A modifiable driver of dementia: cognitive impairment in primary aldosteronism

Primary aldosteronism (PA) is the most common endocrine cause of hypertension, yet emerging longitudinal data indicate that its injurious effects extend to the brain. A nationwide Korean cohort study demonstrated that patients with PA exhibit a significantly higher incidence of all-cause dementia than matched individuals with essential hypertension, independent of blood pressure. However, this association was attenuated for Alzheimer's disease after multivariable adjustment, whereas vascular dementia remained significantly associated with PA. Aldosterone activates mineralocorticoid receptors (MRs) in the brain, triggering oxidative stress, blood-brain-barrier leakage and neuro-inflammation that damage hippocampal and prefrontal networks, leading to deficits in executive function, language and attention. Notably, these effects are amplified by dietary salt intake, and experimental evidence suggests that aldosterone-induced end-organ damage requires a high-salt milieu. In animal models, chronic aldosterone exposure reproduces these cognitive impairments, whereas MR blockade or adrenalectomy reverses learning and memory deficits. However, current PA guidelines omit recommendations for cognitive screening or intervention, rendering this potentially reversible aetiology largely overlooked. Here we systematically synthesize the pleiotropic mechanisms of aldosterone signalling in neurons, glia and cerebral vessels; integrate cross-sectional, prospective and interventional clinical evidence to quantify the strength of the PA-dementia association; and compare the differential cognitive outcomes of surgery versus pharmacotherapy. We also discuss emerging aldosterone synthase inhibitors as a novel therapeutic strategy that eliminates ligand production rather than merely blocking receptor signalling. Finally, we propose a risk-prediction framework that incorporates neuroimaging and fluid biomarkers, and call for a transdisciplinary clinical pathway to enable early recognition and precision intervention.