Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Abstract

Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p = 0.001) and social inappropriateness (12% versus 15% ; p < 0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36% ; p < 0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier.

White Matter Hyperintensities and Cortical Atrophy are associated with Neuropsychiatric Symptoms in Neurodegenerative and Cerebrovascular Diseases

“…Another study found that depressive symptom was two-fold associated with a greater risk of AD in females but not males [112]. Furthermore, the observed higher irritability, nighttime behaviours, delusion, and apathy in males are similar to several studies that reported higher frequencies of the aforementioned NPS in males compared to females [104,[113][114][115], whilst contradicting others that have showed the opposite [104,105,111,114]. These discrepancies may be attributed to multiple factors such as the genetic predisposition to AD including the interaction between sex and apoE 4 in AD/MCI [105,116], sex-related hormonal levels, or the use of pharmacological treatments [115].…”

Late-life onset psychotic symptoms and incident cognitive impairment in people without dementia: modification by genetic risk for Alzheimer’s disease

“…By using the IQCODE as an outcome, this study confirms is the impact of such symptoms on cognitive abilities that affect daily life in advance of dementia, building upon studies that have examined cognitive trajectories or those that have followed individuals to the point of clinical dementia diagnosis [15,16,22].…”

“…Although uncommon, occurring in less than 10% of the sample (with only 0.7% experiencing hallucinations), psychotic symptoms in cognitively normal individuals were found to have a 3.6-fold higher risk of incident cognitive impairment. By using the IQCODE as an outcome, this study confirms is the impact of such symptoms on cognitive abilities that affect daily life in advance of dementia, building upon studies that have examined cognitive trajectories or those that have followed individuals to the point of clinical dementia diagnosis[15,16,22].…”

“…AD PRS tertiles were generated in the whole sample before exclusions. The sample was then stratified on APOE-ε4 status, and then separately on gender (informed by previous research showing interactions between gender and psychosis on cognitive decline [22]), and survival for MBI-psychosis groups explored in each strata. Finally, interaction terms (MBI-psychosis*APOE-ε4 then MBI-psychosis*gender) were fitted.…”

Differential neural circuit vulnerability to β-amyloid and tau pathologies in novel Alzheimer’s disease mice

“…APP /Tau mice of both sexes develop similar cerebral pathologies, but compared to males, aged females show elevated Aβ and tau pathologies specifically in EC and CA3 hippocampus, respectively. This result is relevant considering that life expectancy and elevated amyloid and/or tau pathologies are associated with higher prevalence of dementia in women [21], and emotional disturbances associated with verbal cognitive decline occur more often in middle-aged females than in males [53]. Interestingly, whereas phosphorylated tau appears simultaneously in distinct brain regions, Aβ pathology starts in the hippocampus and extends later to the EC and BLA, coinciding with innate anxious behavior and impaired fear memory extinction.…”