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Background: numerous studies point towards a critical role of Interleukin 6 (IL-6) pathway in frailty pathogenesis yet the causal relationship between the two remains elusive., Methods: we selected genetic variants near the IL-6 receptor locus (IL-6R) associated with reduced C-reactive protein (CRP) levels, a downstream effector of IL-6 pathway, and we used them as genetic proxies of IL-6 signalling downregulation. We then performed a two-sample Mendelian randomisation (MR) to investigate the association with frailty status, as defined by the Frailty Index (FI) in 11,171 individuals from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD) study. MR analysis was repeated after excluding depression or cognition-related FI items as well as following age or sex stratification. Association with frailty was also examined using an alternative instrument, weighted on s-IL-6R levels. Replication was attempted in UK Biobank dataset., Results: genetic predisposition to IL-6 signalling downregulation, weighted on CRP levels, was associated with lower risk of frailty, inserted either as categorical (odds ratio [95% confidence interval] = 0.15 [-3.39, -0.40], P = 0.013) or continuous variable (beta [se] = -0.09 [0.003], P = 0.0009). Sensitivity analyses revealed similar estimates across different MR methods with no evidence for horizontal pleiotropy or heterogeneity. Results remained robust after exclusion of depression or cognition-related FI items and following sex or age stratification. Genetically increased s-IL-6R levels were negatively correlated with frailty and this finding remained significant in a meta-analysis of UK Biobank and HELIAD cohorts., Conclusion: our results support a potential causal effect of IL-6 signalling on frailty and further suggest that downregulation of IL-6 levels may reduce frailty risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Subjective cognitive decline (SCD) is a self-evaluation of cognitive impairment, in the absence of observed objective cognitive deficits on a neuropsychological assessment. Frailty refers to a multidimensional syndrome where the individual has poor health including falls, disabilities, hospitalization, and vulnerability. Both terms are associated with cognitive decline and increased incidence of dementia. The present longitudinal study explored whether the detection of SCD can predict the development of frailty over time., Methods: The Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) is an epidemiological, population-based study. From the original testing sample of 1,984 older Greek individuals (≥65 years old), 1,121 remained in the longitudinal analysis. Participants diagnosed with frailty, Mild Cognitive Impairment (MCI), dementia, severe depression, and anxiety, in the baseline assessment were excluded from the analysis (n=146), resulting in a total sample of 975 participants. The average follow-up interval was 3.1 years (SD=0.84 years). SCD was assessed in the baseline assessment with a series of eighteen questions. The questions regarding SCD were categorized according to cognitive domains. Frailty was assessed according to a phenotypic-physiologic (Fried's definition) and a multidomain approach (Frailty Index). Univariate and multivariate Cox regression analyses were used for exploring the role of SCD in developing frailty., Results: The proportion of individuals with frailty according to Fried's definition was greater compared to the Frailty Index. At follow-up according to Fried's definition, a greater proportion of cases with frailty was found in those who reported SCD complaints regarding orientation (OD) (HR=3.12 95% CI:1.45-6.73 p<0.004) or in those who reported at least three SCD complaints regarding their memory performance (SMC3) (HR=1.92 95% CI:1.05-3.52 p<0.035) at the baseline assessment. Subjective complaints regarding orientation were predictive of a greater hazard of frailty as defined by the Fried scale (HR=3.12 95% CI:1.45-6.73 p<0.004) and the Frailty Index (HR=3.59 95% CI:1.77-7.25 p<0.001)., Conclusion: Our findings demonstrate that healthy older adults who report SCD complaints regarding orientation or state that they have at least three memory complaints have a higher risk of developing frailty. Additionally, the number of participants with a clinical diagnosis of MCI or dementia, compared to individuals with normal aging, at follow-up was found to be significantly greater in cases with frailty according to both frailty definitions applied (p<0.001). Consequently, it is advisable to use screening questionnaires for SCD covering multiple cognitive domains in clinical practice for identifying and managing frailty, thus, implementing effective interventions to promote healthy aging., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The aim of the current prospective study was to examine the relationship between adherence to the Mediterranean diet and incident frailty., Study Design: 1075 Greek community-dwelling older adults from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present longitudinal analysis., Main Outcome Measures: Adherence to the Mediterranean diet was evaluated through the MedDietScore, calculated from the information participants provided on a validated food frequency questionnaire. Frailty was assessed using two multidomain tools: the Frailty Index (FI) and the Tilburg Frailty Indicator (TFI). Analysis of the incidence of frailty as a function of the baseline MedDietScore was performed using Cox proportional hazards models. Additionally, Generalized Estimating Equations (GEE) models were used to explore whether the baseline MedDietScore was associated with the change in the total number of frailty criteria met by participants over time. In testing for a dose-response association between Mediterranean diet and frailty, the MedDietScore was treated either as a continuous variable or as tertiles of low, medium and high adherence to MeDi., Results: 176 and 131 participants developed incident frailty, as measured with the FI and TFI respectively. Each unit of MedDietScore was associated with a 5% (ΗR 0.95, 95% CI 0.91-0.99, p = 0.012) and 10% (ΗR 0.90, 95% CI 0.86-0.95, p ≤ 0.001) decrease in the risk of incident frailty when measured with the FI and TFI respectively. Compared with participants reporting low adherence to the Mediterranean diet (lowest tertile), those with high adherence (highest tertile) had a 41% (ΗR 0.59, 95% CI 0.38-0.91, p = 0.017) and a 57% (ΗR 0.43, 95% CI 0.27-0.70, p ≤ 0.001) lower risk of incident frailty as measured with the FI and TFI respectively. After excluding from the analyses participants diagnosed with dementia at baseline or follow-up, the same results were obtained: each unit of MedDietScore was associated with a 5% (HR 0.95 CI 0.91-0.99, p = 0.023) and a 10% (HR 0.90 CI 0.86-0.94, p ≤ 0.001) decrease in the risk of incident frailty as measured with the FI and TFI respectively., Conclusions: The present longitudinal study showed that non-frail community-dwelling older adults with high adherence to the Mediterranean dietary pattern had a significantly lower incidence of frailty., Competing Interests: N. Scarmeas reports personal fees from Merck Consumer Health, Eisai and NIH unrelated to this paper. Other authors declare no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Previous frailty studies found higher prevalence of frailty in female than in male participants. This was mainly attributed to the fact that compared to men, women show increased longevity. Recent studies have reported that the observed difference between sexes applies irrespectively of the age of older people., Objectives: To provide data on sex differences in incident frailty by applying both phenotypic and multi-domain frailty measures in the same population of Greek community-dwelling older people., Design: Longitudinal study., Setting: Data were drawn from the Hellenic longitudinal Investigation of Aging and Diet (HELIAD), a population-based, multidisciplinary study designed to estimate the prevalence and incidence of dementia in the Greek population., Participants: 1104 participants aged 65 year and above were included in this longitudinal study. This incidence cohort was re-evaluated after a mean follow-up period of 3.04±0.90 years., Measurements: Frailty was operationalized using 5 different definitions in the same population: the Fried Frailty Phenotype (FFP) definition, the FRAIL Scale, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI) and the Groningen Frailty Index (GFI). Frailty incidence was calculated a) for the whole sample, b) separately for men and women and c) after both age and sex stratification., Results: Age and sex stratification revealed that irrespective of age and frailty measurement, women showed higher incidence rates of frailty than men. Specifically, frailty seems to be a condition concerning women >65 years old, but when it comes to men, it is more frequent in those aged more than 75 years old. Finally, in relation to overall frailty incidence and comparing our results to previous studies, we detected a lower frailty incidence in the Greek population., Conclusions: Differences between the two sexes indicate that when exploring the factors that are related to frailty, studies should provide data disaggregated for men and women., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Frailty is a complex geriatric syndrome arising from a combination of genetic and environmental factors and is associated with adverse health outcomes and mortality. A recent study reported an association between variants of the 9p21-23 locus, associated with a number of age-related disorders, including Alzheimer's disease (AD), and frailty. Frailty has been associated with increased risk of developing AD and it has been proposed that frailty burden may modify AD clinical presentation. In view of the overlapping genetic architecture between the two disorders, it is noteworthy to conduct studies to uncover risk variants that contribute to both AD and frailty. The purpose of this study is to test the reproducibility of the association of 9p21-23 locus with frailty in a population that is ethnically different from previous work and in the context of multidimensional definitions of frailty that will allow us to examine the potential impact to domains pertaining to AD pathology., Methods: We operationalized frailty according two definitions and the corresponding instruments, the Frailty Index (FI) and the Tilburg Frailty Indicator (TFI) and we determined genotypes of eight alleles previously identified as risk increasing for frailty in 1172 community-dwelling older participants (57% females) from the HELIAD study with a mean age of 74 years old. We cross-sectionally investigated the association between risk alleles and frailty, as well as with specific components of each definition using linear regression analyses adjusted for age, sex and years of education., Results: Compared to non-carriers, carriers of rs7038172 C risk allele, were associated with a higher FI Score (β=0.089, p=0.002). Similarly, we found a positive association between the presence of at least one rs7038172 C variant and TFI score (β=0.053, p=0.04). Moreover, the rs7038172 variant was associated, irrespectively of dementia status, with the memory and psychological domain of FI and TFI, respectively., Conclusion: Our study confirms the association of the rs7038172 C allele with the frailty syndrome in a Greek population and in the context of multidimensional definitions of frailty. Furthermore, we report novel associations between this allele and the memory domain of FI and the psychological domain of TFI, that includes memory problems on its components. Given that frailty burden has been shown to modify the AD clinical presentation, it is likely that rs7038172 C allele may accelerate the transition of AD or frailty to dementia Overall, our study corroborates the role of the 9p21-23 region in frailty development and draw potential links with AD pathology., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: To investigate the association between frailty, Parkinson's disease (PD), and the probability of prodromal Parkinson's disease (prodromal PD) in Greek community-dwelling older individuals., Methods: Parkinson's disease diagnosis was reached through standard clinical research procedures. Probability of prodromal PD was calculated according to the International Parkinson and Movement Disorder Society's research criteria for PD-free participants. Frailty was evaluated according to definitions of the phenotypic and multidomain approach. Logistic and linear regression models were performed to investigate associations between frailty (predictor) and the probability of prodromal PD, either continuous or dichotomous (≥30% probability score), or PD (outcome)., Results: Data from 1765 participants aged 65 and older were included in the present analysis. Parkinson's disease and prodromal PD prevalence were 1.9% and 3.0%, respectively. Compared to nonfrail participants, those who were frail, as identified with either the Fried frailty phenotype or Frailty Index had approximately 4 (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.54-10.89) and 12 times (OR 12.16, 95% CI 5.46-27.09) higher odds of having a PD diagnosis, respectively. Moreover, compared to the nonfrail, frail participants as identified with either the Fried frailty phenotype or Frailty Index had 2.8 (OR 2.83, 95% CI 1.09-7.37) and 8.3 times (OR 8.39, 95% CI 4.56-15.42) higher odds of having possible/probable prodromal PD, respectively., Conclusions: Frailty status was associated with prodromal PD and PD, suggesting common characteristics or underlying mechanisms of these conditions. Although prospective studies are warranted, acknowledging the possible association of frailty, PD, and prodromal PD may improve their clinical management., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To explore the association between both self-reported quality and quantity sleep characteristics and frailty status in a large non-sex-specific population of older individuals in Greece., Design: Cross-sectional study., Setting and Participants: In total, 1984 older individuals (≥65 years old) were drawn from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD)., Measures: Frailty was assessed using 3 different definitions, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI), and the Groningen Frailty Indicator (GFI). Sleep quality was evaluated through the Sleep Index II, which includes 9 of the 12 self-reported items of the Medical Outcomes Study-Sleep Scale. To examine sleep duration, participants were asked to report on how many hours they slept each night during the past 4 weeks. Logistic regression models adjusted for multiple covariates were explored. Additional analyses, stratified by gender, adjusting for sleep-related medications and excluding participants diagnosed with dementia, were also performed., Results: In total, 389 (20%), 619 (31.9%), and 608 (31.3%) participants were categorized as frail according to the FI, the TFI, and the GFI respectively. Sleep quality was significantly associated with frailty in all models. Even after adjusting for subjective sleep duration, compared with participants who subjectively reported high sleep quality, those with low sleep quality had 3.7, 2.6, and 2.5 more times to be frail as measured with FI, TFI, and GFI respectively. Regarding the associations between frailty and self-reported sleep duration, sex-specific associations were observed: prolonged sleep duration was associated with frailty in the subsample of male participants., Conclusions and Implications: The present study shows a strong correlation between subjective sleep quality and frailty status, contributing substantial information to the growing literature demonstrating that sleep is associated with older people's overall health. Sleep complaints should not be underestimated, and older individuals who self-report sleep disorders should be further assessed for frailty., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence of frailty using five different instruments in a cohort of older adults and explore the association between frailty and various risk factors. Method: 1,867 participants aged 65 years and above were included in the current retrospective cross-sectional study. Frailty was operationalized according to the Fried definition, the FRAIL Scale, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI), and the Groningen Frailty Index (GFI). We explored the role of various frailty risk factors using logistic regression analyses. Results: The prevalence of frailty varied depending on the definition used (Fried definition = 4.1%, FRAIL Scale = 1.5%, FI = 19.7%, TFI = 24.5%, and GFI = 30.2%). The only risk factors consistently associated with frailty irrespectively of definition were education and age. Conclusion: The frailty prevalence reported in our study is similar or lower to that reported in other population studies. Qualitative differences between frailty definitions were observed.

Background : Subjective cognitive decline (SCD) refers to self-evaluations of impairment in cognitive functions in the absence of objective deficits. Frailty is a multidimensional syndrome that results in increased vulnerability. Both terms are associated with cognitive decline and increased incidence of dementia. The aim of this study was to explore potential associations between SCD and frailty in elderly individuals. Methods : In this cross-sectional study, we included 1454 participants aged 65 and older from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) study. Individuals with a diagnosis of dementia, mild cognitive impairment, severe anxiety or depression were excluded. SCD were assessed with eighteen questions categorized into cognitive domains. Frailty was assessed according to the Fried definition, the Frailty Index (FI) and the Tilburg Frailty Indicator (TFI). Logistic regression analysis was used to investigate the association. Results: Lower educational level, female sex and low socioeconomic status were found to be associated with frailty and more SCD complaints. Having two or more types of SCD complaints was significantly associated with frailty according to all frailty definitions. All types of SCD complaints were significantly associated with the FI and the TFI. In addition, SCD complaints concerning problems requiring mathematical reasoning had the strongest association with frailty. Conclusion : We found that SCD complaints may be a valid indicator of frailty in cognitively unimpaired older people. We believe that SCD may provide a crucial proactive assessment to detect frailty and to implement programs that will help maintain good health and quality of life during aging.

Apolipoprotein (APOE) ε4 allele has been associated with a number of age-related diseases but previous studies failed to identify any link with Frailty syndrome. The aim of the present study is to investigate the association between APOE ε4 allele and frailty syndrome. We operationalised Frailty according to the Fried definition, and we determined the APOE genotype in 1234 participants of the hellenic longitudinal investigation of ageing and diet study. Logistic regression analyses were performed to examine the association between APOE ε4 allele and frailty. Models were adjusted for age, education, sex, presence (or absence) of hypertension, diabetes, myocardial infraction, coronary disease, congestive heart failure, arrhythmia or other heart disease, family history of dementia and current smoking. The same models were performed after exclusion of patients with dementia and participants with APOE ε2/ε4 genotype. In the fully adjusted model, carriers of APOE ε4 allele had 2.753 higher odds of frailty relative to non-carriers. After trichotomization of APOE genotype, APOE ε4 heterozygotes had 2.675 higher risk of frailty compared to non-carriers while exclusion of patients with dementia or/and APOE ε2/ε4 genotype did not alter the association. The APOE ε4 allele may be a significant biomarker of frailty with diagnostic and prognostic capacity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Το investigate associations between adherence to the Mediterranean diet and frailty in a Greek population of older adults., Design: Cross-sectional study., Setting: Data were drawn from the Hellenic longitudinal Investigation of Aging and Diet (HELIAD), a population-based, multidisciplinary study designed to estimate the prevalence and incidence of dementia in the Greek population., Participants: Data from 1740 participants aged ≥65 years were included in the present analysis. Participants were selected through random sampling from the records of 2 Greek municipalities., Measurements: Adherence to Mediterranean diet was evaluated through the MedDietScore, calculated from the information participants provided to a validated food frequency questionnaire. Frailty was assessed using 3 different definitions (the phenotypic approach proposed by Fried et al, the Frailty Index, and the Tilburg Frailty Indicator). Unadjusted and adjusted logistic and linear regression models were performed., Results: Of our participants, 70 (4%), 325 (18.7%), and 442 (25.4%) were identified as frail according to the Fried et al definition, the Frailty Index, and the Tilburg Frailty Indicator, respectively. Adjusting for confounding factors, each additional unit in the MedDietScore was associated with a 5% (P = .09), 4% (P = .005), and 7% (P < .001) decrease in the odds for frailty according to the Fried definition, the Frailty Index, and the Tilburg Frailty Indicator, respectively., Conclusions: According to study results, a higher adherence to the Mediterranean diet was associated with lower odds of frailty, irrespective of the definition used. This finding may be of relevance in the setting of population-based prevention efforts as well as in clinical practice., (Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)