Physical Frailty, Genetic Predisposition, and Incident Parkinson Disease.

Zheng Z ，Lv Y ，Rong S ，Sun T ，Chen L ... -  《-》

Physical frailty, genetic predisposition, and incident arrhythmias.

Cross-sectional evidence suggests a possible link between frailty and atrial fibrillation (AF). It remains unclear whether frailty and incident arrhythmias are longitudinally associated. This study aimed to determine whether the frailty phenotype is longitudinally associated with incident arrhythmias, especially AF. In this prospective cohort of UK Biobank, individuals with arrhythmias at baseline, those without data for frailty phenotype, and no genetic data were excluded. Five domains of physical frailty, including weight loss, exhaustion, low physical activity, low grip strength, and slow gait speed, were assessed. A total of 142 single-nucleotide polymorphisms was used to calculate the polygenic risk score (PRS) for AF. Hospital inpatient records and death records were used to identify incident arrhythmias. This study included 464 154 middle-aged and older adults (mean age 56.4 ± 8.1 years, 54.7% female) without arrhythmia at baseline. During a median follow-up of 13.4 years (over 5.9 million person-years), 46 454 new-onset arrhythmias cases were recorded. In comparison with non-frailty, the multivariable-adjusted hazard ratios (HRs) of AF were 1.12 (95% CI: 1.09, 1.15, P < 0.0001) and 1.44 (95% CI: 1.36, 1.51, P < 0.0001) for participants with pre-frailty and frailty, respectively. Similar associations were observed for other arrhythmias. We found that slow gait speed presented the strongest risk factor in predicting all arrhythmias, including AF (HR 1.34, 95% CI: 1.30, 1.39), bradyarrhythmias (HR 1.30, 95% CI: 1.22, 1.37), conduction system diseases (HR 1.29, 95% CI: 1.22, 1.36), supraventricular arrhythmias (HR 1.32, 95% CI: 1.19, 1.47), and ventricular arrhythmias (HR 1.37, 95% CI: 1.25, 1.51), with all P values <0.0001. In addition to slow gait speed, weight loss (HR 1.13, 95% CI: 1.09, 1.16, P < 0.0001) and exhaustion (HR 1.11, 95% CI: 1.07, 1.14, P < 0.0001) were significantly associated with incident AF, whereas insignificant associations were observed for physical activity (HR 1.03, 95% CI: 0.996, 1.08, P = 0.099) and low grip strength (HR 1.00, 95% CI: 0.97, 1.03, P = 0.89). We observed a significant interaction between genetic predisposition and frailty on incident AF (P for interaction <0.0001), where those with frailty and the highest tertile of PRS had the highest risk of AF (HR 3.34, 95% CI: 3.08, 3.61, P < 0.0001) compared with those with non-frailty and the lowest tertile of PRS. Physical pre-frailty and frailty were significantly and independently associated with incident arrhythmias. Although direct causal inference still needs to be further validated, these results suggested the importance of assessing and managing frailty for arrhythmia prevention.

Zhang Y ，Liu M ，Li J ，Ruan L ，Wu X ，Zhang C ，Chen L ... -  《-》

Physical frailty, genetic predisposition, and incident dementia: a large prospective cohort study.

Physical frailty and genetic factors are both risk factors for increased dementia; nevertheless, the joint effect remains unclear. This study aimed to investigated the long-term relationship between physical frailty, genetic risk, and dementia incidence. A total of 274,194 participants from the UK Biobank were included. We applied Cox proportional hazards regression models to estimate the association between physical frailty and genetic and dementia risks. Among the participants (146,574 females [53.45%]; mean age, 57.24 years), 3,353 (1.22%) new-onset dementia events were recorded. Compared to non-frailty, the hazard ratio (HR) for dementia incidence in prefrailty and frailty was 1.396 (95% confidence interval [CI], 1.294-1.506, P < 0.001) and 2.304 (95% CI, 2.030-2.616, P < 0.001), respectively. Compared to non-frailty and low polygenic risk score (PRS), the HR for dementia risk was 3.908 (95% CI, 3.051-5.006, P < 0.001) for frailty and high PRS. Furthermore, among the participants, slow walking speed (HR, 1.817; 95% CI, 1.640-2.014, P < 0.001), low physical activity (HR, 1.719; 95% CI, 1.545-1.912, P < 0.001), exhaustion (HR, 1.670; 95% CI, 1.502-1.856, P < 0.001), low grip strength (HR, 1.606; 95% CI, 1.479-1.744, P < 0.001), and weight loss (HR, 1.464; 95% CI, 1.328-1.615, P < 0.001) were independently associated with dementia risk compared to non-frailty. Particularly, precise modulation for different dementia genetic risk populations can also be identified due to differences in dementia risk resulting from the constitutive pattern of frailty in different genetic risk populations. In conclusion, both physical frailty and high genetic risk are significantly associated with higher dementia risk. Early intervention to modify frailty is beneficial for achieving primary and precise prevention of dementia, especially in those at high genetic risk.

Gao PY ，Ma LZ ，Wang XJ ，Wu BS ，Huang YM ，Wang ZB ，Fu Y ，Ou YN ，Feng JF ，Cheng W ，Tan L ，Yu JT ... -  《-》

Self-Reported Hearing Impairment and Incident Frailty in English Community-Dwelling Older Adults: A 4-Year Follow-Up Study.

To examine the association between hearing impairment and incident frailty in older adults. Cross-sectional and longitudinal analyses with 4-year follow-up using data from the English Longitudinal Study of Ageing. Community. Community-dwelling individuals aged 60 and older with data on hearing and frailty status (N = 2,836). Hearing impairment was defined as poor self-reported hearing. Having none of the five Fried frailty phenotype components (slow walking, weak grip, self-reported exhaustion, weight loss and low physical activity) was defined as not frail, having one or two as prefrail, and having three or more as frail. Participants who were not frail at baseline were followed for incident prefrailty and frailty. Participants who were prefrail at baseline were followed for incident frailty. One thousand three hundred ninety six (49%) participants were not frail, 1,178 (42%) were prefrail, and 262 (9%) were frail according to the Fried phenotype. At follow-up, there were 367 new cases of prefrailty and frailty among those who were not frail at baseline (n = 1,396) and 133 new cases of frailty among those who were prefrail at baseline (n = 1,178). Cross-sectional analysis showed an association between hearing impairment and frailty (age- and sex-adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.37-2.01), which remained after further adjustments for wealth, education, cardiovascular disease, cognition, and depression. In longitudinal analyses, nonfrail participants with hearing impairment were at greater risk of becoming prefrail and frail at follow-up (OR = 1.43, 95% CI = 1.05-1.95), but the association was attenuated after further adjustment. Prefrail participants with hearing impairment had a greater risk of becoming frail at follow-up (OR = 1.64, 95% CI = 1.07-2.51) even after further adjustment. Hearing impairment in prefrail older adults was associated with greater risk of becoming frail, independent of covariates, suggesting that hearing impairment may hasten the progression of frailty.

Liljas AEM ，Carvalho LA ，Papachristou E ，Oliveira C ，Wannamethee SG ，Ramsay SE ，Walters K ... -  《-》

Associations between frailty, genetic predisposition, and chronic kidney disease risk in middle-aged and older adults: A prospective cohort study.

Cross-sectional evidence has shown that frailty is highly prevalent in patients with chronic kidney disease (CKD). However, there is limited evidence of the longitudinal associations between frailty, genetic predisposition to CKD, and the risk of CKD in the general population. Therefore, this study aimed to examine such associations among participants in the UK Biobank. This is a prospective cohort study included 370,965 middle-aged and older adults from the UK Biobank. Physical frailty was assessed using a modified version of the Fried phenotype classification. A weighted genetic risk score was built using 263 variants associated with estimated glomerular filtration rate. Incident CKD was identified from hospital inpatient records. Over a median follow-up of 12.3 years, we documented a total of 11,121 incident CKD cases. Time-dependent Cox proportional hazards regression models indicated that individuals with frailty (hazard ratio [HR]: 1.94, 95 % confidence interval [CI]: 1.81-2.08) and pre-frailty (HR: 1.27, 95 % CI: 1.22-1.33) had an increased risk of developing CKD, compared with non-frail individuals. No significant interaction between frailty and genetic risk score was observed (P for interaction = 0.41). The highest risk was observed among the individuals with high genetic risk and frailty (HR: 2.31, 95 % CI: 2.00-2.68). Our results demonstrated that frailty and pre-frailty were associated with increased risk of incident CKD in middle-age and older adults, regardless of genetic risk of CKD. Our study underscores the importance of frailty screening and intervention as a potential strategy to prevent CKD. Future clinical trials are needed to validate our findings.

Yang H ，Li Z ，Zhang Y ，Chang Q ，Jiang J ，Liu Y ，Ji C ，Chen L ，Xia Y ，Zhao Y ... -  《-》