Women Carrying ApoE4 Gene More Susceptible Than Men to Toxic Tau Clumps in Brain, Study Suggests

Women who are carriers of the ApoE4 gene — a major genetic risk factor for the development of a late-onset form of Alzheimer’s disease, are more susceptible than men to accumulating toxic tau protein aggregates in the brain, a study suggests.

This finding was shared in a study, “Sex Modulates the ApoE ε4 Effect on Tau ¹⁸F-AV-1451 PET Imaging in Individuals with Normal Aging and Mild Cognitive Impairment,” presented during the 2019 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) in Anaheim, California.

“Sex plays an important role in Alzheimer’s disease risk, with females having a higher lifetime risk of developing the disease and an increased vulnerability to genetic risk factors,”  Yun Zhou, a researcher at the Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine and the study’s lead author, said in a press release.

People who carry two copies of the apolipoprotein E4 coding gene, or ApoE4, have significantly higher risk of developing Alzheimer’s disease after age 65. In addition, gender has also been found to affect the genetic risk for the disease, with females with two copies of APOE4 variant age 80 or older having a 24% absolute 10-year risk of Alzheimer’s while men in the same age group had a 19% increased risk.

A hallmark feature of Alzheimer’s disease is the accumulation of tau protein clumps in the brain, which are thought to precede the loss of nerve cells, shrinkage of the brain, and cognitive impairment.

Now, the researchers evaluated how gender might affect the deposition of tau protein in carriers of the ApoE4 gene.

“This is the first study to demonstrate that sex modulates the effect of ApoE ε4 on brain tau depositing, measured using 18F-AV-1451-PET imaging … in the brains of patients with mild cognitive impairment,” Zhou said.

The study recruited 97 elderly patients (mean age 77.97 years) with mild cognitive impairment (MCI), a neurological condition where individuals experience subtle changes in memory. Among these participants, 39 were women who were participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI,  NCT00106899), a major multi-site study focused on clinical trials to improve disease prevention and treatment.

They also evaluated 131 age-matched individuals (66 women) who had normal cognitive function as controls.

All participants underwent brain analysis by positron emission tomography (PET) with a tracer agent, called flortaucipir (also known as [F-18]T807 or 18F-AV-1451), designed to detect abnormal tau protein aggregates. Additional scans using magnetic resonance imaging (MRI) and participants’ demographic information were also analyzed.

Results showed that MCI women who carry the ApoE4 gene variant are more susceptible to accumulating tau protein aggregates in the brain than men with MCI. In contrast, no difference was found between cognitively normal females and males.

“Our work offers a potential explanation for epidemiological evidence demonstrating an increased penetrance of the ApoE ε4 allele in females compared to males,” the researchers said. “In such a model, we propose that female ApoE ε4 carriers are more susceptible to tau-accumulation in preclinical Alzheimer’s disease compared to their male counterparts.”

These findings have implications for future clinical trials testing anti-tau therapies, suggesting that women with MCI may need tailored dosages.

“In designing clinical trials aimed at an MCI cohort, potentially our study suggests that the dosage of anti-tau antibodies should be modified by ApoE ε4-sex group,” said Manish Paranjpe, the study’s lead author. “We hope that insights from our work will shed light on potential treatments for Alzheimer’s disease, including sex-specific tau-targeted and ApoE-targeted drug development.”