Sex differences in cognitive resilience in preclinical autosomal‐dominant Alzheimer's disease carriers and non‐carriers: Baseline findings from the API ADAD Colombia Trial

Abstract

Introduction Females may have greater susceptibility to Alzheimer's disease (AD)‐pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively‐unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers and non‐carriers. Methods We analyzed baseline data from 167 mutation carriers and 75 non‐carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir‐ and fludeoxyglucose‐PET, MRI based hippocampal volume and cognitive testing. Results Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. Discussion Our findings suggest that, among cognitively‐unimpaired individuals at genetic risk for autosomal‐dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex‐specific differences in autosomal‐dominant AD is key to elucidating mechanisms of AD risk and resilience.

Consideration of sex and gender in Alzheimer's disease and related disorders from a global perspective

“…This pattern of findings has been reported for multiple AD‐related neuroimaging biomarkers including hippocampal atrophy volume, 249 amyloid positron emission tomography (PET), 250–253 brain glucose hypometabolism 254 and postmortem tau pathology 255 . Similarly, research among individuals at genetic risk for autosomal‐dominant AD from a Colombian cohort suggests that females may also have greater cognitive resilience to AD pathology and neurodegeneration than males 256 …”

“…255 Similarly, research among individuals at genetic risk for autosomaldominant AD from a Colombian cohort suggests that females may also have greater cognitive resilience to AD pathology and neurodegeneration than males. 256 Fluid-based biomarkers of AD include low cerebrospinal fluid (CSF) or blood Aβ42 or the Aβ42/Aβ40 ratio as a marker of amyloid pathology, elevated CSF, or blood phosphorylated tau (P-tau) as markers of neurofibrillary tangle pathology, and elevated CSF or blood total tau (T-tau) or neurofilament light chain (NfL) as markers of neurodegeneration. 257 Most studies of blood and CSF AD biomarkers have adjusted for sex, with few examining sex differences.…”

Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort

“…AD mouse models mirror the human population, in that they are familial AD mutation carriers and females are resistant to AD-related cognitive decline prior to menopause/estropause. Our findings are consistent where women PSEN1 mutation carriers exhibited better verbal memory than men [ 80 ] and the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial study (30-53 years old) found that women mutation carriers had better delayed recall than men [ 86 , 87 ]. In women, the average age of menopause onset is between 50−52 years [ 39 , 88 ].…”

Alzheimer’s Disease: An Updated Overview of Its Genetics

“…The African American population is twice as likely to develop the disease [ 14 ]; hence, it is necessary to increase the studies on these populations. In the same way, only one of the studies [ 150 ] focused on identifying possible genes involved in AD taking into account the gender of the patients, although women are at a higher risk of developing AD and have worse clinical and pathological outcomes [ 151 ]. In addition, some of these studies could be biased, as the sample between controls and patients with AD was not balanced and neither were the risk factors or modifiers of the study subjects, including comorbidities, gender, age range, environmental exposure, and medication, among others.…”

“…In this context, growing evidence suggests that, among cognitively healthy patients with a genetic risk of developing AD, women exhibit better global cognition than men. This event is maintained during the early stages of the disease, despite showing increased Tau pathology, hippocampal atrophy, and metabolic dysfunction [ 151 ]. This indicates that although women have greater resilience to the disease, there are still unidentified factors that cause them to have a greater risk of developing the disease.…”