In this episode of unPAUSED, Dr. Mary Claire Haver continues her conversation with Dr. Lisa Mosconi, neuroscientist and associate professor of neuroscience in neurology and radiology at Weill Cornell Medicine, New York Presbyterian Hospital. Dr. Mosconi directs the Alzheimer's Prevention Program, including the NIH-funded Women's Brain Initiative and the Alzheimer's Prevention Clinic, and was recently named director of the $50 million Program in Women's Health, Cutting Alzheimer's Risk Through Endocrinology. She is also the author of the bestselling book The Menopause Brain.

Dr. Mosconi and Dr. Haver go deeper into why brain fog, memory lapses, and cognitive changes in midlife are not just frustrating. They are biologically significant, and for some women, they may signal an inflection point for Alzheimer's risk. The conversation covers the statistics women are rarely given starting at age 45, a woman has twice the risk of Alzheimer's as a man of the same age. Women are also twice as likely to be diagnosed with anxiety or depression, three times more likely to develop an autoimmune disorder affecting the brain, four times more likely to suffer from migraines, and more likely to be killed by a stroke after menopause.

Dr. Mosconi explains why Alzheimer's is not a disease of old age but a disease of midlife, with amyloid plaques and neurofibrillary tangles beginning to form decades before symptoms appear. She walks through the critical distinction between Alzheimer's disease, the biology, and Alzheimer's dementia, the symptoms, and why that gap represents the most important window for prevention. Importantly, having plaques does not mean a woman will develop dementia, and understanding what determines that difference is at the heart of her research.

The episode covers the finding that went viral when Dr. Robbie Brinton testified before the FDA: when the brain can no longer access adequate energy from glucose during the hormonal transition, it shifts to burning amino acids and then fat, including in animal models the white matter that insulates neurons. Dr. Mosconi explains why this is an adaptive response and not a pathology, and why the human brain appears to compensate in ways that rodent models cannot fully replicate.

Dr. Mosconi also shares one of the most surprising findings from her lab: rather than downregulating estrogen receptors after menopause as animal models predicted, the human brain actually increases receptor density for up to 15 years after the final menstrual period. Her team is the only one currently FDA-authorized to use a PET imaging tracer to measure estrogen binding directly in the brain.  The episode also covers maternal inheritance of Alzheimer's risk through mitochondrial DNA, why menopause does not cause Alzheimer's but can unmask underlying vulnerabilities, and the importance of the distinction between endogenous estradiol and hormone therapy when evaluating neuroprotection.

The conversation closes with Dr. Mosconi's CARE program, a $50 million global initiative spanning 17 research sites, more than 70 scientists across six continents, and a projected dataset of 100 million women. The goal is to cut Alzheimer's risk in half for women by 2050, develop hormone therapy protocols guided by brain imaging, and build the first Alzheimer's risk calculator for women that can be integrated directly into clinical practice through Epic.

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Guest links:

• Lisa Mosconi
  
• Lisa Mosconi (Instagram)
  
• Lisa Mosconi (Facebook)
  
• Lisa Mosconi Bio (LEAP)

Books:

• “The Menopause Brain: New Science Empowers Women to Navigate the Pivotal Transition with Knowledge and Confidence,” by Lisa Mosconi
  
• “The XX Brain: The Groundbreaking Science Empowering Women to Maximize Cognitive Health and Prevent Alzheimer's Disease,” by Lisa Mosconi
  
• “Brain Food: The Surprising Science of Eating for Cognitive Power,” by Lisa Mosconi

Articles:

• Population prevalence of autosomal dominant Alzheimer’s disease: A systematic review (Alzheimer’s & Dementia)
  
• Alzheimer’s Disease: An Updated Overview of Its Genetics (International Journal of Molecular Sciences)
  
• Sex and gender considerations in Alzheimer’s disease: The Women’s Brain Project contribution (Frontiers in Aging Neuroscience)
  
• Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat (Journal of Neuroscience)
  
• Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery (PLoS One)
  
• The intersection between menopause and depression: overview of research using animal models (Frontiers in Psychiatry)
  
• Anxiety Disorders Among Women: A Female Lifespan Approach (FOCUS)
  
• Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials (Experimental Gerontology)
  
• Kicking Back Cognitive Ageing: Leg Power Predicts Cognitive Ageing after Ten Years in Older Female Twins (Gerontology)
  
• White matter microstructural and macrostructural profiles during midlife reveal sex differences between men and women at different menopausal stages (Nature)
  
• The Role of Magnesium in Sleep Health: a Systematic Review of Available Literature (Biological Trace Element Research)
  
• Midlife cardiovascular fitness and dementia (Neurology)
  
• Irisin, Two Years Later (International Journal of Endocrinology)
  
• Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study (Neurology)
  
• Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia (Frontiers in Aging Neuroscience)
  

Other Resources:

• The Memory Disorders Program (Weill Cornell Medicine)
  
• WHI Memory Study (WHIMS)