Metabolic programming by parental obesity aggravates Alzheimer disease-linked cognitive and cardiac impairments

Alzheimer disease (AD) is a rapidly growing health problem characterized by neurocognitive and cardiovascular dysfunction. Our previous studies indicate that parental obesity programs adverse cardiovascular effects, including hypertension and cardiorenal dysfunction, in offspring. In this study, we tested the hypothesis that parental obesity worsens cardiac, metabolic, and cognitive outcomes in lean offspring from obese AD-susceptible mice (3xTg-AD). Male and female offspring from control diet-fed or high fat diet (HFD)-fed parents were examined at 26-28 weeks of age. Cognitive function was assessed by Morris Water Maze, cardiac function by echocardiography and invasive hemodynamic measurements, and mitochondrial (MT) function by high-resolution respirometry in isolated cardiac fibers. AD offspring from obese parents (HFD-Offs) exhibited worse memory retention compared to AD offspring from lean parents (ND-Offs). We observed preserved cardiac systolic function, including similar ejection fraction and fractional shortening, between groups. However, male (but not female) HFD-Offs showed impaired diastolic relaxation, as evidenced by prolonged isovolumetric relaxation time (IVRT), while E/e’ ratio (left ventricular filling pressure) remained unchanged. Left ventricular catheterization showed reduced load-dependent indices of contractility and relaxation, including maximal and minimal rates of pressure changes: dP/dtmax (8,038±1011 vs. 18,704±183 mmHg/sec), dP/dtmin (-7,724±471 vs. -13,634±1139), and prolonged Tau (4.0±0.1 vs. 2.9±0.1) in HFD-Offs compared to ND-Offs. Cardiac fibers from male HFD-Offs exhibited reduced MT glucose and fatty acid oxidation, suggesting impaired energetic flexibility. These findings indicate that parental obesity worsens cognitive decline in AD offspring and impairs cardiac metabolism and function in male, but not female, AD offspring, suggesting sex-specific amplification of AD-related cardiac-cognitive dysfunction. (NHLBI R01-HL163076, NIDDK R01-DK01121411, NIGMS P30GM149404, and U54GM115428) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.