Diabetes-related foot ulcers, often abbreviated as DFUs, are among the most feared complications of diabetes mellitus. They arise when prolonged high blood sugar damages nerves and blood vessels in the lower limbs, leaving the foot insensitive, poorly perfused, and vulnerable to wounds that refuse to heal. Globally, they affect a substantial share of the diabetic population, and their consequences are grim: infection, hospitalisation, amputation, and elevated mortality. Yet in recent years, clinicians have noticed something else. Patients with DFUs appear to perform worse on cognitive tests than their peers with diabetes but no ulcers, and the review’s authors cite emerging evidence of a potential association between these lower-extremity complications and declining brain function.

The connection is biologically plausible. Diabetes is already a recognised risk factor for vascular dementia and Alzheimer-type pathology, operating through chronic hyperglycaemia, inflammation, endothelial dysfunction, and recurrent hypoglycaemic episodes. A foot ulcer may act as both a marker and an amplifier of this systemic damage. It signals long-standing, poorly controlled disease, and it can itself trigger inflammatory cascades, pain, sleep disruption, depression, and social isolation, all of which have been linked to cognitive decline. Understanding which factors drive cognitive impairment in this population could therefore reshape how clinicians screen, monitor, and support patients whose wounds and minds deteriorate together.

To find those factors, the team followed the PRISMA guidelines, the international standard for conducting and reporting systematic reviews. They searched five major databases, MEDLINE via EBSCOhost, PubMed, CINAHL, EMBASE, and PsycINFO, from their inception to June 2025, looking for observational studies that assessed cognition in people with DFUs. Two reviewers independently screened the results for eligibility, a safeguard against individual bias. Methodological quality was appraised with the Mixed Methods Appraisal Tool, a validated instrument for judging the rigour of diverse study designs, and data were extracted using a customised template by two independent reviewers. The search initially identified 460 records, of which 317 were screened, and just four studies survived the process.

That number is striking. Four studies, all conducted at single centres, represent the entire quantitative evidence base on factors associated with cognitive impairment in a complication that affects tens of millions of people worldwide. Three of the four were case-control studies, which compare people with and without a condition retrospectively, and the remaining two were cross-sectional studies, which capture a snapshot of a population at a single point in time. No cohort studies, which follow patients forward in time and can establish temporal sequences, were available. Crucially, none of the included studies was designed to identify risk factors for cognitive impairment, meaning the review could describe associations but not causation.

Despite these constraints, the review identified fourteen factors that remained statistically significant in multivariate analyses, the statistical technique that adjusts for the influence of other variables, in at least one of the included studies. The factors clustered into five domains. Sociodemographic characteristics included older age, male sex, and lower educational attainment, all well-established correlates of cognitive performance in the general population. Lifestyle factors encompassed smoking, body mass index, and depression, the latter being both a common companion of chronic wounds and a recognised contributor to cognitive difficulties. Diabetes-specific factors included glycated haemoglobin, or HbA1c, the standard measure of long-term blood sugar control, and the duration of diabetes itself, both proxies for cumulative metabolic injury.

The remaining two domains point directly to the burden of advanced disease. Comorbidities associated with cognitive impairment included cardiovascular disease, cerebrovascular disease, nephropathy, and retinopathy, conditions that share vascular pathology with both diabetes and dementia. Foot-related complications, meanwhile, included peripheral neuropathy, the nerve damage that often precedes ulceration, and amputation, the most drastic outcome of a non-healing wound. The pattern is coherent: the more organ systems damaged by diabetes, and the more severe the lower-limb involvement, the more likely a patient is to show measurable cognitive deficits. This supports the hypothesis that DFUs and cognitive impairment are parallel manifestations of systemic vascular and metabolic deterioration rather than coincidental neighbours.

The methodological details of the underlying studies matter for interpreting these findings. Cognitive assessment in the included research relied on standard screening instruments such as the Mini-Mental State Examination and the Montreal Cognitive Assessment, alongside tests like the Trail Making Test, which probes executive function and processing speed. Such tools are sensitive to education and language, which complicates comparisons across populations. The authors judged the studies with the Mixed Methods Appraisal Tool but found the evidence too heterogeneous, in design, measures, and populations, to pool statistically. No meta-analysis was possible, and the single-centre designs limit generalisability. Bivariate associations that failed to hold up under multivariate adjustment were excluded, which strengthens confidence in the fourteen surviving factors but also underscores how much depends on small samples.

The clinical implications are nonetheless significant. If cognitive impairment is common among DFU patients, it has direct consequences for wound care. Self-management of a foot ulcer demands vigilance: daily inspection of the feet, dressing changes, offloading pressure, glycaemic control, and prompt reporting of deterioration. A patient with impaired memory, attention, or executive function may struggle with every one of these tasks, creating a vicious cycle in which cognitive decline worsens the ulcer and the ulcer’s systemic effects worsen cognition. The review’s findings suggest that clinicians should consider cognitive screening when assessing DFU patients, particularly those who are older, less educated, depressed, smokers, or carrying multiple diabetic complications, and that caregivers may need to be involved in treatment plans.

The authors are careful about what their review cannot claim. Because no study was designed to identify risk factors, the temporal relationship between ulcer onset and cognitive decline remains unresolved: poor cognition may contribute to ulcer development through neglected self-care, or the ulcer’s inflammatory and psychological burden may accelerate cognitive deterioration, or both. The review concludes that these associated factors, spanning sociodemographic, lifestyle, diabetes-related, comorbid, and foot-related domains, must be explicitly considered in future research to establish a robust relationship between cognition and DFUs. More rigorous cohort studies, the authors argue, are warranted to identify true risk factors for cognitive impairment in this population. Until such studies exist, the review stands as both a synthesis of what is known and a pointed indictment of how little has been studied at the intersection of a wound and a mind.

Subject of Research: Cognitive impairment and its associated factors in people with diabetes-related foot ulcers

Article Title: Factors associated with cognitive impairment in people with diabetes-related foot ulcers: a systematic review

Article References: Karunathilaka, N., Lokeesan, V., & Rathnayake, S. (2026). Factors associated with cognitive impairment in people with diabetes-related foot ulcers: a systematic review. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02561-y

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02561-y

Keywords: diabetes-related foot ulcers, cognitive impairment, systematic review, diabetes complications, peripheral neuropathy, HbA1c, depression, vascular disease, amputation, PRISMA, MMSE, cohort studies