Impact of a high-fat diet on spatial learning and memory: the role of sex, <em>APOE</em> genotype, and postnatal chlorpyrifos exposure. 

function, particularly in genetically susceptible individuals. Chlorpyrifos (CPF), an organophosphate pesticide,

and high-fat diets (HFD) have been independently associated with cognitive impairment, yet their combined

effects remain poorly understood. Apolipoprotein E (APOE) genotype influences vulnerability to cognitive

decline, with the ε4 allele being a major risk factor for neurodegenerative diseases. This study assessed the

interplay between APOE genotype, sex, early-life CPF exposure, and HFD on spatial learning and memory. Male

and female C57BL/6, apoE3- and apoE4-targeted replacement (TR) mice were orally exposed to CPF during

postnatal days 10–15 and subsequently subjected to a HFD for 8 weeks. At the end of the HFD challenge, body

weight gain was calculated, and spatial learning and memory assessed using the Morris Water Maze test. Results

indicate that HFD-driven weight gain was influenced by sex and APOE genotype. All groups acquired the spatial

learning task, but postnatal CPF exposure affected performance in certain groups. Retention was more variable in

females, suggesting increased susceptibility to environmental exposures. Notably, apoE4-TR females showed

improved memory retention following either CPF exposure or HFD, whereas apoE4-TR males exhibited impaired

long-term memory after HFD exposure. These findings highlight the complex interactions between genetic and

environmental factors. Understanding these dynamics is essential for developing targeted nutritional and public

health strategies to mitigate cognitive decline. Importantly, dietary recommendations should not be generalized

but tailored to individual profiles to optimize cognitive health and disease prevention.<