Mechanisms of Cognitive Fluctuations in ADRD Populations (R01 - Clinical Trial Optional) | RFA NS 25 014

Opportunity Information: Apply for RFA NS 25 014

Mechanisms of Cognitive Fluctuations in ADRD Populations (R01 - Clinical Trial Optional) is an NIH research grant opportunity (RFA-NS-25-014) focused on understanding why cognition can vary dramatically over short or extended periods in people living with Alzheimer’s disease and related dementias (ADRD). The funding call highlights that cognitive fluctuations are especially central to Dementia with Lewy Bodies, but can also appear across multiple dementia syndromes. These fluctuations can occur over seconds to days, tend to be unpredictable (not simply a late-day "sundowning" pattern), and are strongly linked to worse day-to-day functioning and quality of life. The overall goal is to move beyond describing the symptom and instead identify the underlying physiology that drives these up-and-down cognitive states, laying groundwork for future treatments and better symptom management.

The opportunity encourages applicants to test specific biological or physiological mechanisms that may contribute to cognitive fluctuations in ADRD populations. It notes that small prior studies have connected fluctuations to epileptiform discharges and disrupted brain oscillatory activity as measured by EEG, suggesting that abnormal electrical activity could play a role in transient cognitive changes. At the same time, the announcement emphasizes that these mechanisms may not fully explain the phenomenon, particularly because many affected patients also experience dysautonomia, orthostatic hypotension, and sleep disturbances. In practical terms, NIH is signaling interest in multi-factorial models where fluctuating cognition could arise from interacting systems, such as altered brain network rhythms, intermittent seizure-like activity, blood pressure instability, autonomic dysfunction, or sleep-wake regulation problems. The initiative also recognizes that causes may differ by dementia subtype, which opens the door to projects that either deeply characterize multiple candidate mechanisms within one ADRD group or explicitly compare mechanisms across different ADRD diagnoses.

A major methodological theme in the announcement is the need to capture fluctuations as they happen. Because these episodes can be brief, sporadic, and hard to predict, the call anticipates that wearable or other digital devices will be important tools for collecting time-aligned data in real-world settings. Applicants are encouraged to consider devices capable of measuring signals relevant to their hypotheses, which could include ambulatory EEG, actigraphy or sleep wearables, heart rate and heart rate variability, continuous blood pressure proxies, posture and gait sensors, or other physiologic monitoring approaches that help link cognitive status changes to concurrent physiologic events. The intent is to support studies that can connect moment-to-moment cognitive performance or alertness changes with objective physiologic signatures rather than relying only on infrequent clinic visits or retrospective caregiver reports.

This is an R01 mechanism and is designated "clinical trial optional," meaning applicants may propose either studies that do not meet the NIH definition of a clinical trial or projects that do, depending on the research aims and design. The activity category is health research, and the opportunity is associated with CFDA numbers 93.853 and 93.866. The award ceiling listed is $825,000, and the original closing date is June 24, 2024. While the announcement does not spell out the number of expected awards in the provided text, it frames the program as a targeted effort to advance mechanistic understanding of a clinically meaningful and under-explained symptom domain in ADRD.

Eligibility is broad and includes many domestic organization types commonly eligible for NIH grants: state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; nonprofit organizations with or without 501(c)(3) status (excluding higher education when specified); public housing authorities/Indian housing authorities; federally recognized Native American tribal governments; other-than-federally-recognized tribal organizations; for-profit organizations (other than small businesses); small businesses; and other eligible entities. The opportunity explicitly names additional eligible applicant categories such as Historically Black Colleges and Universities, Hispanic-serving institutions, Tribally Controlled Colleges and Universities, Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions, as well as faith-based or community-based organizations and eligible federal agencies. Foreign organizations (non-U.S. entities) are not eligible to apply, and non-domestic components of U.S. organizations are not eligible to apply, but foreign components as defined by the NIH Grants Policy Statement are allowed, which typically means a U.S.-based applicant may include specific foreign work or collaborations when justified and compliant with NIH policy.

Taken together, the grant call is looking for rigorous, physiology-grounded research that explains what drives cognitive fluctuations in ADRD, supports careful measurement in naturalistic or high-frequency ways (often via wearables), and clarifies whether different dementia populations share common mechanisms or show distinct pathways. The longer-term payoff NIH is aiming for is a mechanistic foundation that can inform targeted interventions, monitoring strategies, and clinical management approaches that reduce the functional burden of fluctuating cognition for patients and caregivers.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Mechanisms of Cognitive Fluctuations in ADRD Populations (R01 - Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.853, 93.866.
• This funding opportunity was created on 2024-03-18.
• Applicants must submit their applications by 2024-06-24. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $825,000.00 in funding.
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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