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 (APOE4, 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...