NINDS Contributions to ADRD Research Activities

NINDS Contributions to ADRD Research Activities

Amidst these uncertain times, the current COVID-19 pandemic is prevalent in headlines and constantly on our minds, and it’s easy to overlook the contributions that NIH is making toward other aspects of the biomedical enterprise. Today, however, I would like to share a bit about NINDS’s research strategy to prevent and effectively treat Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (AD/ADRDs), which we develop and implement in close coordination with the National Institute of Aging. To achieve this ambitious goal, NINDS balances investigator-initiated projects with targeted initiatives and an iterative strategic planning process. In addition, together with our colleagues at the National Institute of Aging, we are launching a new Center for Alzheimer’s and Related Dementia (CARD) on the NIH’s Bethesda campus to compliment the work that is ongoing in Universities across the country.

It is likely that someone you know – perhaps a friend or family member – has suffered from dementia. Losing the ability to think, remember, and reason well – the cognitive functions that shape us as humans – is devastating, and places great stress on caregivers and loved ones. Dementia conveys substantial health and financial costs, affecting more than 47 million people worldwide. While AD is the most common dementia diagnosis, ADRDs share many cognitive and pathological features with and can be difficult to distinguish from AD. NINDS leads ADRD research at the NIH, which includes frontotemporal dementia (FTD), Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and mixed etiology dementias (MED). NINDS also leads a broad spectrum of neurological disorders research, many of which are associated or sometimes co-occur with AD/ADRDs. In fact, more often than not, patients with a diagnosis of Alzheimer’s disease present with different mixtures of brain pathologies, complicating both the diagnosis, as well as the treatment. At this time, there are no known treatments to prevent or stop AD or ADRD progression.

NINDS’s strategic planning for ADRDs is informed by several coordinated activities. Preventing and effectively treating Alzheimer’s disease and related dementias is a central goal of the National Plan to Address Alzheimer’s Disease, a living framework for the National Alzheimer's Project Act (NAPA) that guides federal efforts and was mandated by Congress and signed into law in 2011. NAPA defines “Alzheimer’s” as Alzheimer's disease and related dementias (AD/ADRDs). In the context of the National Plan, this means that the label “Alzheimer’s” does not refer to Alzheimer’s disease alone, but rather to the full spectrum of AD and ADRD disorders. Leading the nation’s research response, the National Institute on Aging undertakes Alzheimer’s disease research, broadly, and is the lead NIH Institute responding to the National Plan. At NINDS, our scope encompasses the development of ADRD research strategy and objectives, primarily through triennially-held Summits, with previous efforts in 2013, 2016, and 2019. The summits present research progress, encourage discussion among experts, and seek input from recognized dementia-science experts, as well as from public and private stakeholders to generate consensus research recommendations to address the goals of the National Plan.

Since the first Summit in 2013, NINDS has issued 37 funding announcements, including 8 in FY2020, inviting applications to fill critical research needs. These efforts have resulted in several ADRD research initiatives, including:

  • DISCOVERY: NINDS’s most recently launched ADRD initiative, this 6-year prospective clinical research study aims to determine the specific subsets of stroke events that cause cognitive impairment and dementia in post-stroke populations, especially within racial and ethnic minorities that experience health disparities.
  • ALLFTD: an integrated consortium conducting detailed natural history studies of FTD, ultimately aimed at developing sensitive clinical assessments and biomarker tools for future use in FTD clinical trials (co-managed with NIA).
  • CONNECT-TBI: a large program spanning 12 research institutions to study traumatic brain injury (TBI) and its connection to AD/ADRD.
  • DetectCID: a consortium to develop tools that can help health care providers detect cognitive impairment and dementia in primary care and other everyday clinical settings. Up to half of the funded research focuses on addressing barriers to detecting cognitive impairment in populations that experience health disparities, including racial and ethnic minorities.

Many central themes emerged from the 2019 ADRD Summit and are described in detail in this report, including the pressing need for biomarkers (especially given the mixed pathologies in ADRD), continued efforts in basic, clinical and translational research, the ever-growing importance of identifying and addressing health disparities, need for additional resource infrastructure, recognition of training and workforce needs, and proposing a process to achieve common nomenclature among the ADRD community.

Research initiatives planned as result of the ADRD Summits are already contributing to our enhanced understanding of AD/ADRDs.
For example:
  • Progress in identifying early signs of VCID and preventing vascular-related cognitive decline:: Recent compelling evidence from the SPRINT-MIND study (funded by NHLBI, NINDS, and NIA) showed that intensively lowering blood pressure in mid-life decreased the risk of cognitive impairment and lessened the accumulation of white matter lesions, a known vascular contribution to cognitive impairment and dementia (VCID) (JAMA, 2019 Feb; JAMA, 2019 Aug). In order to improve diagnosis of small vessel disease (a predominant cause of VCID?), the NINDS and NIA-supported Mark-VCID consortium has developed and is currently testing 11 different biomarker kits—which include several types of vascular imaging and fluid-based biomarkers—across several clinical research sites, including within the SPRINT-MIND research consortium.
  • Salt, tau, and cognition: researchers recently demonstrated in mice that a high salt diet can lead to impaired cognitive performance that is dependent upon and precipitated by pathological build-up of tau in the brain. This is the first link between salt intake and dementia-related tau pathology (Nature, 2019).
  • Using cutting edge technology to examine AD one cell at a time: For the first time in AD samples, researchers used single-cell RNA sequencing to analyze tens of thousands of individual cells. With this approach, the researchers were able to identify and pool together several different cell types and showed that each exhibited their own distinctive RNA profile or signature of AD-related changes (Nature, 2019). 

I am pleased that the 47 refined research recommendations from this year’s ADRD Summit were approved by the NINDS Advisory Council and accepted by the federal Advisory Council on Alzheimer’s Research, Care, and Services in January of this year (see NINDS’s presentation). The recommendations will be integrated as implementation milestones within the National Plan. Further, many of the 2019 ADRD Summit recommendations are being addressed by actively funded NINDS projects. In addition, several new potential funding announcements for release in FY20 and FY21 were just approved by NANDS Council, adding to the suite of NINDS’s ADRD programs, including: 

  • Mechanisms of Selective Vulnerability in LBD and FTD – to increase basic and clinical research on why certain brain regions are more vulnerable to abnormal protein accumulation and damage in LBD and FTD patients.
  • Mechanisms of Pathological Spread of Abnormal Proteins in LBD and FTD – to increase basic and clinical research on how abnormal proteins spread in the nervous system of LBD and FTD patients.
  • Connecting Pre-mortem Clinical Information with Post-Mortem Brain Analysis in LBD – to increase the linkage of comprehensive pre-mortem clinical information with gold standard post-mortem diagnostic analysis in patients with LBD.
  • Treatments for LBD-Exploratory Clinical Trial – to encourage exploratory clinical trials (Phase I or II) testing either new or repurposed drugs or devices to treat patients with LBD.
  • Center Without Walls for Molecular Mechanisms of Neurodegeneration in FTD – to continue support for interdisciplinary team science aimed at elucidating the molecular mechanisms underlying neurodegeneration in FTD, with a focus on examining the role of tau, TDP-43 or FUS pathogenesis, and specific genetic causes and risks factors.
  • Small Vessel VCID Biomarker Validation for Clinical Trials and Coordinating Center – to continue support for a consortium (currently implemented as MarkVCID) to develop and validate high-quality small vessel VCID biomarkers ready for use in clinical trials, and for generating scientific breakthroughs in the understanding and treatment of VCID.

These planning efforts require a herculean amount of work from scientists, physicians, patient groups, administrators, and other public stakeholders. I want to take a moment to acknowledge the efforts of Dr. Rod Corriveau, the NIH/NINDS Summit lead and Program Director for NINDS’s ADRD research, the Scientific Chair for this year’s summit, Dr. Julie Schneider, as well as Dr. Richard Hodes, the NIA Director who has enabled such a productive collaboration between our Institutes.

Tuesday, June 9, 2020