes, chronic kidney disease, cardiovascular disease, and mortality. These findings suggest that midlife eCRF may serve as a prognostic marker for subclinical atherosclerosis, arterial stiffness, cardiometabolic health, and mortality in later life.

Abstract 15328: Higher Non-exercise Estimated Cardiorespiratory Fitness in Midlife is Associated With Lower Risk of Incident Heart Failure: The Framingham Heart Study

Introduction: Non-exercise estimated cardiorespiratory fitness (eCRF) algorithms have shown similar accuracy to CRF estimated from submaximal and maximal exercise tests in healthy adults. Using easily accessible health indicators, eCRF measurement does not involve in-person exercise testing, trained personnel, or specialized equipment for measuring CRF. Thus, eCRF may be a cost-effective alternative for heart disease risk stratification. The relation between eCRF and Heart failure (HF) remains unclear. Hypothesis: We hypothesized that higher midlife eCRF is associated with a lower risk of incident HF in later life. Methods: We evaluated 2,226 Framingham Offspring cohort participants attending examination cycles 2 and 7 (mean age of 42- 61years; 53% women). We used a validated longitudinal non-exercise algorithm for eCRF including age, sex, body mass index, waist circumference, resting heart rate, physical activity, and smoking status. Midlife eCRF was defined as a sex-specific standardized average of eCRF (z-score of the average eCRF with mean=0 and a standard deviation [SD]=1) between cycles 2 and 7. The sex-specific midlife eCRF were then categorized into three groups based on tertiles and was also analyzed as a continuous variable (per 1 SD increment). We used multivariable Cox proportional hazards regression models for pooled sexes to relate the midlife eCRF to incident HF after examination cycle 7. Results: Overall, 189 participants developed HF during a median of 17 years of follow-up. Participants in either moderate or high eCRF group experienced a 52% lower risk of HF compared to those in the low eCRF group, after adjustment for potential confounders. Additionally, each SD increment in midlife eCRF was associated with a 40% lower risk of HF in later life. The associations remained significant after excluding participants on antihypertensive treatment (Table). Conclusions: Lower eCRF during midlife may be a marker of higher HF risk in later life.

Abstract P378: Higher Non-exercise Estimated Cardiorespiratory Fitness in Midlife is Associated With Lower Risk of Cardiovascular Disease and Mortality in Later Life: The Framingham Heart Study

Introduction: Studies have demonstrated that higher cardiorespiratory fitness (CRF) is associated with a lower risk of cardiovascular disease (CVD) and mortality. However, exercise CRF test is not routinely performed in clinical settings because it requires specialized equipment and trained personnel. Therefore, non-exercise estimated CRF (eCRF) using easily accessible health indicators in clinical practice may be a time- and cost-effective alternative for evaluating fitness. Hypothesis: We hypothesized that higher eCRF in midlife will be associated with a lower risk of CVD and all-cause mortality in later life. Methods: We evaluated 2,501 Framingham Offspring cohort participants (mean age 65 yrs., 52% women). We used a longitudinal non-exercise algorithm that includes age, sex, body mass index, waist circumference, resting heart rate, physical activity, and smoking status. We then used SAS PROC TRAJ to identify sex-specific latent patterns of eCRF (low, moderate, and high eCRF categories) between exam 2 and 8 (1979-2008). Multivariable Cox proportional hazards regression models were used to relate the long-term trajectories of eCRF to incident CVD and all-cause mortality on follow-up. Results: We identified three distinct trajectories of eCRF (Low [n=268, 10.7%] vs. moderate [n=1,273, 50.9%] vs. high [n=960, 38.4%]). Overall, 265 participants developed CVD and 429 died during 10 years of median follow-up. Participants in the “high eCRF” group were at lower risk of CVD and all-cause mortality compared to those in the “low eCRF” group, after adjustment for potential confounders ( Table ). Conclusions: Our findings suggest that lower eCRF during midlife may be a marker of risk of CVD and mortality in older adulthood.

Cognitive efficiency in late midlife is linked to lifestyle characteristics and allostatic load.

We investigated whether cognitive fitness in late midlife is associated with physiological and psychological factors linked to increased risk of age-related cognitive decline. Eighty-one healthy late middle-aged participants (mean age: 59.4 y; range: 50-69 y) were included. Cognitive fitness consisted of a composite score known to be sensitive to early subtle cognitive change. Lifestyle factors (referenced below as cognitive reserve factors; CRF) and affective state were determined through questionnaires, and sleep-wake quality was also assessed through actimetry. Allostatic load (AL) was determined through a large range of objective health measures. Generalized linear mixed models, controlling for sex and age, revealed that higher cognitive reserve and lower allostatic load are related to better cognitive efficiency. Crystallized intelligence, sympathetic nervous system functioning and lipid metabolism were the only sub-fields of CRF and AL to be significantly associated with cognition. These results show that previous lifestyle characteristics and current physiological status are simultaneously explaining variability in cognitive abilities in late midlife. Results further encourage early multimodal prevention programs acting on both of these modifiable factors to preserve cognition during the aging process.

Changes in midlife fitness, body mass index, and smoking influence cancer incidence and mortality: A prospective cohort study in men.

Cancer prevention efforts include modification of unhealthy lifestyle, such as smoking cessation and resisting gain in body weight. Although physical activity is inversely related to risk of several cancers, it is poorly studied whether changes in physical activity or fitness influence future cancer risk. Thus, we aimed to investigate whether changes in midlife cardiorespiratory fitness (CRF), body mass index (BMI), and smoking habits influence cancer incidence and mortality. The study cohort includes 1689 initially healthy men, aged 40‐59 years. Measurements of CRF, BMI and information on smoking habits were collected in two repeated waves, 7 years apart. Cox regression models estimated associations as hazard rates (HR) with 95% confidence intervals (CI), between midlife changes in the modifiable lifestyle factors and cancer incidence and mortality. The men were followed prospectively for more than 30 years. Compared to CRF loss (>5%), improved CRF (>5%) was associated with lower cancer incidence (HR 0.81, 95% CI 0.67‐0.98) and mortality (HR 0.70, 95% CI 0.54‐0.92), and maintaining the CRF stable yielded lower cancer incidence (HR 0.76, 95% CI 0.61‐0.95). No association was seen for BMI gain, but maintaining the BMI stable was related to lower cancer incidence (HR 0.77, 95% CI 0.60‐0.98), compared to BMI loss. Continue smoking was associated with higher cancer incidence and mortality, compared to men who stopped smoking. In particular, this study adds new knowledge about the potential preventive role of CRF in cancer development and emphasizes lifestyle modification as a highly important effort in cancer prevention.

Abstract MP32: Mid-Life Fitness and Plasma Markers of Alzheimer’s Pathology

Introduction: Motor function in older adults is known to correlate with neurodegenerative changes and Alzheimer’s Disease (AD) pathology in the brain, however the relationship between mid-life fitness and AD pathology is unknown. AD pathology accumulates early and is difficult to measure; precise estimation requires brain imaging not accessible beyond research settings. Plasma Amyloid and Tau, on the other hand are easy to measure, and are markers of AD pathology and neuronal loss. We tested the association between physical fitness measures in mid-life (gait speed, grip strength and chair stand speed) and plasma markers of AD in the Framingham Heart Study (FHS) Offspring cohort. If these measures correlate with and predict plasma measures of AD burden, these could potentially be used to screen for risk of dementia. Hypothesis: We hypothesized that superior physical fitness will be cross-sectionally associated with higher plasma Amyloid Aβ42 and lower Tau; also, that physical fitness measures will be longitudinally associated with Tau measured at a later exam. Methods: The FHS Offspring cohort had plasma Aβ40 and Aβ42 measured at their 7th clinic exam (1998-01) and plasma total Tau measured at Exam 8 (2005-08). They had grip strength, gait speed and chair stand speed measured at Exam 7, and grip strength and gait speed measured at Exam 8. Grip strength was measured using the Jamar dynamometer, fast gait speed was measured over a 4-meter walkway and chair stand speed was assessed by asking the participants to stand up and down five times, as quickly as they can with their hands folded across their chest. Quantification of Aβ isoforms in plasma was performed using INNO-BIA assays and tau using Single Molecule Array technology.We used linear regression models to examine the association between physical fitness measures and plasma markers of AD adjusting for known confounders (diabetes, cardiovascular disease, atrial fibrillation, smoking, APOE4, systolic blood pressure, waist-to-hip ratio, total cholesterol level, physical activity index, and plasma homocysteine). Results: In this sample of 1886 community living adults (mean age 61, 54% women), hand grip strength was independently associated with plasma Aβ40 (Beta coefficient -0.28; SD 0.10; p value 0.003) and plasma Tau measured 5 years later (Beta coefficient -0.003; SD 0.001; p value 0.001). Gait speed and chair stand speed demonstrated associations with Aβ40 and total Tau which were attenuated by vascular risk factors. Conclusions: Hand grip strength is associated with AD pathology. Grip strength measurement could be a valid screening tool for identifying individuals at a higher risk for AD alongside other validated markers. Future research should examine the correlation between grip strength and AD burden measured by PET imaging.

Editors' note: Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women

“Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women” investigated whether greater cardiovascular fitness in midlife is associated with a decreased risk of dementia in women. The authors found that women with high fitness had a lower adjusted hazard ratio for all-cause dementia and delayed age at onset of dementia compared with women with medium fitness. Commenting on the article, Kivimäki et al. believe that the results are overoptimistic. They explain that because of the small number of dementia cases, the results reported are unlikely to be robust. They support their argument by analyzing an alternative scenario with just 2 additional dementia cases in the high-fitness group, which would decrease the population attributable fraction to less than 60%. Hörder et al. agree that the results may be overoptimistic, but they justify the low number of dementia cases in the highest-fitness group as a consequence of the strong effect of high midlife fitness on dementia risk. They add that high fitness could be regarded as a sum of a number of beneficial factors related to dementia risk (e.g., genetics, exercise, diet, nonsmoking, and blood pressure). “Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women” investigated whether greater cardiovascular fitness in midlife is associated with a decreased risk of dementia in women. The authors found that women with high fitness had a lower adjusted hazard ratio for all-cause dementia and delayed age at onset of dementia compared with women with medium fitness.

Reader response: Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women.

Horder et al.1 advanced the hypothesis that midlife cardiovascular fitness protects against old-age dementia. However, the limitations of the data were not fully discussed. The estimated benefit of greater fitness in terms of dementia prevention is overoptimistic. Using data from tables 3 and 4 in the article,1 we calculated a population attributable fraction (PAF) of 78.3%, suggesting that 8 of 10 dementia cases would be avoided if all women had high cardiovascular fitness (table). This is more than 2 times greater than the collective PAF for all known modifiable risk factors in the most recent synopsis,2 which is itself an upper-bound estimate.3

Author response: Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women.

We are grateful for the comments by Kivimäki et al. on our article.1 We agree that the effect of dementia prevention in our study is probably overoptimistic. However, the results still suggest that there is a strong effect of midlife cardiovascular fitness on dementia risk in old age. Kivimäki et al. conclude that results based on 2 individuals with dementia are entirely based on chance. However, 44 individuals developed dementia during the 44-year follow-up period. Two of those were in the highest quintile of fitness. The low number of dementia cases in the highest-fitness group is thus the consequence of the strong effect of high midlife fitness on dementia risk. However, as Kivimäki et al. point out, this makes the exact estimation of the benefit of fitness less robust, but it still suggests a strong effect. Kivimäki et al. report that with 2 more cases, the population attributable fraction would decrease from 78% to approximately 60%. We would argue that this is also a strong effect. In addition, high fitness could be regarded as a sum of a number of beneficial factors related to dementia risk (e.g., genetics, exercise, diet, nonsmoking, and blood pressure).

Association of Midlife Cardiorespiratory Fitness With Incident Depression and Cardiovascular Death After Depression in Later Life

Cardiorespiratory fitness (hereinafter referred to as fitness) as estimated by exercise testing is a modifiable risk factor independently associated with chronic diseases, cardiovascular disease (CVD) events, and mortality, but the association of fitness at midlife with incidence of later-life depression and the risk of CVD mortality after a depression diagnosis is unknown. To determine whether fitness measured in midlife would be inversely associated with later-life CVD mortality with antecedent depression. This retrospective cohort study at a single-center, community-based preventive medicine clinic was performed as part of the Cooper Center Longitudinal Study. Data were collected from January 13, 1971, through December 31, 2009, and analyzed from October 6, 2015, through August 14, 2017. Participants included generally healthy men and women who presented for preventive medicine examinations at midlife and who were eligible for Medicare from 1999 to 2010. Those with a self-reported history of depression, myocardial infarction, or stroke at examination were excluded. Objective midlife fitness estimated from results of treadmill exercise testing. Depression diagnosis from Medicare claims files using established algorithms and CVD mortality from National Death Index records. A total of 17 989 participants (80.2% men) with a mean (SD) age of 50.0 (8.7) years were included. After 117 218 person-years of Medicare follow-up, 2701 depression diagnoses, 610 deaths due to CVD without prior depression, and 231 deaths due to CVD after depression were observed. A high level of fitness in midlife was associated with a 16% lower risk of depression (hazard ratio [HR], 0.84; 95% CI, 0.74-0.95) compared with a low level of fitness. A high fitness level was also associated with a 61% lower risk of death due to CVD without depression (HR, 0.39; 95% CI, 0.31-0.48) compared with a low level of fitness. After a diagnosis of depression, a high fitness level was associated with a 56% lower risk of death due to CVD (HR, 0.44; 95% CI, 0.31-0.64) compared with a low fitness level. Midlife fitness is associated with a lower risk of later-life depression, CVD mortality, and CVD mortality after incident later-life depression. These findings suggest the importance of midlife fitness in primary prevention of depression and subsequent CVD mortality in older age and should encourage physicians to consider fitness and physical activity in promoting healthy aging.

Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women.

ObjectiveTo investigate whether greater cardiovascular fitness in midlife is associated with decreased dementia risk in women followed up for 44 years.MethodsA population-based sample of 1,462 women 38 to 60 years of age was examined in 1968. Of these, a systematic subsample comprising 191 women completed a stepwise-increased maximal ergometer cycling test to evaluate cardiovascular fitness. Subsequent examinations of dementia incidence were done in 1974, 1980, 1992, 2000, 2005, and 2009. Dementia was diagnosed according to DSM-III-R criteria on the basis of information from neuropsychiatric examinations, informant interviews, hospital records, and registry data up to 2012. Cox regressions were performed with adjustment for socioeconomic, lifestyle, and medical confounders.ResultsCompared with medium fitness, the adjusted hazard ratio for all-cause dementia during the 44-year follow-up was 0.12 (95% confidence interval [CI] 0.03–0.54) among those with high fitness and 1.41 (95% CI 0.72–2.79) among those with low fitness. High fitness delayed age at dementia onset by 9.5 years and time to dementia onset by 5 years compared to medium fitness.ConclusionsAmong Swedish women, a high cardiovascular fitness in midlife was associated with a decreased risk of subsequent dementia. Promotion of a high cardiovascular fitness may be included in strategies to mitigate or prevent dementia. Findings are not causal, and future research needs to focus on whether improved fitness could have positive effects on dementia risk and when during the life course a high cardiovascular fitness is most important.

Fitness, Fatness, Physical Activity, and Autonomic Function in Midlife.

Although low cardiorespiratory fitness (CRF), physical inactivity, and obesity are associated with impaired autonomic function, they are also extensively interrelated. The present study aimed to assess the extent to which they contribute to autonomic function independently of each other. At the age of 46 yr, 1383 men and 1761 women without cardiorespiratory diseases and diabetes underwent assessments of vagally mediated heart rate (HR) variability (root mean square of successive differences in R-R interval (rMMSD)), peak HR during a submaximal step test (CRF), and 60-s HR recovery (HRR). Moderate-to-vigorous physical activity (MVPA; ≥3.5 METs, 2 wk) was measured by wrist-worn accelerometer and body fat percentage (Fat%) by bioimpedance. In men, CRF and Fat% were significantly associated with higher rMSSD (standardized β = 0.31 and -0.16) and HRR (β = 0.19 and -0.18), whereas higher MVPA was linked with higher HRR (β = 0.13) when including CRF, MVPA, and Fat% in the initial regression. After adjustments for other lifestyle and cardiometabolic factors, CRF remained significantly associated with rMMSD (β = 0.24) and HRR (β = 0.14), as did MVPA with HRR (β = 0.11). In women, CRF was associated with rMSSD (β = 0.23) and HRR (β = 0.15), and MVPA (β = 0.17) and Fat% (β = -0.07) with HRR, when CRF, MVPA, and Fat% were adjusted for each other. After further adjustments, CRF remained a significant determinant of rMSSD (β = 0.20) and HRR (β = 0.13), as did MVPA with HRR (β = 0.15). The final models explained 23% and 21% of variation in rMSSD and HRR in men, and 10% and 12% in women, respectively. CRF was a more important determinant of cardiac autonomic function than MVPA and body fat. Furthermore, MVPA but not body fat was independently associated with cardiac autonomic function in both men and women.