This review by Mary A. O’Neal from the Department of Neurology at Brigham and Women’s Hospital, Harvard Medical School, explores the reasons why women may be at greater risk for Alzheimer's disease (AD). Recent findings suggest that sex and gender differences in AD can be explained by biological and psychosocial factors. Key mechanisms include: 1. **Apolipoprotein E 4 (APOE4) allele**: Women carrying the APOE4 allele are more likely to develop mild cognitive impairment (MCI) and AD compared to men, with a fourfold increased risk at younger ages (65-75 years). 2. **Telomere shortening**: Telomere length is significantly shorter in women with the APOE4 allele, indicating premature aging. Estrogen increases telomerase activity and reduces oxidative stress, potentially explaining why postmenopausal women with APOE4 show less telomere attrition with hormonal therapy. 3. **Hormonal effects**: Hormone replacement therapy (HRT) has shown mixed results in reducing AD risk, with some studies suggesting a protective effect when started early postmenopause. 4. **Pregnancy complications**: Women with preeclampsia or hypertensive disorders during pregnancy have an increased risk of AD later in life, possibly due to vascular damage. 5. **Psychiatric co-morbidities**: Women have twice the risk of depression compared to men, which is a risk factor for AD. Insomnia, also more prevalent in women, may accelerate cognitive decline and AD. 6. **Educational status and cognitive reserve**: Lower education levels and occupational attainment pose similar risks for AD in both sexes, but women older than 65 have fewer opportunities for higher education and professional achievement, reducing their cognitive resilience. In conclusion, the higher risk of AD in women is multifactorial, involving genetic, hormonal, psychiatric, and psychosocial factors.This review by Mary A. O’Neal from the Department of Neurology at Brigham and Women’s Hospital, Harvard Medical School, explores the reasons why women may be at greater risk for Alzheimer's disease (AD). Recent findings suggest that sex and gender differences in AD can be explained by biological and psychosocial factors. Key mechanisms include: 1. **Apolipoprotein E 4 (APOE4) allele**: Women carrying the APOE4 allele are more likely to develop mild cognitive impairment (MCI) and AD compared to men, with a fourfold increased risk at younger ages (65-75 years). 2. **Telomere shortening**: Telomere length is significantly shorter in women with the APOE4 allele, indicating premature aging. Estrogen increases telomerase activity and reduces oxidative stress, potentially explaining why postmenopausal women with APOE4 show less telomere attrition with hormonal therapy. 3. **Hormonal effects**: Hormone replacement therapy (HRT) has shown mixed results in reducing AD risk, with some studies suggesting a protective effect when started early postmenopause. 4. **Pregnancy complications**: Women with preeclampsia or hypertensive disorders during pregnancy have an increased risk of AD later in life, possibly due to vascular damage. 5. **Psychiatric co-morbidities**: Women have twice the risk of depression compared to men, which is a risk factor for AD. Insomnia, also more prevalent in women, may accelerate cognitive decline and AD. 6. **Educational status and cognitive reserve**: Lower education levels and occupational attainment pose similar risks for AD in both sexes, but women older than 65 have fewer opportunities for higher education and professional achievement, reducing their cognitive resilience. In conclusion, the higher risk of AD in women is multifactorial, involving genetic, hormonal, psychiatric, and psychosocial factors.