Disease Mechanisms: Mechanisms of vulnerability and resilience

Create new research programs that use data-driven, systems-based approaches to integrate the study of fundamental biology of aging with neurobiology of aging and research on neurodegeneration, AD and AD-related dementias to better understand the mechanism(s) of vulnerability and resilience in AD across all levels of biologic complexity (from cellular to population level) and to gain a deeper understanding of the complex biology and integrative physiology of healthy and pathologic brain aging.

Launch at least 6 new research programs that use data-driven, systems-based approaches to integrate AD and ADRD research with the study of the fundamental biology of aging/neurobiology of aging.
These programs should support studies that integrate epidemiologic, genomic, and basic research to understand: the dynamic interaction between aging and neurodegeneration mechanisms underlying individual differences in trajectories of brain aging, disease risk, age-of-onset, progression and clinical presentation.
Ensure that these integrative research studies include under-represented, minority populations and patients with extreme phenotypes, atypical presentations of AD.

Summary of Key Accomplishments

NIA has launched more than ten targeted initiatives that combine epidemiologic, genomic, and basic research and employ cutting-edge technologies to gain deeper understanding of the transitions from healthy to pathologic brain aging.

In addition to leveraging data and biosamples, these programs use cell-based and animal models to tease out detailed molecular mechanisms of neurodegeneration. Some of the key questions being addressed through these programs are: a) the impact of metabolic and vascular factors on brain aging; b) the mechanisms by which neuropsychiatric symptoms influence the onset and progression of AD; c) the role of cellular senescence; and d) the nature of resilience to disease in the presence of various risk factors for AD.

Other NIA activities include the launch of a new initiative that funded nine awards to conduct targeted research on brain aging and AD/ADRD through interdisciplinary collaborations across experimental and computational laboratories. Examples of the research taking place include the development of a multi-scale model of brain aging that uses advanced diffusion magnetic resonance imaging which has immense potential to disentangle the extent of neuro-inflammation and neurodegeneration in aging and the onset of AD and ADRD. Another study uses innovative artificial intelligence to analyze multi-omic brain datasets to identify drivers of brain aging. Mathematical modeling, along with the combination of in vitro and in vivo approaches will assist scientists in understanding the interaction of proteins such as tau and α-synuclein, and regional gene expression during trans-neuronal transmission.

NIA continues to expand these avenues of research as they provide foundational knowledge necessary to inform the development of a precision medicine approach to AD treatment and prevention.

NIH-funded researchers have also identified new molecular subtypes of cognitive impairment, which may help better inform how cognitive impairment is diagnosed and lead to novel treatments in the future. NIA is currently funding efforts to examine the role of glycosphingolipids, a specialized type of membrane lipid, in Alzheimer's pathology and generate the first complete map of these lipids in the brain.

The key accomplishments summary is current as of September 2025.