There is a statistically greater association between APOE ε4 and cerebrospinal fluid (CSF) total tau and phosphorylated tau in women compared with men, especially in those who are amyloid positive, according to a study in JAMA Neurology.

Investigators evaluated 10 longitudinal cohort studies that focused on normal aging and Alzheimer’s disease (AD). All studies included participants with recorded APOE genotype data and CSF data. The investigators analyzed specific AD biomarkers, including β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Additionally, the studies reported results of autopsy analyses for neuritic plaques (Consortium to Establish a Registry for Alzheimer’s Disease staging) and neurofibrillary tangles (Braak staging).

A total of 1798 patients, of whom 226 had AD, were included in the CSF biomarker cohort. In addition, the autopsy cohort included 5109 patients. There was a significant association between APOE ε4 and sex on phosphorylated tau (β =0.24; 95% CI, 0.09-0.38; P =.001) and CSF total tau (β =0.41; 95% CI, 0.27-0.55; P <.001), with women demonstrating a stronger interaction between APOE and CSF levels than men.

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In addition, the association was strong among those who were positive for amyloid (β = 0.41; 95% CI, 0.20-0.62; P <.001) but not among those who were negative for amyloid (β =0.06; 95% CI, −0.18 to 0.31; P =.62). No significant associations were observed between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden.

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In terms of demographics, the homogenous nature of each of the study’s cohorts potentially limits the generalizability of the main study’s findings.

The study’s observable sex difference “in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner.”


Hohman TJ, Dumitrescu L, Barnes LL, et al; for the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau [published online May 7, 2018]. JAMA Neurol. doi:10.1001/jamaneurol.2018.0821