# Circulating fatty acids, genetics of inflammation and AD-related dementia and cognitive decline

> **NIH NIH R56** · TUFTS UNIVERSITY BOSTON · 2020 · $337,327

## Abstract

PROJECT SUMMARY
Chronic, systemic inflammation is an established mediator of cognitive decline and Alzheimer’s disease (AD)
and Alzheimer’s disease-related dementias (ADRD) in older adults. Large-scale genetic studies have
strengthened evidence that inflammatory genes play a major role in neuroinflammation that leads to
neurodegeneration and cognitive loss. Dietary omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids
(from fish, nuts, seeds, and certain oils) can be anti-inflammatory. However, evidence of anti-inflammatory and
cognitive protection from dietary fatty acids is mixed, even in randomized, controlled interventions. Genetic
variants that affect systemic inflammation likely contribute to inconsistent associations between n-3 and n-6
fatty acids and cognitive function. To investigate this hypothesis, we will conduct genome-wide interaction
analyses of common variants with linoleic acid (18:2, n-6), arachidonic acid (20:4, n-6), alpha-linolenic acid
(18:3, n-3), eicosapentaenoic acid (20:5, n-3), docosahexaenoic acid (22:6, n-3) for the outcomes of high-
sensitivity C reactive protein (CRP) and interleukin 6 (IL-6) in multi-ethnic cohorts (Hispanic and African
Americans, Chinese and European descent) and combine them meta-analytically. Next, we will conduct similar
interaction analyses with the same five n-3 and n-6 fatty acids and low frequency/rare genetic variants, which
are likely to be of larger effect size. Genetic variants that we identity though interaction analyses as predicted
to respond to each fatty acid for CRP and IL-6 will then be combined to generate a polygenic risk score for
evaluation of association with 1) incident dementia and 2) a harmonized overall cognitive function score in a
subset of CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) cohorts with robust
cognitive outcomes. Several aspects of our design increase its rigor. First, CHARGE populations are located in
the US, Europe and Asia and provide a critical multi-ethnic platform to identify genetic sources of variability in
response to fatty acids. The multi-national, multi-ethnic aspect is essential because fatty acids profiles, dietary
patterns and genetic architecture differ by ethnicity and across the globe. Second, participating cohorts have
already measured a panel of individual, common fatty acids in the blood, providing an objectively assessed
biomarker of dietary intake and endogenous metabolism. This blood-based fatty acid measurement is valuable,
because it provides a precise measurement of essential dietary fatty acids, to improve gene-diet interaction
discovery. This research will provide critical evidence of how five common dietary fatty acids ameliorate the
genetic risk of systemic inflammatory biomarkers to reduce dementia. Findings from this multi-cohort,
interdisciplinary project will inform the design of multi-site dietary interventions to reduce systemic
inflammation, to prevent or delay AD and ADRD.

## Key facts

- **NIH application ID:** 10230534
- **Project number:** 1R56AG066808-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Caren Elizabeth Smith
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,327
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230534

## Citation

> US National Institutes of Health, RePORTER application 10230534, Circulating fatty acids, genetics of inflammation and AD-related dementia and cognitive decline (1R56AG066808-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10230534. Licensed CC0.

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