Signs of frailty may signal future dementia more than a decade before cognitive symptoms occur, in new findings that may provide a potential opportunity to identify high-risk populations for targeted enrollment in clinical trials of dementia prevention and treatment.

Results of an international study assessing frailty trajectories showed frailty levels notably increased in the 4-9 years before dementia diagnosis. Even among study participants whose baseline frailty measurement was taken prior to that acceleration period, frailty was still positively associated with dementia risk, the investigators noted.

“We found that with every four to five additional health problems, there is on average a 40% higher risk of developing dementia, while the risk is lower for people who are more physically fit,” study investigator David Ward, PhD, of the Centre for Health Services Research, The University of Queensland, Brisbane, Australia, told Medscape Medical News.

The findings were published online on November 11 in JAMA Neurology.

A Promising Biomarker

An accessible biomarker for both biologic age and dementia risk is essential for advancing dementia prevention and treatment strategies, the investigators noted, adding that growing evidence suggests frailty may be a promising candidate for this role.

To learn more about the association between frailty and dementia, Ward and his team analyzed data on 29,849 participants aged 60 years or above (mean age, 71.6 years; 62% women) who participated in four cohort studies: the English Longitudinal Study of Ageing (ELSA; n = 6771), the Health and Retirement Study (HRS; n = 9045), the Rush Memory and Aging Project (MAP; n = 1451), and the National Alzheimer’s Coordinating Center (NACC; n = 12,582).

The primary outcome was all-cause dementia. Depending on the cohort, dementia diagnoses were determined through cognitive testing, self- or family report of physician diagnosis, or a diagnosis by the study physician. Participants were excluded if they had cognitive impairment at baseline.

Investigators retrospectively determined frailty index scores by gathering information on health and functional outcomes for participants from each cohort. Only participants with frailty data on at least 30 deficits were included.

Commonly included deficits included high blood pressure, cancer, and chronic pain, as well as functional problems such as hearing impairment, difficulty with mobility, and challenges managing finances.

Investigators conducted follow-up visits with participants until they developed dementia or until the study ended, with follow-up periods varying across cohorts.

After adjusting for potential confounders, frailty scores were modeled using backward time scales.

Among participants who developed incident dementia (n = 3154), covariate-adjusted expected frailty index scores were, on average, higher in women than in men by 18.5% in ELSA, 20.9% in HRS, and 16.2% in MAP. There were no differences in frailty scores between sexes in the NACC cohort.

When measured on a timeline, as compared with those who didn’t develop dementia, frailty scores were significantly and consistently higher in the dementia groups 8-20 before dementia onset (20 years in HRS; 13 in MAP; 12 in ELSA; 8 in NACC).

Increases in the rates of frailty index scores began accelerating 4-9 years before dementia onset for the various cohorts, investigators noted.

In all four cohorts, each 0.1 increase in frailty scores was positively associated with increased dementia risk.

Adjusted hazard ratios [aHRs] ranged from 1.18 in the HRS cohort to 1.73 in the NACC cohort, which showed the strongest association.

In participants whose baseline frailty measurement was conducted before the predementia acceleration period began, the association of frailty scores and dementia risk was positive. These aHRs ranged from 1.18 in the HRS cohort to 1.43 in the NACC cohort.

The ‘Four Pillars’ of Prevention

The good news, investigators said, is that the long trajectory of frailty symptoms preceding dementia onset provides plenty of opportunity for intervention.

To slow the development of frailty, Ward suggested adhering to the “four pillars of frailty prevention and management,” which include good nutrition with plenty of protein, exercise, optimizing medications for chronic conditions, and maintaining a strong social network.

Ward suggested neurologists track frailty in their patients and pointed to a recent article focused on helping neurologists use frailty measures to influence care planning.

Study limitations include the possibility of reverse causality and the fact that investigators could not adjust for genetic risk for dementia.

Unclear Pathway

Commenting on the findings for Medscape Medical News, Lycia Neumann, PhD, senior director of Health Services Research at the Alzheimer’s Association, noted that many studies over the years have shown a link between frailty and dementia. However, she cautioned that a link does not imply causation.

The pathway from frailty to dementia is not 100% clear, and both are complex conditions, said Neumann, who was not part of the study.

“Adopting healthy lifestyle behaviors early and consistently can help decrease the risk of — or postpone the onset of — both frailty and cognitive decline,” she said. Neumann added that physical activity, a healthy diet, social engagement, and controlling diabetes and blood pressure can also reduce the risk for dementia as well as cardiovascular disease.

The study was funded in part by the Deep Dementia Phenotyping Network through the Frailty and Dementia Special Interest Group. Ward and Neumann reported no relevant financial relationships.