Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes including falls, disability and death. The underlying pathophysiological pathways of frailty are not known but the hypothalamic–pituitary–adrenal axis and heightened chronic systemic inflammation appear to be major contributors.

Background: the term frailty refers to a condition of increased vulnerability to stressors among older people, leading to a decline in homeostatic reserve. Frailty often leads to falls, hospitalisation and mortality, hence its importance for the delivery of health care to older adults. The pathophysiological mechanisms behind frailty are not well understood, but the decreased steroid-hormone production and elevated chronic systemic inflammation of older people appear to be major contributors. Method: we used a sample of 3,160 individuals aged 50 or older from the English Longitudinal Study of Ageing and assessed their frailty status according to a Frailty Index. We selected 620 single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways. We performed linear association analysis. The outcome variable was the square root transformation of the Frailty Index, with age and sex entered as covariates. Results: the strongest signal was detected in the pro-inflammatory Interleukin-18 gene (rs360722, P = 0.0021, β = −0.015). Further significant signals were observed in the Interleukin-12 (rs4679868, P = 0.0062, β = −0.008 and rs9852519, P = 0.0077, β = −0.008), low density lipoprotein receptor-related protein 1 (rs1799986, P = 0.0065, β = 0.011) and Selectin-P (rs6131, P = 0.0097, β = −0.01) genes. None of these associations remain significant after Bonferroni correction. Conclusions: we show potential associations between genetic variants of four genes and the frailty index. These genes are involved in the cholesterol transport and inflammatory pathway and, as such, our results provide further support for the involvement of the immunological processes in frailty of the elderly.

This study was designed to investigate the relationship between a systematic inflammatory biomarker measure, concurrent and later cognitive performance, and future dementia risk. The literature has reported the potential involvement of inflammation in cognitive performance as well as Alzheimer’s Disease, but not consistently. We used a population-based cohort of 500,000 people in the UK and assessed the association between a composite inflammatory biomarker and cognitive performance measures across five domains measured concurrently and 4–13 years later, taking advantage of the large sample size. We also assessed the same biomarker’s association with dementia diagnosis 3–11 years later in the initially dementia-free sample. We report small but significant associations between elevated biomarker levels and worsened cognitive performance at baseline for four cognitive tasks (OR = 1.204, p<0.001 for Prospective memory, β = -0.366, p<0.001 for Fluid intelligence, β = 8.819, p<0.001 for Reaction time, and β = -0.224, p<0.001 for Numeric memory), comparing the highest quartile of the biomarker to the lowest. We also found that for one measure (Pairs matching) higher biomarker levels were associated with fewer errors, i.e. better performance (β = -0.096, p<0.001). We also report that the 4^th quartiles of the baseline biomarker levels were significantly associated with cognitive task scores assessed years later on the p< = 0.002 level, except for the Pair matching test, for which none of the quartiles remained a significant predictor. Finally, the highest biomarker quartile was significantly associated with increased dementia risk compared to the lowest quartile (HR = 1.349, p<0.001). A case-only analysis to assess disease subtype heterogeneity suggested probable differences in the association with the highest biomarker quartile between vascular dementia and Alzheimer disease subtypes (OR = 1.483, p = 0.055). Our results indicate that systemic inflammation may play a small but significant part in dementia pathophysiology, especially in vascular dementia.

Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-to-face clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p = 0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p = 0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p = 0.004) and decreased positive memory bias (p = 0.021) together with reduced activity in the posterior (p(FWE) = 0.045) and anterior (p(FWE) = 0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.

The concept of frailty has been used in the clinical and research field for more than two decades. It is usually described as a clinical state of heightened vulnerability to poor resolution of homeostasis after a stressor event, which thereby increases the risk of adverse outcomes, including falls, delirium, disability and mortality. Here we report the results of the first genome-wide association scan and comparative gene ontology analyses where we aimed to identify genes and pathways associated with the deficit model of frailty. We used a discovery-replication design with two independent, nationally representative samples of older adults. The square-root transformed Frailty Index (FI) was the outcome variable, and age and sex were included as covariates. We report one hit exceeding genome-wide significance: the rs6765037 A allele was significantly associated with a decrease in the square-root transformed FI score in the Discovery sample (beta = -0.01958, p = 2.14E-08), without confirmation in the Replication sample. We also report a nominal replication: the rs7134291 A allele was significantly associated with a decrease in the square-root transformed FI score (Discovery sample: beta = -0.01021, p = 1.85E-06, Replication sample: beta = -0.005013, p = 0.03433). These hits represent the KBTBD12 and the GRIN2B genes, respectively. Comparative gene ontology analysis identified the pathways ‘Neuropathic pain signalling in dorsal horn neurons’ and the ‘GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells’, exceeding the p = 0.01 significance in both samples, although this result does not survive correction for multiple testing. Considering the crucial role of GRIN2B in brain development, synaptic plasticity and cognition, this gene appears to be a potential candidate to play a role in frailty. In conclusion, we conducted genome-wide association scan and pathway analyses and have identified genes and pathways with potential roles in frailty. However, frailty is a complex condition. Therefore, further research is required to confirm our results and more thoroughly identify relevant biological mechanisms.