Miley Nguyen, PharmD, RPh & Husna Rahim, PharmD, RPh
Have YOU EVER WONDERED ……why Alzheimer’s disease affects women more severely than men?
- Alzheimer’s disease disproportionately affects women in the U.S., accounting for almost two-thirds of cases, and they face a higher risk of the disease progressing more rapidly (Alzheimer’s Association, 2025).
- Donepezil shows a 20–60% response rate due to multiple factors, including genetic variation, affecting both safety and efficacy (Lu et al., 2020).
- Pharmacogenomic (PGx) testing of CYP2D6 may guide safer, more effective donepezil use, personalizing care for women most at risk.
The Challenge
Alzheimer’s disease is a progressive neurological condition that significantly affects memory, cognition, and daily functioning, ultimately leading to death.
- It is projected that by 2025, Alzheimer’s disease will affect approximately 7.2 million individuals aged 65 and older in the United States. Women account for nearly two-thirds, approximately 4.8 million, highlighting a significant gender disparity in disease prevalence. Sex-based differences in brain structure, particularly in memory-related regions like the hippocampus, may help explain variations in Alzheimer’s risk and progression between men and women (Alzheimer’s Association, 2025).
- Women with Alzheimer’s often show greater neuropsychiatric symptom burden and may be more biologically susceptible to disease-related brain changes, contributing to faster decline. While evidence suggests that women may respond more favorably to cholinesterase inhibitors like donepezil, they also face a higher risk of adverse effects such as slow heart rate, highlighting the need for sex-specific treatment considerations (Ambrosino et al., 2020).
Benefits & Real-World Applications of PGx
CYP2D6 genetic variants can affect donepezil metabolism, and PGx testing can guide dose optimization, particularly in women at higher risk for adverse effects or reduced efficacy.
- Donepezil, a cholinesterase inhibitor, has been a first-line treatment for slowing down the progression of mild to moderate Alzheimer’s disease for over two decades. However, therapeutic response rates range from 20% to 60%, with genetic variability playing a major role in this difference (Lu et al., 2020).
- Donepezil is metabolized primarily by CYP2D6. Genetic variability in the CYP2D6 enzyme, particularly the *2A variant (rs1080985), has been associated with reduced therapeutic efficacy (Xiao et al., 2016). Given the higher prevalence of Alzheimer’s in women and their increased risk of adverse effects, CYP2D6 genotyping offers a promising strategy to optimize treatment and support precision medicine in women’s cognitive health.
Conclusion
PGx helps bridge this gap by guiding treatment selection based on an individual’s genetic makeup.
- The PGx approach may enable a more effective donepezil therapy by accounting for genetic variation. This is particularly important for women, who face higher Alzheimer’s prevalence and greater risk of adverse effects, supporting safer, more effective treatment.
Learn more about UGenome.
Personalized Medication Service, ProPEx, or contact UGenome. You can also find case studies for UGenome’s bioinformatics services Metabolite Identification, Bone Metastasis Risk Analysis in Breast Cancer, Survival Analysis with gene signatures in cancer
#ugenome, #ugenomeai, #genetics, #pharmacogenetics, #genomicmedicine, #sequencing, #datascience, #lifesciences, #bioinformatics, #biostatistics, #pharma, #bullpen, #NVIDIAInception, #foundershub