Sex matters for Alzheimer’s risk

Written by Jenny Straiton

PET images show that female carriers of the E4 allele of the APOE gene show greater susceptibility to tau accumulation than male carriers.

Already known to be the strongest genetic risk factor for developing late-onset Alzheimer’s disease, the E4 allele of the APOE gene has now been found to increase a woman’s susceptibility to accumulate tau, a protein known to play a key role in Alzheimer’s neuropathology. Researchers used positron emission tomography (PET) scans to demonstrate that women who are carriers of the allele and who are already displaying mild cognitive impairment (MCI) are more likely to accumulate neurotoxic levels of the neurofibrillary tau tangles.

“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,” explained project leader Yun Zhou (Washington University in St. Louis, MO, USA).

“This is the first study to demonstrate that sex modulates the effect of APOE E4 on brain tau depositing, measured using 18F-AV-1451-PET imaging, in the entorhinal cortex, amygdala, parahippocampal gyrus, and posterior cingulate of the brains of patients with MCI. Strikingly, females experience greater APOE E4-associated increases in brain tau deposition in these regions compared to their male counterparts.”



A total of 228 participants were involved in the cross-sectional study; 131 individuals (66 women) were cognitively normal and 97 were diagnosed with MCI (39 women). The participants had a mean age of 77 and were taken from the Alzheimer’s Disease Neuroimaging Initiative database.

Pre-processed 18F-AV-1451 PET images, T1-weighted structural MRI scans and demographic information were taken from the database and a partial volume correction method was applied on all PET images in order to improve contrast and spatial resolution. The structural MRIs were used for spatial normalization of PET. All statistical analyses were performed after controlling for baseline age and education.

In addition to the disparity in susceptibility to tau accumulation in the brains of MCI individuals of different sex, Zhou noted that the study “also confirmed that sex does not modulate the APOE E4-associated tau deposition in the brains of cognitively normal elderly individuals, and it extends our understanding of how sex modulates the APOE E4 effect on tau deposition in the brains of individuals at the early stage of Alzheimer’s disease.”

The full study method and results were recently presented at the 2019 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (Anaheim, CA, USA, 22–25 June 2019) by lead author Manish Paranjpe (University of California, San Francisco, CA, USA).

“Our results have implications for clinical trials, biomarkers, and therapeutic development in Alzheimer’s. 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 E4-sex group. Moreover, 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,” commented Paranjpe.