Examining the sex-specific association between APOE ε4 status and increased neuropsychiatric symptom burden in populations at risk for Alzheimer's disease.

The APOE gene is implicated in the development of Alzheimer's disease (AD), with the ε4 allele being the strongest known genetic risk factor for sporadic AD. In individuals with Alzheimer's disease, female APOE e4 homozygotes have recently been shown to be at increased risk of neuropsychiatric symptom (NPS) burden. This sex-specific association has also been found in groups at increased risk of developing AD, specifically those with mild cognitive impairment (MCI) and/or a history of major depressive disorder (MDD). While the mechanisms underlying this association are not yet known, one potential contributing factor is regional cortical thinning, which has been found to occur in early AD. The purpose of this study was to examine whether there is a female-specific association between cortical thickness and APOE ε4 status. Data was obtained from PACt-MD (Prevention of Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression"), a clinical trial that included older adults with MCI and MDD. Patients for whom the following data was available were included in the analysis: age, sex, highest level of education, MMSE score, MoCA score, APOE genotyping, Neuropsychiatric Inventory Questionnaire (NPI-Q) score, and measurements of cortical thickness from brain MRI. For APOE status, patients were categorized as either E4-positive (hetero- or homozygous) or E4-negative. Statistical analyses were conducted using RStudio. Multiple regression models were used to examine 1) the E4-by-sex interaction effect on cortical thickness, and 2) the association between cortical thickness and NPI-Q total scores. There were 61 individuals (34 females) in the E4-positive group, and 158 individuals (97 females) in the E4-negative group. There was a statistically significant E4-by-sex interaction on thickness of the left (p=0.02) and right (p=0.01) inferior parietal cortices, and the right pericalcarine cortex (p=0.003). Specifically, there was a reduction in cortical thickness for males who were E4-positive compared to E4-negative. Meanwhile, there was either no change (inferior parietal cortices) or an increase (right pericalcarine cortex) in cortical thickness for females who were E4-positive compared to E4-negative. The mean NPI-Q total score was 2.37. No significant association was found between the cortical thickness in these, or any other, brain regions and NPI-Q total scores. The presence of the APOE ε4 allele has a sex-specific effect on cortical thickness in the bilateral inferior parietal cortices and right pericalcarine cortex. However, this sex-based difference was not in the direction we hypothesized based on previous studies. [ABSTRACT FROM AUTHOR]