A new systematic review has identified 17 modifiable risk factors shared by at least two of three major age-related brain disorders — stroke, dementia, and late-life depression (LLD) — in new findings that may help reduce the significant burden of these three common conditions.

These conditions are leading contributors to disability-adjusted life years (DALYs) and share common vascular and small vessel pathologies. Epidemiological studies have documented overlapping risk factors, but the extent to which each factor influences the incidence and burden of these disorders remains unclear.

“Dementia, stroke, and late-life depression are connected and intertwined, so if you develop one of them, there’s a substantial chance you may develop another one in the future,” first author Jasper Senff, MD, postdoctoral fellow at the Singh Lab at the Brain Care Labs, Somerville, Massachusetts, said in a release.

“Our study identified 17 modifiable risk factors shared between stroke, dementia, and/or late-life depression, emphasizing that there are many different individual steps individual can take to lower their risks for these age-related brain diseases,” added principal investigator Sanjula Singh, MD, PhD, MSc, Brain Care Labs at Massachusetts General Hospital in Boston.

The study was published online on April 3 in the Journal of Neurology, Neurosurgery and Psychiatry.

Modifiable Risk Factors Identified

Previous research suggests effective control of modifiable risk factors could prevent or delay up to 60% of strokes, 40% of dementia cases, and 35% of LLD cases, potentially extending disease onset to the natural limits of the human lifespan.

In addition, although prior studies have identified considerable overlap in modifiable risk factors for stroke, dementia, and LLD, their relative contribution to a combined outcome across these age-related brain disorders remains unclear.

The goal of the study was to systematically identify shared risk factors across stroke, dementia, and LLD and quantify the relative impact of each modifiable risk factor on a composite outcome.

The researchers conducted a systematic review of studies published between January 2000 and September 2023, drawing from PubMed, Embase, and PsycInfo. They focused on meta-analyses reporting effect sizes of modifiable risk factors on the incidence of stroke, dementia, and LLD.

The target population was all adults aged 18 years or older regardless of demographic, genetic, or environmental differences, without a previous diagnosis of primary stroke, dementia, or LLD.

The search identified 182 meta-analyses that met inclusion criteria; of these, 59 were selected to calculate DALY-weighted risk estimates for a composite outcome.

Seventeen modifiable risk factors shared by at least two of the diseases were identified, namely, alcohol use (−34), blood pressure level (130), body mass index (70), fasting plasma glucose level (94), total cholesterol level (22), leisure time cognitive activity (−91), depressive symptoms (57), diet (51), hearing loss (60), kidney function (101), pain (42), physical activity (−56), purpose in life (−50), sleep (76), smoking (91), social engagement (53), and stress (55).

Hypertension ≥ 140/90 mm Hg in midlife (relative risk [RR], 2.03; 95% CI, 1.67-2.38), severe kidney disease characterized by an estimated glomerular filtration rate < 30 mL/min/1.73 m² (RR, 1.74; 95% CI, 1.48-2.00), and high fasting blood glucose level > 126 mg/dL (RR, 1.67; 95% CI, 1.57-1.76) had the strongest relative impact on incidence and burden of stroke, dementia, and LLD.

In contrast, leisure time cognitive activity (RR, 0.61; 95% CI, 0.42-0.90) and high physical activity (RR, 0.74; 95% CI, 0.69-0.79) showed the highest protective effects.

However, the researchers cautioned that these associations may reflect reverse causality, as individuals with brain disease may be less able to engage in physical and cognitive leisure activities.

Long sleep duration (> 8 hours) was another significant risk factor in the study, although the investigators suggested this particular finding may be associated with underlying comorbidities (obesity, hypertension, and diabetes), reverse causality, or confounding by aging.

Cholesterol levels had minimal impact on the three brain conditions; even low-density lipoprotein levels showed no significant effect. One possible explanation, the authors noted, is that the study did not distinguish between stroke subtypes, which is important since cholesterol’s impact differs between ischemic and hemorrhagic stroke.

An ‘Empirical Foundation’

The research goal is for these findings to serve as an “empirical foundation” for developing tools that help prevent and reduce risk for age-related brain disease.

The researchers used their findings to update the McCance Brain Care Score, a tool developed by Mass General Brigham, Boston, researchers to help prevent the onset of brain disease. Currently, the tool evaluates 12 modifiable physical, lifestyle, and social factors, supporting patients in prioritizing behaviors that reduce risk for brain diseases.

The investigators noted that existing methods for assessing modifiable risk factors “lack a holistic approach that addresses the shared underlying pathophysiology.” They hope these findings will support the development of more integrated strategies for risk assessment and prevention.

“Future research can use our findings as an empirical foundation for building such tools. Tools incorporating the effect sizes obtained in this study could use the comprehensive overview of the impact of individual risk factors based on the included recent meta-analyses, offering both practitioners and patients an evidence-based summary on which guidelines for targeted risk factor modification and potential preventive measures could be based,” they wrote.

Disclosures and conflicts of interest of the investigators can be found listed in the original article.