# Early risk factors of accelerated neural aging trajectories and cognitive decline: a nonhuman primate longitudinal model

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $1,178,818

## Abstract

Abstract:
A strong link between early life stress/adversity (ELS/ELA) and age-related disorders, such as cardiometabolic
disease, cognitive and psychiatric/neurological disorders, have been established mostly based on retrospective
human reports. Yet, prospective, longitudinal, studies across the life span are critical to identify biomarkers of
ELA risk embedded earlier in life, during middle age to develop early intervention strategies. Animal models
with short life spans (invertebrates, rodents) have significant limitations to inform about human aging and the
therapeutics developed from those models have failed in clinical trials. Longitudinal nonhuman primate (NHP)
studies could provide significant information on early biological and neural markers of ELA-related cognitive
decline due to their long life span and gradual aging-related cognitive impairments and brain pathology similar
to those in humans emerging in middle age. This proposal builds on our data linking ELA in macaques with
early markers of accelerated cellular aging (accelerated DNA methylation age, shortened telomere length),
inflammation, and neurocognitive alterations detectable from infancy to young adulthood. The goal is to use a
prospective, longitudinal design in NHPs to identify early biomarkers/pathways and underlying mechanisms of
ELA-related accelerated neural aging trajectories and cognitive decline from young adulthood to middle age.
This unique population of adult female macaques with ELA (social subordination stress) are currently living in
social groups at the Yerkes National Primate Research Center and were longitudinally characterized from birth
through puberty as part of NIH-funded studies. These animals (High-ELA: subordinates; low-ELA: dominant)
will be studied longitudinally between 7(early adulthood) and 11 (middle age) years of age. Aim 1 will examine
trajectories of ELA-accelerated neural aging in brain regions that control cognitive and stress/emotional
functions studied in Aim 2 (prefrontal cortex -PFC-, hippocampus -HIPP-, amygdala); it will use (a) MRI, DTI
and resting state fMRI to examine myelin loss, cortical thinning and loss of long-range connectivity; (b)
measures of neuropathology with MR spectroscopy (reductions in N-Acetylaspartate) and markers preceding
dementia in humans (reduced amyloid β(Aβ42)/tau ratio in CSF); and (c) markers of neuroinflammation and
neurotoxicity (CSF levels of kynurenine pathway metabolites). Aim 2 will test whether ELA accelerates age-
related deficits in stress/emotional regulation mediated by PFC-amygdala circuits (HPA axis, Human Intruder
and dot-probe tasks), and cognition: attention (continuous performance task), executive function and cognitive
flexibility mediated by PFC circuits (Intradimensional/Extradimensional discrimination), and spatial relational
memory mediated by HIPP-PFC circuits (spatial memory span). Aim 3 will examine associations between
longitudinal trajectories of neural measures (Aim 1) and cog...

## Key facts

- **NIH application ID:** 10458748
- **Project number:** 5R01AG070704-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** MARIA C ALVARADO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,178,818
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458748

## Citation

> US National Institutes of Health, RePORTER application 10458748, Early risk factors of accelerated neural aging trajectories and cognitive decline: a nonhuman primate longitudinal model (5R01AG070704-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10458748. Licensed CC0.

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