The global demographic landscape is undergoing an unprecedented shift, with the proportion of individuals aged 65 and older rising faster than any other age group [1]. This transition is inextricably linked to an increased prevalence of multimorbidity—the coexistence of two or more chronic conditions—which necessitates complex pharmacological interventions [2]. Consequently, polypharmacy, typically defined as the concurrent administration of five or more physician-prescribed medications, has become a hallmark of geriatric care [3]. While the primary goal of such regimens is to manage chronic pathologies and extend life expectancy, the escalating medication burden in the elderly population presents a paradoxical challenge to clinical medicine, often bridging the gap between therapeutic benefit and iatrogenic harm [4].

Although pharmacological treatment is essential for managing chronic diseases and extending life expectancy, polypharmacy poses a paradoxical challenge in older populations. Age-related changes in pharmacokinetics and pharmacodynamics, including reduced renal clearance, impaired hepatic metabolism, and diminished physiological reserve, increase vulnerability to adverse drug reactions and drug–drug interactions [5–7]. These risks raise concerns that polypharmacy may function not only as a marker of disease burden but also as an independent contributor to geriatric syndromes [8, 9].

Cognitive health is perhaps the most critical determinant of successful aging and autonomy. The relationship between polypharmacy and cognitive impairment is multifaceted and potentially bidirectional [10, 11]. Chronic exposure to central nervous system (CNS)-active drugs, such as anticholinergics or sedatives, has been consistently linked to acute delirium and long-term cognitive decline [12, 13]. However, the debate persists regarding whether the sheer number of medications serves as an independent neurotoxic factor or if it merely reflects the high burden of comorbidities that independently contribute to vascular or neurodegenerative changes [14, 15]. Previous studies have yielded conflicting results, often due to limitations in controlling for confounding variables such as education, income, and the severity of chronic diseases.

Simultaneously, functional status—defined by a person’s ability to perform activities essential for daily living (ADL) and Instrumental Activities of Daily Living (IADL)—serves as a comprehensive indicator of an older adult’s health and social integration. Functional decline is often a precursor to institutionalization and increased caregiver burden [16, 17]. Polypharmacy may impair functional status through various pathways, including drug-induced dizziness, muscular weakness, or cognitive slowing, all of which increase the risk of falls and disability [18, 19]. Despite the clinical importance of these outcomes, empirical evidence from large-scale, nationally representative cohorts that simultaneously examines the dual impact of polypharmacy on cognition and function remains insufficient, particularly in the post-pandemic era, where healthcare utilization patterns have shifted significantly.

South Korea represents a unique and urgent case study, as it is currently experiencing one of the fastest rates of population aging in the world. As of 2023, the complexity of medication use among Korean community-dwelling older adults has reached a level that demands rigorous scientific scrutiny. To address these gaps, the present study utilizes the 2023 Korean Elderly Survey (KES), a robust, nationally representative dataset administered by the Ministry of Health and Welfare [20]. Unlike previous regional or clinic-based studies, this analysis incorporates a vast sample of 9,898 non-demented older adults, allowing for a high degree of generalizability and the power to perform sophisticated sequential adjustment models.

By leveraging this comprehensive dataset, we seek to provide a nuanced understanding of how polypharmacy independently contributes to the geriatric syndrome of decline. Therefore, this study aimed to investigate the associations of polypharmacy with cognitive impairment and functional status, including basic and IADL, among community-dwelling older adults. By accounting for sociodemographic characteristics, health-related behaviors, and the number of chronic diseases, this study sought to elucidate the independent contribution of polypharmacy to cognitive decline and functional deterioration, and to provide empirical evidence to inform comprehensive geriatric assessment and rational medication management in aging populations.

This study investigated the complex associations between polypharmacy, cognitive impairment, and functional status among community-dwelling older adults, utilizing a large-scale, nationally representative dataset from the 2023 KES [20]. Our findings reveal a nuanced landscape of geriatric health: while polypharmacy was initially associated with both cognitive and functional decline in crude models, the independent effect of medication count remained statistically significant only for functional status (K-ADL and K-IADL) after rigorous adjustment for multimorbidity and socioeconomic factors. This discrepancy suggests that the pathways through which polypharmacy impacts the aging brain and body follow distinct biological and clinical trajectories, necessitating a more granular approach to medication management in late life [3, 21].

The attenuation of the association between polypharmacy and cognitive impairment in the final adjusted model warrants careful interpretation. Although polypharmacy was associated with increased odds of cognitive impairment in the crude model (OR = 1.70, 95% CI: 1.40–2.05), this significance vanished upon accounting for sociodemographic factors and the number of chronic diseases. This phenomenon suggests that cognitive deterioration may be more closely linked to the underlying pathophysiological burden of multimorbidity—such as chronic inflammation, vascular damage, or metabolic dysregulation—rather than the pharmacological agents themselves [11, 22]. In other words, the higher medication count often serves as a proxy for the severity of underlying health conditions that independently contribute to neurodegenerative changes [23]. This aligns with recent longitudinal studies suggesting that when vascular risk factors like hypertension and diabetes are optimally managed, the incremental risk posed by the number of medications may diminish [24]. Notably, after further adjustment for chronic disease burden, the direction of the association reversed (OR = 0.64, 95% CI: 0.51–0.81). This finding should not be interpreted as a protective effect of polypharmacy, but may instead reflect survival bias or the effects of adequate medical management among non-demented older adults, in whom effective control of vascular and metabolic conditions could mitigate cognitive. Because medication burden was strongly correlated with the number of chronic diseases in this study, adjustment for multimorbidity may have introduced statistical phenomena such as over-adjustment or collider bias. Therefore, the reversed association observed in the fully adjusted model should not be interpreted as a protective effect of polypharmacy but rather as a residual association after accounting for underlying disease burden.

In stark contrast to the findings on cognition, the association between polypharmacy and functional impairment remained robust and independent throughout all stages of analysis. Even after accounting for the number of chronic diseases, older adults taking five or more medications showed significantly higher dependency in both basic (B = 0.14, p = 0.007) and instrumental (B = 0.43, p < 0.001) ADL. This suggests that polypharmacy itself serves as a direct stressor to functional homeostasis [25]. The pharmacological burden may induce a state of subclinical toxicity, where drug-drug or drug-disease interactions lead to cumulative side effects such as muscular weakness, orthostatic hypotension, and impaired balance [26, 27]. For instance, the concurrent use of cardiovascular and psychotropic medications is a well-documented risk factor for falls and subsequent functional dependency. Our results reinforce the notion that functional status is a highly sensitive and immediate indicator of the physiological strain imposed by extensive medication use in the elderly, often preceding more permanent cognitive decline [28, 29]. These findings suggest that functional decline may represent a more immediate and clinically observable manifestation of medication-related vulnerability in older adults than cognitive impairment.

The persistence of functional decline as an independent outcome of polypharmacy underscores the urgent need for comprehensive geriatric assessments that integrate medication review with functional evaluation. In clinical practice, the management of multimorbidity often follows a disease-specific approach, which inadvertently leads to the accumulation of medications [30]. Our findings advocate for a paradigm shift toward patient-centered prescribing, where the potential for functional preservation outweighs the incremental benefit of adding yet another guideline-directed therapy [31, 32]. Deprescribing—the supervised process of medication reduction—should be prioritized, particularly for patients showing early signs of IADL limitations, such as difficulty managing finances or using transportation, which often serve as early warning signs for escalating frailty [33].

A major strength of this study is the use of a recent, large-scale national cohort (n = 9,898), which provides high external validity for the South Korean elderly population. By excluding individuals already diagnosed with dementia, we focused on the “gray zone” of functional and cognitive decline where preventive interventions are most effective. However, several limitations must be acknowledged. First, the cross-sectional design precludes definitive causal inferences. In particular, reverse causation cannot be excluded, as declining functional status may lead to increased healthcare utilization and the accumulation of medications rather than being solely a consequence of polypharmacy. Second, the study relied on self-reported medication counts, which may be subject to recall bias. Furthermore, while we adjusted for the number of chronic diseases, we did not evaluate the impact of specific high-risk drug classes, such as those with high anticholinergic or sedative burdens. Additionally, certain medications with CNS effects, such as anticholinergic or sedative agents, may influence cognitive outcomes differently from medication count alone. Therefore, the absence of drug-class-specific information may have limited our ability to identify medication-specific cognitive risks. Future research should employ longitudinal designs and incorporate specialized scales to further elucidate the dose-response relationship between specific pharmacological properties and geriatric syndromes.

In conclusion, polypharmacy is a potent and independent risk factor for functional decline in community-dwelling older adults, whereas its impact on cognition appears to be largely mediated by the underlying burden of chronic disease. These findings emphasize that rational medication management is not merely about reducing numbers, but about safeguarding the functional independence and quality of life of the aging population.