# Optimizing CNS DHA delivery in elderly adults at risk for dementia

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $784,995

## Abstract

ABSTRACT
There exists an urgent need to develop and evaluate early interventions to mitigate neurodegenerative
processes in aging adults at increased risk for Alzheimer’s disease (AD), including those with subjective
cognitive decline (SCD). Prospective longitudinal evidence indicates that greater habitual fish consumption by
pre-symptomatic elderly adults is associated with a significant reduction in risk for developing dementia. Fish is
a primary dietary source of the omega-3 fatty acid docosahexaenoic acid (DHA) which is concentrated in the
mammalian brain and is significantly lower in cerebrospinal fluid (CSF) and postmortem brains of AD patients.
Preclinical evidence indicates that correcting age-related reductions in brain DHA levels is ‘sufficient’ to
promote neurotrophic signaling and mitigate degenerative processes including Aβ deposition in aged rodents
and AD mouse models. However, attempts to translate these promising findings in aging adults at risk for AD
using processed fish ‘oils’ that exclusively supply triglyceride-esterified DHA (TAG-DHA) have proven
unsuccessful. Importantly, recent evidence indicates that TAG-DHA has limited passage across the blood-
brain barrier (BBB) compared with DHA obtained from fish, which is also esterified to phosphatidylcholine (PC-
DHA). More specifically, DHA esterified to lysophosphatidylcholine (LPC-DHA), a biosynthetic product of PC-
DHA, is preferentially transported across the BBB by a recently discovered transporter MFSD2A. Critically,
LPC-DHA, but not TAG-DHA, supplementation increases brain DHA levels in rodents and AD mouse models,
increases neurotrophic signaling (BDNF), enhances memory performance, and has robust neuroprotective
effects. While these findings suggest that LPC-DHA is more effective than TAG-DHA for increasing central
DHA levels and mitigating neurodegenerative processes, the effects of LPC-DHA on central DHA delivery has
never been investigated in human subjects. The recent availability of capsules enriched with preformed LPC-
DHA provides a novel opportunity to address this gap. We propose to conduct the first proof-of-concept
randomized, double-blind, placebo-controlled trial to compare the effects of LPC-DHA and TAG-DHA
supplementation on CSF DHA levels, and to investigate effects on neurodegenerative (p-tau217 & Aβ42) and
neurotrophic (BDNF) biomarker levels, in elderly adults with SCD. In addition, we will investigate associations
with executive functioning and episodic memory performance, and the potential moderating effects of relevant
genetic variants (APOE4, MFSD2A, BDNF). Our primary HYPOTHESIS is that LPC-DHA supplementation will
be more effective than TAG-DHA for increasing CSF DHA levels in elderly adults with SCD. We additionally
hypothesize that LPC-DHA will be more effective than TAG-DHA for increasing CSF and blood BDNF levels
and decreasing the p-tau217/Aβ42 ratio. Results of this study are anticipated to provide a strong empirical
foundation to support...

## Key facts

- **NIH application ID:** 10979987
- **Project number:** 1R01AG084834-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** ROBERT KRIKORIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $784,995
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979987

## Citation

> US National Institutes of Health, RePORTER application 10979987, Optimizing CNS DHA delivery in elderly adults at risk for dementia (1R01AG084834-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10979987. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*