Abstract
BackgroundSex-related difference in Alzheimer’s disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD.ObjectiveWe aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes).MethodsData of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex–ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers.ResultsSignificant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-β (Aβ): p = 0.0169 and phosphorylated-tau (p-tau): p = 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aβ (p = 0.0135) and total-tau (t-tau) (p < 0.0001) as well as longitudinal changes of the biomarkers (Aβ: p = 0.0104; t-tau: p = 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p < 0.0001) and t-tau (p < 0.0001) and did not aggravate AD biomarkers longitudinally.ConclusionThe associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.
Highlights
Alzheimer’s disease (AD) is the leading cause of dementia characterized by abnormal accumulation of β-amyloid (Aβ) (Hardy and Selkoe, 2002) and aggregation of hyperphosphorylated tau in the brain (Zempel and Mandelkow, 2014)
During the 5-year-follow-up, 2 cognitively normal (CN) controls and 85 mild cognitive impairment (MCI) patients progressed to AD, and the mean cerebrospinal fluid (CSF) apolipoprotein E (ApoE) is 7.03 μg/ml when these two groups are combined as a whole
The mean CSF ApoE is 7.37 μg/ml in study participants who did not progress to AD
Summary
Alzheimer’s disease (AD) is the leading cause of dementia characterized by abnormal accumulation of β-amyloid (Aβ) (Hardy and Selkoe, 2002) and aggregation of hyperphosphorylated tau in the brain (Zempel and Mandelkow, 2014). A greater number of women have been diagnosed with AD compared with men according to the epidemiological indicators (Alzheimer’s Association, 2014), which can be partially explained by the sex-related differences in neural anatomy and function (Ingalhalikar et al, 2014; Ritchie et al, 2018). Women between the ages of 65 and 75 with APOE ε3/ε4 have an increased risk of developing mild cognitive impairment (MCI) or AD compared with men (Neu et al, 2017), and the association between APOE ε4 and cerebrospinal fluid (CSF) tau level is stronger among women than men (Hohman et al, 2018). Sex-related difference in Alzheimer’s disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD
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