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Women showed a stronger association between the apolipoprotein E (APOE) gene and cerebrospinal fluid (CSF) tau levels than men, particularly if they were amyloid-positive, researchers reported.

However, in the meta-analysis of 10 longitudinal studies of Alzheimer's disease, there was no sex difference in the association between APOE and amyloidosis, or between APOE and neurofibrillary tangles at autopsy, reported Timothy Hohman, PhD, of Vanderbilt University Medical Center in Nashville, and colleagues in

The stronger association between APOE and tau in women "is surprising because APOE has a much stronger biological and statistical association with amyloid than tau," Hohman said.

It "suggests that the known sex differences in the APOE effect may be driven by the downstream response to amyloidosis, rather than driven by a direct effect on amyloid," he told 番茄社区, adding that this is the most robust evidence to date that APOE may play a greater role in women than men in Alzheimer's pathology.

"We're coming to appreciate sex differences in Alzheimer's pathology may be a very important topic in the field," noted Ronald Petersen, MD, of the Mayo Clinic in Rochester, Minnesota, who was not involved in the study. "This study raises a lot of important hypotheses and starts to examine the mystery of sex differences in Alzheimer's disease more closely."

Several factors may account for sex differences, he stated. "Clearly, there are hormonal ones," he told 番茄社区. "But men tend to die sooner, more likely of heart attacks and the like, so there might be a mediating mechanism of vascular disease. There's a combination of influences still needs to be unraveled."

APOE is the strongest genetic risk factor for sporadic Alzheimer's disease, and its ε4 allele increases Alzheimer's risk in a dose-dependent manner. The strength of the association varies by age and sex, with the effect of APOE-ε4 stronger among women ages 65-75.

Hohman's group analyzed CSF results of 10 longitudinal cohorts, including four datasets from study volunteers and six data sets of autopsy findings of Alzheimer's patients.

Of 1,798 patients in the CSF biomarker cohort, 862 were women, 226 had Alzheimer's disease, 1,690 were white, and the average age was 70. Of 5,109 patients in the autopsy cohort, 2,813 were women, 4,953 were white, and the average age was 84.

The researchers observed a statistically significant interaction between APOE-ε4 and sex in CSF total tau (β coefficient 0.41, P<0.001) and phosphorylated tau (β coefficient 0.24, P=0.001), with APOE showing a stronger association among women than men. Further analyses suggested this sex difference was present in amyloid-positive individuals (β coefficient 0.41, P<0.001), but not in those who were amyloid-negative (β coefficient 0.06, P=0.62).

They reported that they did not see sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangles. The lack of sex differences in neurofibrillary tangles at autopsy suggested that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis, the authors concluded.

"It may be hard to find sex differences in autopsy samples, because autopsied patients have reached the end of the disease process, and everyone tends to end up at the same severe disease state," added Peter Davies, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York, who was not involved in the study.

"Cerebrospinal fluid results are obtained earlier in the course of the disease, sometimes before disease has even started, and this is where one would look for subtle differences between sexes and patients with different genotypes," he told 番茄社区.

One important limitation of this analysis was the potential influence of sex differences in survival to older adulthood, the authors noted. The cross-sectional nature of the biomarker and autopsy data also limited the ability to make causal inferences. The cohorts were relatively homogeneous across race and ethnicity, so findings may not be generalizable to other groups that may be at greater risk of Alzheimer's disease.

But practically speaking, these findings are "a reminder that sex is an important biological variable that can have an impact anywhere along the disease cascade," Hohman said. "It also suggests that sex needs to be considered in treatment approaches that target the neurodegeneration that occurs downstream of amyloidosis. The best therapeutic target may ultimately depend on the sex and genetic profile of the individual."

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