APOE4's differential risk in women

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Lisa Mosconi is a world-renowned neuroscientist and the director of the Women's Brain Initiative at Weill Cornell Medicine, where she studies how sex differences and hormonal transitions influence brain aging and Alzheimer's disease risk. In this episode, Lisa explores why Alzheimer's disease disproportionately affects women and why longer lifespan alone does not explain their nearly twofold risk compared to men. She explains why Alzheimer's disease may be best understood as a midlife disease for women, beginning decades before symptoms appear, and how menopause represents a fundamental brain event that reshapes brain energy use, structure, and immune signaling. The conversation also examines what advanced brain imaging reveals about preclinical Alzheimer's disease, estrogen receptors in the brain, and why genetic risks such as APOE4 appear to affect women differently from men. Finally, Lisa discusses the nuanced evidence around menopause hormone therapy, the legacy of the WHI, her new CARE Initiative to cut women's Alzheimer's risk in half by 2050, and practical, evidence-based strategies to support brain health through midlife—including lifestyle, sleep, metabolism, mood, and emerging therapies such as GLP-1 agonists and SERMs (selective estrogen receptor modulators).

We discuss:

• How Lisa's personal family history and scientific background led her to focus on the intersection of women's health, brain aging, and Alzheimer's disease (AD) [2:45];
• The long preclinical phase of AD and the emotional burden carried by patients before dementia becomes severe [7:15];
• How AD compares to other common forms of dementia: prevalence, pathology, symptoms, diagnostic challenges, and more [10:45];
• Why AD disproportionately affects women: how AD is not simply a disease of old age or longevity but a midlife disease in which women develop pathology earlier [16:15];
• Menopause as a leading explanation for women's increased Alzheimer's risk, and how advanced braining imaging can detect early changes in the brain [26:15];
• How a new method for imaging estrogen receptors in the brain is changing how we think about the menopause transition [35:45];
• What estrogen receptor imaging can and cannot tell us about hormone therapy's potential impact on brain health [48:45];
• Lisa's studies on the relationship between levels of systemic estrogen and density of estrogen receptors in the brain [58:00];
• Why blood estrogen levels poorly reflect brain estrogen signaling, and how tightly regulated brain hormone dynamics complicate our understanding of menstrual-cycle and lifestyle effects [1:02:15];
• The CARE Initiative: Lisa's research program looking to slash AD rates in women [1:07:45];
• The dramatic difference in AD risk between men and women associated with APOE4 [1:10:45];
• What the evidence suggests about menopausal hormone therapy (MHT) and AD risk, and why timing, formulation, and uterine status appear to matter [1:12:00];
• How the CARE initiative plans to study MHT and AD risk, within the practical constraints of a three-year research window [1:17:30];
• How to think about starting hormone therapy during perimenopause: balancing symptom relief, hormonal variability, and individualized care [1:21:00];
• Investigating selective estrogen receptor modulators (SERMs) as a targeted approach to brain health during and after menopause [1:25:00];
• Why estrogen became wrongly associated with cancer risk and what the evidence actually shows [1:29:30];
• Why better biomarkers are central to advancing women's Alzheimer's research [1:38:30];
• Modifiable risk factors for dementia, the limitations of risk models, and questionable conclusions drawn from observational data [1:44:15];
• GLP-1 agonists and brain health: exploring potential neuroprotective effects of GLP-1 agonists beyond metabolic benefits [1:49:00];
• The importance of lifestyle factors in reducing risk of dementia: practical strategies for women to support brain health [1:53:45];
• Why long-term, consistent lifestyle habits are essential for building cognitive resilience and protecting brain health over decades [2:01:15]; and
• More.

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