Notice of Special Interest: Sex and Gender Differences in Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD)
Notice Number:
NOT-AG-20-038

Key Dates

Release Date:

August 5, 2020

First Available Due Date:
November 12, 2020
Expiration Date:
November 13, 2021

Related Announcements

PAR-19-070 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

PAR-19-071 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)

Issued by

National Institute on Aging (NIA)

Purpose

This Notice of Special Interest (NOSI) is intended to promote multidisciplinary research to clarify sex and gender differences in the risk, development, progression, diagnosis, and clinical presentation of Alzheimer's disease or Alzheimer's disease-related dementias (AD/ADRD). Studies that examine sex and gender differences in outcomes (e.g., clinical, functional, well-being) among people living with AD/ADRD are also relevant. Broad areas of interest include biological (e.g., hormonal, genetic, metabolic, comorbidity-related), neuroscientific (e.g., neural systems and functions), behavioral (e.g., physical activity, substance use, social engagement), social (e.g., history of maltreatment or adversity, child rearing, marital status, education, employment), psychological (e.g., depression, cognitive ability, emotional function, stress reactivity, personality), and healthcare profession (e.g., provider knowledge and attitudes about dementia) and healthcare system-level (e.g., access to care) factors and processes that separately or together may drive observed differences by sex and gender and/or may operate differently by sex and gender. Studies that account for methodological and measurement issues that may drive sex and gender differences are also of interest.

Studies that are using systems-based, data-driven approaches to understand the molecular mechanisms by which sex differences impact AD/ADRD risk and responsiveness to various types of pharmacologic and non-pharmacologic treatments for AD/ADRD are more appropriate for RFA-AG-21-029.


For the purpose of this NOSI:

  • “Sex” refers to biological factors and processes (e.g., sex chromosomes, endogenous hormonal profiles) related to differentiation between males (who generally have XY chromosomes) and females (who generally have XX chromosomes).
  • “Gender” refers to culturally- and socially-defined roles for people, sometimes but not always along the lines of a gender binary (girls and women, boys and men). “Gender” incorporates individuals’ self-perceptions (gender identity); the perceptions, attitudes, and expectations of others (gender norms); and social interactions (gender relations). There is a great deal of variation in how individuals and groups understand, enact, and express gender.

Background

Understanding sex and gender differences in AD/ADRD is critical for research recommendations to diversify research cohorts and improve methods and tools for conducting health disparities research related to AD/ADRD. These recommendations are found in the National Alzheimer’s Project Act, the 2012 Alzheimer’s Disease Research Summit, the health disparities session of the 2013 Alzheimer’s Disease and Related Dementias Meeting, the 2015 Alzheimer’s Disease Research Summit, the 2018 Alzheimer’s Disease Research Summit, and NIA’s ADRD Research Implementation Milestones.

A core challenge of understanding sex and gender differences in processes and outcomes related to AD/ADRD is that the terms “sex” and “gender” are often used interchangeably. However, “sex” refers to biological factors and processes (e.g., sex chromosomes, endogenous hormonal profiles) related to differentiation between males and females, whereas “gender” refers to culturally- and socially-defined roles that sometimes influence how individuals see themselves (gender identity); the perceptions, attitudes, and expectations of others (gender norms); and social interactions (gender relations).

 A lack of clarification on “sex” and “gender” can obfuscate the identification of specific biological and neural systems and psychological, behavioral, sociocultural, and environmental pathways that may help identify individuals at higher risk of AD/ADRD as well as potential differences in disease progression. Ultimately, understanding the unique roles of sex and gender may facilitate the identification of therapeutic targets and interventions. For example, prior work suggests, but does not definitively indicate, that women may be at higher risk for AD/ADRD than men. Women’s survival advantage may explain part, but not all, of their potential elevated AD/ADRD risk, as age is the strongest risk factor for AD/ADRD. This survival advantage itself is thought to be a combination of biological factors (i.e., sex differences) which drive female survival advantages in many species, as well as a host of non-biological factors (i.e., gender differences). These gender differences include factors such as smoking, which until relatively recently was far more common among men than women. As the gender gap in smoking has narrowed as a result of societal change in the range of acceptable behavior for women in some societies, women’s longevity advantage over men has also decreased. How these and other gendered processes (e.g., changes in educational attainment, employment) and structural gender inequalities (e.g., barriers to access healthcare services and high-quality care) will impact AD/ADRD outcomes such as overall population prevalence of AD/ADRD and gender differences in AD/ADRD over time are unknown. Other unanswered questions include how a variety of putative risk (e.g. low education, depression) and protective (e.g., social connectedness, self-regulation) factors for AD/ADRD operate along sex and gender lines. Finally, questions remain about the best methodological and measurement assessments in epidemiological and other studies to evaluate sex and gender in AD/ADRD, including survival bias, competing risks, and sample selection.

Example research topics that may elucidate sex and/or gender differences in AD/ADRD risk, development, progression, diagnosis, clinical presentation, and outcomes include, but are not limited to, the following:

  • Sex and/or gender differences in longevity, survival bias, and comorbidities
  • Life course factors (e.g., early life adversity, place of birth, neurodevelopment, educational experiences, reproductive history, occupational careers, caregiving responsibilities, etc.)
  • Complex interactions among sociocultural, behavioral, psychological, neural systems, and biological processes and their responses to the sociocultural and physical environments, and the timing, level, and duration of exposures
  • Cohort differences related to social and behavioral factors (e.g., caregiver-child interactions, changes in family structure, fertility, educational attainment, labor force participation, occupational characteristics (e.g., job control, cognitive demands, etc.)) and health behaviors (e.g., tobacco use) which may shape AD/ADRD trends
  • Intersectional approaches which consider sex and gender differences among racial and ethnic minority, socioeconomically disadvantaged, underserved rural, and sexual and gender minority (SGM) populations. SGM populations include, but are not limited to, individuals who identify as lesbian, gay, bisexual, asexual, transgender, two-spirit, queer, and/or intersex as well as other individuals whose sexual orientation, gender identity or expression, or reproductive development is characterized by non-binary constructs of sexual orientation, gender, and/or sex
  • Structural gender inequalities (e.g., barriers to access healthcare services and high-quality care) that impact AD/ADRD outcomes
  • Sex-specific risk factors (e.g., oophorectomy; menopause, including role of hot flashes and sleep disturbances; pregnancy, including preeclampsia and gestational diabetes; androgen-deprivation therapy; and testosterone loss) across the lifespan that may impact AD/ADRD outcomes
  • Sex and gender differences in AD/ADRD risk factors common to both sexes (e.g., cardiovascular disease, diabetes, education, hearing loss, depression, etc.)
  • Sex differences in immune responses related to risk of AD/ADRD
  • Role of hormone changes and/or therapy on brain function (e.g., metabolism) and risk for AD/ADRD and how these may interact with other factors (e.g., sleep)
  • Sex differences in genetic risk factors for AD/ADRD (e.g., APOE, x-linked, common variants, autosomal dominant mutations)
  • Sex and gender differences in the clinical detection, diagnosis, management, and treatment of AD/ADRD

Application and Submission Information

This notice applies to due dates on or after November 12, 2020 and subsequent receipt dates through November 13, 2021. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice:

  • PAR-19-070 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
  • PAR-19-071 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-AG-20-038" (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Amelia Karraker, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-3131
E-mail: amelia.karraker@nih.gov


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