As research reveals more about the complex interplay of changes in the brains of people with dementia, we are learning that many people who may have been diagnosed with Alzheimer’s disease, frontotemporal dementias, or other related dementias likely had multiple different abnormal protein deposits and pathologies contributing to their symptoms. This is known as multiple-etiology dementia (MED), or mixed dementia. The pathologies and changes include, but are not limited to, different combinations of amyloid-beta, tau, TDP-43, alpha-synuclein, and vascular pathologies. The presence of multiple co-pathologies is associated with a faster decline in cognition and worse dementia outcomes. Researchers are still working to understand how underlying disease processes in MEDs inﬂuence each other and how they affect clinical presentation and progression of a syndrome. Recent discoveries underscore the complexity of dementia-causing conditions and the need to find treatments that work in diverse individuals and populations with a variety of brain changes.
- Multiple-etiology dementias can also be referred to as Mixed-etiology dementias, or Dementia-multifactorial.
- Multiple-etiology dementia symptoms may be identical to those of Alzheimer’s disease or another type of dementia, or they may vary depending on the type and extent of brain changes involved.
- Majority of all dementia cases (age 65+) are multiple-etiology or mixed dementias (e.g., Neurology. 2007 Dec 11;69(24): 2197-204, Brain. 2018 July 1; 141(7): 2181-2193, JAMA. Neurol. 2020 Oct 1; 77(10): 1299-1307, Lancet Healthy Longev. 2023 Mar; 4(3): e115-e125).
MED and the National Plan to Address Alzheimer’s Disease
The 2022 Alzheimer’s Disease-Related Dementias (ADRD) Summit addressed research needs for ADRD, including MED and three MED-related Special Topics: LATE (limbic-predominant age-related TDP-43 encephalopathy)/TDP-43 in Common Late-Onset Dementias; Post-TBI (Traumatic Brain Injury) AD/ADRD; and Impact of COVID-19 on AD/ADRD Risk and Outcomes. Research priorities for each, which now represent formal NIH AD+ADRD Research Implementation Milestones, are highlighted below:
1. Multiple Etiology Dementias:
- Detection and Diagnosis of Cognitive Impairment and MED
- Evaluate pragmatic approaches to objectively detect cognitive impairment and link to quality care when a patient, care partner, or clinician reports cognitive, behavioral or functional changes
- Evaluate the benefits, burdens, and harms of screening for cognitive impairment in older adults in the absence of a patient, care partner or clinician report of cognitive, behavioral or functional changes
- Conduct multimodal clinical and translational research to support the identification of multiple etiologies in diverse populations
- Basic Research in MED
- Advance basic research on the common and interacting risk factors and mechanisms of multiple etiology cognitive impairment and dementia in diverse populations
- Interventions and Treatments for MED
- Conduct clinical studies on approved or promising interventions and treatments to mitigate risk for cognitive decline
- Implement and evaluate outcomes for effective dementia care programs that support persons living with dementia and their caregivers, including those of socially, ethnically and racially diverse populations
- Dementia Capable Workforce
- Promote education and training on multiple etiology cognitive impairment and dementia to increase the dementia capable workforce, advance researchers including from groups underrepresented in science, and foster inclusive research practices
- Data Harmonization
- Conduct research to improve pre- and post-data collection harmonization and sharing practices across multiple etiology cognitive impairment and dementia studies
2. LATE (limbic-predominant age-related TDP-43 encephalopathy)/TDP-43 in Common Late-Onset Dementias:
- Define LATE (pathologic, clinical, genetic, molecular) classification and diagnostic boundaries across FTLD-TDP, AD and other dementia related pathologies and their syndromes to enhance diagnosis, research, and awareness assuring diversity, inclusion, and equity
- Develop biomarkers, classifiers, and risk profiles to establish in-vivo diagnostic criteria for LATE in persons without cognitive symptoms and in persons with amnestic or other relevant late-life dementia syndromes, assuring diversity, inclusion and equity
- Build new experimental models that incorporate aging with behavioral, pathologic, and molecular phenotypes of TDP-43 proteinopathy or hippocampal sclerosis, to advance knowledge and enable testing of therapeutics
- Study the intersection of hippocampal sclerosis (HS) and LATE-NC, within and across all disciplines (clinical, pathologic, diagnostic, genetic, molecular, etc.) and consider the roles of vasculopathy, senescence, and other potential contributing factors, assuring diversity, inclusion and equity
3. Post-TBI AD/ADRD:
- Promote collaboration among TBI and dementia researchers through working groups, retrospective and prospective data and measurement harmonization, and interdisciplinary research
- Characterize the heterogeneous clinical and biological phenotypes and time course of progressive dementia following varied TBI exposure histories by developing biomarkers and methods to quantify lifetime head trauma exposure and diagnose post-TBI dementias
- Establish research infrastructure, including multimodal longitudinal studies with autopsy endpoints that employ standardized CDEs and methodologies, to study post-TBI AD/ADRD
- Basic and translational research to elucidate the mechanistic pathways, development, and progression of post-TBI AD/ADRD neuro-pathologies to better understand clinical symptom expression
4. Impact of COVID-19 on AD/ADRD Risk and Outcomes:
- Establish research infrastructure enabling clinical, epidemiological and basic research studies of COVID-19 impact on AD/ADRD risk and outcomes, prioritizing disproportionally affected populations and clinical trials readiness
- Characterize the clinical phenotype and develop diagnostic criteria for neurocognitive impairment and dementia associated with COVID-19 in those with and without neurocognitive impairment/dementia prior to infection
- Explore interaction of social, structural, and systemic inequalities, comorbidities and social and medical interventions with risk and neurocognitive sequelae of COVID-19
- Advance understanding of basic mechanisms underlying neurocognitive impairment and dementia due to COVID-19 in order to develop biomarkers, risk profiles, and the foundation for early interventional trials
NINDS is interested in all aspects of MED research, particularly that which aligns with the above ADRD Summit 2022 recommendations. Investigators can consider applying to NIH parent R01 or R21 mechanisms or specific funding opportunities (Focus on Alzheimer's Disease and Related Dementias). NINDS and NIA work together to ensure similar paylines at the two institutes for AD/ADRD research applications.
COVID-19 and AD/ADRD: