Parental obesity exacerbates cognitive dysfunction and cardiac vulnerability in offspring of an Alzheimer disease model.

Alzheimer disease (AD) is a growing health problem characterized by neurocognitive and cardiovascular dysfunction. Although parental obesity programs adverse cardiometabolic complications, including obesity, hypertension, and cardiorenal dysfunction in their offspring, whether parental obesity worsens cardiac, metabolic, and cognitive function in lean offspring that are susceptible to AD (3xTg-AD mice) remains unclear. Male and female offspring from control diet-fed or high-fat diet (HFD)-fed parents were examined at 26-28 wk of age. Cognitive function was assessed by Morris water maze and New Object Recognition (NOR) tests, cardiac function by echocardiography and invasive hemodynamic measurements, and mitochondrial (MT) function by high-resolution respirometry in isolated cardiac fibers and brain cortex. AD offspring from obese parents (HFD-Offs) exhibited worse memory retention compared with AD offspring from lean parents [normal diet (ND)-Offs], whereas recognition memory assessed by NOR was not significantly different between groups, although there was greater variability in HFD-Offs. Although systolic function by echocardiography was similar between groups, male HFD-Offs showed impaired diastolic relaxation with prolonged isovolumetric relaxation time, whereas E/e' remained unchanged. Left ventricular catheterization showed reduced indices of contractility and relaxation, including maximal and minimal rates of pressure changes: dP/dtmax (8,038 ± 1,011 vs. 18,704 ± 183 mmHg/s), dP/dtmin (-7,724 ± 471 vs. -13,634 ± 1,139), and prolonged Tau (4.0 ± 0.1 vs. 2.9 ± 0.1) in HFD-Offs compared with ND-Offs. Male HFD-Offs exhibited reduced MT glucose and fatty acid oxidation in the heart and brain. These findings indicate that parental obesity exacerbates AD-related cognitive decline and cardiac dysfunction in a sex-specific manner, suggesting parental metabolic status as an important determinant of AD-related cardiometabolic vulnerability.NEW & NOTEWORTHY Parental obesity is associated with worsened cognitive performance and male-specific impairments in cardiac metabolism and function in AD-susceptible offspring, highlighting developmental programming as a modifier of heart-brain vulnerability.