NEW $50M Program in Women’s Health

care

Cutting Alzheimer’s Risk through Endocrinology

We are pleased to announce the selected performers.

Kaarin Anstey & Kristine Yaffe: University of South Wales & University of California, San Francisco

Roberta Diaz Brinton: University of Arizona

Iris Broce-Diaz: University of California, San Diego

Kaitlin Casaletto: University of California, San Francisco

Alexander Drzezga: University of Cologne

Francesca Farina: University of Chicago

Silvia Fossati: Temple University

Liisa Galea: Center for Addiction and Mental Health

Howard Hodis: University of Southern California

Neda Jahanshad: University of Southern California

Judy Pa: University of California, San Diego

Natalie Rasgon: Mount Sinai School of Medicine

Shireen Sindi: Karolinska Institute

Rebecca Thurston: University of Pittsburgh

Andrea Trabocchi: University of Florence

Hadine Joffe: Harvard University

Hooman Kamel: Weill Cornell Medicine

Worldwide, someone develops Alzheimer’s disease every 3.2 seconds. Nearly two-thirds of all patients are women.

CARE aims to cut the lifetime risk of Alzheimer’s among women by half, reducing risk for 330 million women globally – and, given current conversion rates, preventing 54.5 million Alzheimer’s cases by 2050.

Alzheimer’s disease is the most common form of dementia worldwide, affecting over 55 million individuals. As the population ages, the number of affected individuals is expected to increase by 2050, reaching an estimated 130 million patients globally1.

We have known since the 1990’s that, after advanced age, being a woman is the second strongest risk factor for Alzheimer’s disease2, 3. Women outnumber men ~2:1 in the Alzheimer’s population, with postmenopausal women constituting over 60% of all those affected1. The estimated lifetime risk for Alzheimer’s for a 45-year-old woman is 1 in 5, twice as high as the 1 in 10 risk for a man of the same age1. While the risks for both sexes are slightly higher at age 65, the ratio remains stable – 21% for women and 11% for men.

These statistics raise questions about the specific factors that contribute to this disparity and how best to mitigate the higher lifetime risk in women.

For many years, Alzheimer’s disease was considered an inevitable consequence of aging or genetics—or a combination of both. However, this perspective has shifted as research has uncovered the significant role of modifiable factors in Alzheimer’s risk. Today, we understand that while age and genetics cannot be modified, other factors can be intervened upon—such as lifestyle, health behaviors, and socioeconomic conditions—that account for a cumulative 45% of Alzheimer’s risk4, 5.

This means that 55% of Alzheimer’s risk remains unexplained. Current estimates are sex-aggregated, meaning they do not account for differences in risk profiles between men and women. Female-specific risks remain unquantified in available population-attributable risk (PAR) models. These gaps highlight the need for a deeper comprehension of Alzheimer’s mechanisms linked to sex-specific biology; robust, sex-specific risk biomarkers; and tailored interventions to support cognitive function and prevent neurodegeneration in women.

Emerging evidence of blood-based biomarkers of Alzheimer’s along with advancements in neuroimaging and machine learning techniques, coupled with more detailed mechanistic understanding of estrogen action in the brain, means that we can identify at-risk individuals with unprecedented accuracy, develop tailored prevention strategies, and intervene earlier to significantly reduce the burden of the disease – at scale.

We have the tools. Now is the time. CARE is focused on women, beginning in midlife, when the potential for preventing Alzheimer’s is greatest. Deep phenotypic identification of female-specific risks, coupled with rapid stratification and patient-specific matching to the most promising treatment options, has the potential to cut Alzheimer’s risk in the female population in half. In the United States alone, this would result in $4.56 trillion USD in savings. The global implications would be multiples of this number. Therefore, the program will also emphasize advances that increase access and reduce cost.

What needs to change? New considerations of neuroendocrine effects.

A prevalent but reductive explanation for the higher representation of Alzheimer’s in women has been that Alzheimer’s is a disease of old age, and women live longer than men. In actuality, the difference in life expectancy between women and men is small — 4.5 years in the US and 5 years globally. More importantly, there is now consensus that Alzheimer’s is not a disease of old age, but a disease of midlife, with symptoms that start in old age6.

Alzheimer’s begins with a lengthy “silent” (preclinical) phase, during which brain pathology develops in the absence of overt symptoms6. Notably, the early phase of Alzheimer’s coincides with the neuroendocrine aging transition of menopause for women, pointing to a critical window of vulnerability and highlighting the impact of female-specific neuroendocrine (hormonal) risks.

Increasing evidence implicates a longer reproductive span and longer lifetime exposure to sex-steroid hormones — chiefly estrogen — as female-specific protective factors against Alzheimer’s and dementia7, 8. An earlier age at menopause has been consistently associated with a higher risk of Alzheimer’s and all-cause dementia9-12. Women experiencing surgical menopause following oophorectomy (surgical removal of the ovaries) or medically-induced menopause following endocrine therapy for reproductive cancers represent an important target population for prevention strategies. There is also observational evidence that women undergoing spontaneous menopause exhibit increased biomarker indicators of Alzheimer’s risk compared to premenopausal women and age-controlled men13-20.

These findings suggest that the higher lifetime risk for Alzheimer’s in women may result from the loss of neuroprotective effects of endogenous sex steroid hormones. In this scenario, the postmenopausal Alzheimer’s risk increase presents a window of opportunity for extension of neuroprotection through hormonal interventions.

While preclinical research has demonstrated estrogen’s neuroprotective potential, the clinical application of menopausal hormone therapy (MHT) for reducing Alzheimer’s risk remains a subject of active debate. The lack of detailed, state-of-the-art data surrounding the use of estrogen therapy for Alzheimer’s prevention may be limiting our ability to make clear clinical decisions regarding effective therapies that are female-specific, time-sensitive, and formulation / dose appropriate to reduce Alzheimer’s risk. Key will be quantitative stratification using genetic, medical, neuroendocrine and biomarker assessments to determine who may benefit most from hormonal interventions, so as to develop targeted preventive protocols.

We need better answers. If successful, CARE could offer a path to prevention in midlife for millions of women, when the potential for preservation of cognitive function is greatest.

Program goal.

Our ultimate goal is to cut women’s lifetime risk of Alzheimer’s in half. CARE is focused on the intersection of neuroendocrine risks and neurodegeneration so as to identify personalized preventative strategies and treatments. This approach utilizes an individualized medicine framework — leveraging biomarkers, advanced imaging, genetic profiling— to tailor interventions to the specific needs of women at risk for Alzheimer’s due to neuroendocrine aging.

How do we get there?

To achieve a 50% risk reduction by 2050, we must ensure high biomarker accuracy for effective screening, expand outreach, and maximize treatment efficacy and optimize frequency. The CARE program includes three primary thrust areas designed to achieve this overall goal, designed to stratify at-risk individuals into progressively specialized diagnostic pathways. This tiered approach optimizes resources and widespread application, while ensuring comprehensive risk assessments and cost-effective prevention strategies. Detailed descriptions of these thrust areas appears in the full program announcement, available for download below.

Thrust Area 1. Identify high-precision female-specific neuroendocrine targets and therapies for Alzheimer’s risk reduction.

Biomarker screening accuracy and outreach (percentage of the at-risk population reached) must combine to identify at least 330 million women globally who are both at risk and reachable for treatment. This thrust area focuses on development of high-performance neuroendocrine predictors of Alzheimer’s risk in women, identification of the ‘window of opportunity’ for neuroendocrine intervention, and demonstration of Alzheimer’s risk reduction with a specific focus on hormone therapy, while ensuring that treatment does not increase the risk of reproductive cancers like breast cancer.

Thrust Area 2. Develop high-affinity in vivo brain imaging probes for neuroendocrine function in clinical populations and their potential therapeutic application.

Thrust 2 focuses on developing high-affinity neuroendocrine imaging tests. These imaging tools are key to enabling precise quantification of hormonal receptor density and/or function in the brain. We are also interested in the potential for these probes to have therapeutic application. As such, this thrust includes a focus on neuroendocrine imaging probes with high specificity and affinity to assess in vivo brain hormone receptor activity in clinical populations and proof-of-concept demonstration of the dual application of these probes as theranostics – namely neuroendocrine imaging probes that also have therapeutic application.

Thrust Area 3. Development of predictive models that halve Alzheimer’s risk in women and their deployment as risk assessment tools for clinical use.

Tools should be designed to provide accurate and scalable methods to identify and monitor at-risk individuals, enabling early intervention and more precise targeting of preventative treatments to reduce Alzheimer’s risk globally, to include: demonstration of a >50% reduction in population-attributable risk (PAR) in female Alzheimer’s cases by modeling neuroendocrine risks and therapies, and the integration of program findings across thrusts into a practical tool for assessing Alzheimer’s risk in women.

Program Director.

Lisa Mosconi, PhD, is a neuroscientist specializing in the early detection and risk reduction of Alzheimer’s disease, with a strong focus on women’s brain health. She is the founder and director of the Alzheimer’s Prevention Program and the Women’s Brain Initiative at Weill Cornell Medicine/ NY-Presbyterian, where she serves as an associate professor of Neuroscience in Neurology and Radiology. She earned her PhD in Neuroscience and Nuclear Medicine / Molecular Imaging from the University of Florence, Italy, with a research fellowship at New York University School of Medicine.

Call for abstracts and proposals.

We are soliciting abstracts and proposals for work over three (3) years in one or more of the following thrust areas (see Thrust areas in full program announcement). Proposers should clearly relate work in these thrust areas to one or more of the program goals.

It is not necessary to form a large consortium or teams to address all facets of the program. The strength of this approach will manifest through program-level integration of efforts from individuals and small agile teams with deep (and sometimes narrow) expertise. Across all projects, Wellcome Leap will facilitate iterative and collaborative integration of findings to refine models and improve and validate predictive measures and adapt approaches as teams make progress towards shared goals.

Download full program description

Process and timeline
Program announcement.

30 DAYS FOR PREPARATION AND SUBMISSION OF ABSTRACT

15-Day Abstract review round.
/ Day 1
Submission deadline: 14 March 2025
/ Day 15
Abstract feedback sent: 29 March 2025

30 DAYS FOR PREPARATION OF FULL PROPOSALS AFTER ABSTRACT FEEDBACK

30-Day Full proposal review round.
/ Day 45
Submission deadline: 28 April 2025
/ Day 75
Proposal decision sent: 28 May 2025

Frequently asked questions.

If you have questions, please review our FAQ section here. – updated 14 March 2025.

Send inquiries to care@wellcomeleap.org

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  13. Mosconi L, Berti V, Quinn C, et al. Correction: Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS One. 2018;13(2):e0193314. doi:10.1371/journal.pone.0193314
  14. Mosconi L, Berti V, Quinn C, et al. Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology. Sep 26 2017;89(13):1382-1390. doi:10.1212/WNL.0000000000004425
  15. Mosconi L, Rahman A, Diaz I, et al. Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PLoS One. 2018;13(12):e0207885. doi:10.1371/journal.pone.0207885
  16. Mosconi L, Berti V, Dyke J, et al. Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Sci Rep. Jun 9 2021;11(1):10867. doi:10.1038/s41598-021-90084-y
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