Changes in gait, especially decreased gait velocity, may be a harbinger of cognitive decline in aging. Motoric cognitive risk syndrome (MCR), a pre-dementia syndrome combining slow gait and cognitive complaints, is a powerful clinical tool used to identify older adults at a high risk of developing dementia. The mean prevalence of MCR worldwide, including in a Korean cohort, was around 10%. The reported risk factors for incident MCR include older age, low education, cardiovascular disease, obesity, physical inactivity, and depression. In addition to dementia, MCR is also a risk factor for other age-related adverse conditions such as falls, disability, frailty, and mortality. The use of MCR has advantages over other pre-dementia syndromes in being much simpler to implement and requires fewer resources. Identification of mechanisms responsible for MCR may help in developing interventions to reduce the growing burden of dementia and disability worldwide.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

Background: The interrelationships between gait, cerebral small vessel disease (CSVD), and cognitive impairments in aging are not well-understood—despite their common co-occurrence. Objective: To systematically review studies of gait impairment in CSVD, pre-dementia, and dementia, and to identify key gaps for future research and novel pathways toward intervention. Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided search strategy was implemented in PubMed to identify relevant studies. Potential articles (n = 263) published prior to 1 December 2021 were screened by two reviewers. Studies with sample sizes >20 and including some adults over > 65 years (n = 202) were included. Results: The key findings were that (1) adverse gait and cognitive outcomes were associated with several (rather than select) CSVD pathologies distributed across the brain, and (2) poor gait and CSVD pathologies were more strongly associated with dementia with a vascular, rather than an Alzheimer’s disease-related, cause. Discussion: A better understanding of the interrelationships between gait performance in CSVD, pre-dementia, and dementia requires studies examining (1) comprehensive patterns in the clinical manifestations of CSVD, (2) racially/ethnically diverse samples, (3) samples followed for extended periods of time or across the adult life span, (4) non-traditional CSVD neuroimaging markers (e.g. resting-state functional magnetic resonance imaging (fMRI)), and (5) continuous (e.g. wearable sensors) and complex (e.g. dual-task) walking performance.

Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan^® assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid‐binding proteins, including fatty acid‐binding protein (FABP) (p = 1.96 × 10⁻¹⁹) and FABPA (p = 8.10 × 10⁻¹⁶), leptin (p = 1.43 × 10⁻¹⁴), and ANTR2 (p = 7.95 × 10⁻²⁰). Pathway analysis with the top 143 frailty‐associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell‐to‐cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 × 10⁻¹⁶). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 × 10⁻¹⁶) than observed frailty (r = 0.37, p = 1.2 × 10⁻¹⁵). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction.

The Covid-19 pandemic forced providers to alter their delivery of care to special populations, including older adults with cognitive impairment. The Montefiore–Einstein Center for the Aging Brain, ...

Background: Emerging evidence suggests that there is significant variability in the progression of frailty in aging. We aimed to identify latent subpopulations of frailty trajectories, and examine their clinical and biological correlates. Methods: We characterized frailty using a 41-item cumulative deficit score at baseline and annual visits up to 12 years in 681 older adults (55% women, mean age 74·6 years). Clinical risk profile and walking while talking performance as a clinical marker of trajectories were examined. Mortality risk associated with trajectories was evaluated using Cox regression adjusted for established survival predictors, and reported as hazard ratios (HR). Proteome-wide analysis was done. Findings: Latent class modeling identified 4 distinct frailty trajectories: relatively stable (34·4%) as well as mild (36·1%), moderate (24·1%) and severely frail (5·4%). Four distinct classes of frailty trajectories were also shown in an independent sample of 515 older adults (60% women, 68% White, 26% Black). The stable group took a median of 31 months to accumulate one additional deficit compared to 20 months in the severely frail group. The worst trajectories were associated with modifiable risk factors such as low education, living alone, obesity, and physical inactivity as well as slower walking while talking speed. In the pooled sample, mild (HR 2·33, 95% CI 1·30–4·18), moderate (HR 2·49, 95% CI 1·33–4·66), and severely frail trajectories (HR 5·28, 95% CI 2·68–10·41) had higher mortality compared to the stable group. Proteomic analysis showed 11 proteins in lipid metabolism and growth factor pathways associated with frailty trajectories. Conclusion: Frailty shows both stable and accelerated patterns in aging, which can be distinguished clinically and biologically.