Updated project metadata. Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although, ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD remains unclear. Here, we show in hippocampal neurons from patients and mice with HF that the ryanodine receptor type 2 (RyR2)/intracellular Ca 2+ release channels were post-translationally modified (PTM) and leaky. RyR2 PTM was caused by hyper-adrenergic stress and activation of the transforming growth factor (TGF-β) pathway. HF mice treated with either a RyR2 stabilizer drug (S107), beta-blocker (propranolol) or TGF-β inhibitor (SD-208), or mice insensitive RyR2 Ca 2+ leak (RyR2-S2808A), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness that include cardiogenic dementia, and intracellular Ca 2+ leak is a common effector in multiple components of HF.