APOE4 packs a punch in women: Sex‐specific vulnerability for tau and neuroinflammation

Abstract

AbstractBackgroundThe role that sex plays in Alzheimer’s disease (AD) has long been the subject of intense investigation. Considerable amount of literatures showed a disproportionally high prevalence of AD in women. Moreover, sex differences were observed in disease manifestation, rates of cognitive decline, cerebral atrophy, as well as the response to treatments, suggesting that sex serves as a crucial factor in the disease heterogeneity. APOE is the strongest genetic risk factor for sporadic AD, with the ε4 allele conferring increased risk. It was found that female ε4 carriers show stronger risk for clinical AD. Other studies showed that female ε4 carriers have higher p‐tau levels in cerebrospinal fluid and show worse memories than male ε4 carriers. Despite evidence supports APOE has a stronger association among women compared with men, limited work has evaluated the effects of ApoE4 on AD core neuropathology including amyloid, tau and microglial activation in a sex‐specific manner.MethodThis was a cross‐sectional study in APOE ε4 carriers with AD (n=31), MCI (n=23), cognitively normal controls (n=47) and young healthy controls (n=9) from the TRIAD study at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid load, tau neurofibrillary tangles and microglia activation were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]AZD4694 ([18F]NAV4694), [18F]MK6240 and [11C]PBR28 respectively.ResultNo significant difference was found in age, education and MMSE score between male and female subjects. Female ε4 carriers showed significant higher tau burden in hippocampus (P<0.01), entorhinal cortex (P<0.05) and parahippocampal cortex (P<0.05) compared to male ε4 carriers. A sex‐specific vulnerability for tau and neuroinflammation was observed. More specifically, in amyloid‐positive female ε4 carriers, higher tau burden was found to be strongly associated with worse cognitive function assessed by Mini‐Mental State Examination (MMSE). In addition, an positive correlation between amyloid load and microglial activation level was also identified in female APOE ε4 carriers.ConclusionWe provide striking evidence that female is more vulnerable for the effects of APOE ε4 on tau and neuroinflammation, suggesting APOE may modulate AD pathology in a sex‐specific manner, particularly in the presence of amyloidosis.