Frailty and Dementia: A Causal Link?

 Make damn sure your competent? doctor HAS EXACT PROTOCOLS TO PREVENT FRAILTY! Doesn't have them, your doctor is fuckingly incompetent! Fire them!

Let's see how long your doctor and hospital have been incompetent in not having frailty prevention protocols!

frailty (28 posts to January 2018)

So, 6+ years of TOTAL INCOMPETENCE OF THE BOARD OF DIRECTORS! How do they live with themselves?

Frailty and Dementia: A Causal Link?

Physical frailty is strongly associated with an increased dementia risk in older adults, and according to researchers, the link may be causal.

In an analysis of nearly half a million UK Biobank participants, researchers found that frail adults had almost a three-fold increased risk of developing dementia compared to their nonfrail peers, while those with prefrailty had a 50% increased dementia risk.

“We’ve known that frailty is associated with a higher risk of dementia, but our study provides evidence that frailty may be an actual cause of dementia,” study investigator Yacong Bo, PhD, School of Public Health, Zhengzhou University, China, said in a press release.

The study implicates genetic factors, immunometabolic functions, and alterations in brain structure in the link between frailty and dementia. 

“Our study offered further insights into the mechanisms linking physical frailty with dementia,” the investigators write.

The findings were published online September 17 in Neurology.

Early Identification Imperative

In 2021, about 57 million people around the world were diagnosed with dementia, but that estimate is projected to rise to 153 million by 2050. Current dementia treatments have limited effectiveness, so early identification and a deeper understanding of dementia risk factors are imperative, the investigators note.

One such risk factor is frailty, a syndrome marked by reduced physiological reserve and greater vulnerability to stressors. Whether frailty contributes directly to dementia — and which biological or neurological mechanisms may be involved — remains unclear. 

The new analysis included 489,573 participants without dementia at enrolment in the UK Biobank, a large population-based cohort study. The mean age of participants was 57.03 years, 54.37% were female, and 94.45% were White.

Participants completed questionnaires on health, sociodemographic, and lifestyle factors, provided biological samples, and underwent physical examinations. 

Researchers assessed physical frailty using five components: weight loss, exhaustion, physical inactivity, slow walking speed, and low grip strength. Participants were classified as frail (≥ 3 components, 4.6%), prefrail (1-2 components, 43.9%), or nonfrail (0 components, 51.5%).

Investigators evaluated biological biomarkers, including peripheral blood cell counts, blood biochemical markers, and metabolomic markers. From the brain MRIs, they analyzed gray and white matter, as well as cortical and subcortical regions.

They also assessed genetic predisposition to dementia, classifying polygenic risk scores (PRS) as high (quintile 1) or intermediate (quintiles 2-4), and identifying individuals with one or two epsilon-4 alleles as APOE epsilon-4 carriers. 

Investigators adjusted for age, ethnicity, employment, socioeconomic status, education level, smoking and drinking habits, BMI, and physical activity.

An Early Indicator? 

Over a median follow-up of 13.6 years, 8900 dementia cases were reported. After adjustment, dementia risk was 50% higher in prefrail individuals (hazard ratio [HR], 1.50; 95% CI, 1.44-1.57) and nearly threefold higher in frail individuals (HR, 2.82; 95% CI, 2.61-3.04) compared with nonfrail peers. 

Dementia risk rose with increasing frailty, with HRs of 1.37 (95% CI, 1.31-1.44), 1.91 (1.80-2.04), 2.78 (2.56-3.02), 3.06 (2.67-3.50), and 4.36 (3.23-5.89) for frailty scores of 1 through 5, respectively. 

Each frailty component was independently associated with an increased risk of dementia. HRs were 1.36 (95% CI, 1.29-1.44) for weight loss; 1.49 (1.42-1.55) for low grip strength; 1.49 (1.42-1.55) for physical inactivity; 1.55 (1.46-1.64) for exhaustion; and 1.82 (1.71-1.93) for slow walking speed. 

Subgroup analyses revealed a stronger relationship among participants younger than 65 vs those 65 years and older. This, said the researchers, suggests frailty may function as an early indicator or biomarker. Sensitivity analyses confirmed the robustness of the relationships.

Researchers categorized participants into six groups based on APOE‑epsilon-4 status and frailty. Compared with frail individuals with the lowest genetic risk (by PRS), frail individuals with the highest genetic risk had a markedly higher risk of dementia (HR, 3.87; 95% CI, 3.30-4.55). 

Frail APOE-epsilon-4 carriers had the highest dementia risk (HR, 8.45; 95% CI 7.51-9.51) compared with those who were neither APOE-epsilon-4 carriers nor frail.

Researchers performed a bidirectional Mendelian randomization (MR) analysis to investigate a potential causal relationship between frailty and dementia. MR leverages genetic variants as proxies to evaluate the causal effect of a modifiable exposure on a health outcome — in this case, dementia. 

The forward MR analysis aimed to evaluate the causal effect of physical frailty on dementia. Here, a one-point increment in frailty was associated with a 79% increased risk of dementia (odds ratio, 1.79; 95% CI 1.03-3.12; P = .039). Results of the reverse MR study suggested dementia is unlikely to increase physical frailty risk. 

A Causal Role?

The investigators found several brain regions played a significant mediating role in the relationship between frailty and dementia. Among others, these included the right frontal pole, left inferior parietal, left precuneus, supra-marginal, left middle temporal, left para hippocampal, posterior cingulate, putamen, and right inferior parietal.

“This observation supports the notion that physical frailty and dementia may share a common neurobiological foundation,” the investigators wrote.

Researchers also assessed various immunometabolic markers, including C-reactive protein, glucose, apolipoprotein A, apolipoprotein B, glycated hemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides. The results suggest the impact of frailty on dementia risk may be mediated through these immunometabolic-related pathways.

In addition to neuroanatomical and immunometabolic factors, other pathways may link frailty and dementia. The investigators note, for example, that frailty is associated with a higher risk of depression, which may be a prodromal symptom of dementia and — with an increased risk of stroke — a well-established contributor to cognitive impairment. 

While the robustness of MR analyses and multiple sensitivity checks support a causal role for frailty, it remains possible that frailty reflects early pathophysiological changes. “[W]e can’t rule out the possibility that frailty is instead a marker of the early changes in the disease process,” Bo said in the release. 

One limitation of the study is that four of the five frailty components were based on self-report, which could introduce reporting bias and potentially underestimate the effect of frailty. Another limitation is that frailty data were not collected during follow-up, preventing assessment of how changes in frailty might influence dementia risk. 

In addition, identifying dementia through hospital and death records may have missed individuals with mild symptoms, limited access to healthcare, or those who died before receiving a dementia diagnosis. Furthermore, because the UK Biobank cohort is predominantly White, the generalizability of these results to other racial groups is limited. 

Timely, Important Research

Asked to comment, Shaheen Lakhan, MD, PhD, a neurologist, and researcher based in Miami, told Medscape Medical News the study is timely and important. 

“This study makes frailty the new vital sign for brain health. If frailty truly drives dementia through immune and brain pathways, then preventing dementia becomes synonymous with slowing biological aging itself,” he said. 

He added the results present a “real opportunity” to embed frailty detection into routine care. “This would allow us to intervene years before cognitive decline even begins.” 

The study was supported by the Chinese National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, the Chinese International Postdoctoral Exchange Fellowship Program and the Henan Medical Science and Technology Research Program. The investigators report no relevant disclosures. Lakhan has no relevant conflicts of interest.