Study Aims for RADCO

RADCO assembles an unprecedentedly large sample of prospectively studied centenarian cognitive superagers (n=596, essentially, centenarians with cognitive function that falls within the norms of septuagenarians) along with centenarians with normal cognition (n=230), centenarian offspring cognitive superagers (n=300, those with the cognitive function norms of people 30 years younger), offspring with normal cognition (n=180) and spouses of offspring (n=144).

Via the RADCO cores, participants undergo careful, comprehensive and cutting edge neuropsychological, biomarker, neuroimaging and neuropathological phenotyping. These generated data are used by two projects with the overall scientific objective of gauging cognitive resilience in this sample, understanding the underlying protective biology and translating that into therapeutic targets.

Project 1. The Cognitive Resilience and Resistance Phenotypes Project gauges cognitive resilience by neuroimaging, neurodegeneration, neuroinflammation and Alzheimer’s Disease plasma biomarkers risk and neuropathology and therefore generates a range of resilience endophenotypes.

In Project 1, the 3 specific aims are:

Aim 1. Cognitive Function-Neuroimaging Correlation. Gauge cognitive resilience in centenarian cognitive superagers, assessing discordance between cognitive function measures and structural and functional MRI correlates of cognitive impairment and AD.

Aim 2. Cognitive Function–Biomarker Risk of AD Correlation. Gauge cognitive resilience in the RADCO sample by assessing discordance between cognitive function measures and longitudinally assayed biomarker indices of AD, neurodegeneration and neuroinflammation.

Aim 3. Cognitive Function-Neuropathology Correlation. Gauge cognitive and brain resilience and resistance to AD and other neuropathologies in brain donors by assessing discordance between cognitive function measures and neuropathological measures.

Project 2. The Protective Factors and Mechanisms Project is the translation arm of RADCO. The project discovers genes, candidate biological pathways and sets of micro-RNA regulators associated with the resilience endophenotypes characterized in Project 1. In-vitro models of Alzheimer’s Disease (called “AD in a Dish”) incorporate cortical neurons, microglia cells and astrocytes created from centenarian and centenarian offspring cognitive superager induced pluripotent stem cell (iPSC) lines. The invitro models are used to test the candidate pathways for mechanisms conferring resilience against cognitive impairment and AD. The discovery of targetable protective pathways could lead to the development of protective therapeutics.

Project 2’s specific aims are:

Aim 1.  Using whole-exome sequence data to, 1a.  Exploit extreme outlier approaches to identify genetic variants and their combinations associated with the centenarian cognitive superager phenotype; 1b. Identify genetic variants associated with resilience endophenotypes generated by RADCO’s Project 1.

Aim 2a.i. RNA sequence centenarian cognitive superager and offspring brain area-specific tissues and iPSC-derived cortical neuron, astrocyte and microglia cell lines and assay concordant serum miRNAs. Aim 2a.ii. Determine modules of co-expressed genes and their regulatory miRNAs that associate with endophenotypes of cognitive superager resilience. Aim 2a.iii.   Discover cognitive superager resilience and resistance pathways and their regulatory miRNAs.

Aim 2b. Predict and prioritize drugs/combinations that enhance resilience and assess miRNA biomarkers of resilience. Aim 2b.i Validate key molecular resilience themes by mimicking with candidate drugs using the 3D organoid models in Aim 3. Aim 2b.ii Assess identified regulatory miRNAs for potential as circulating biomarkers of cognitive and AD pathology status.

Aim 3. Study protective mechanisms in 3D human neural-glial culture models of age-related brain pathology. 3a.  Generate  cortical neurons, astrocytes, and microglia from sex-matched deceased average life expectancy and AD controls and centenarian cognitive superager iPSCs.  3b. Study neuronal and glial resilience using 3D non-cell-autonomous and 3D triculture models.  3c. Investigate the biological impact of candidate resilience-enhancing drugs suggested by work from all three Project 2 aims.