Research Highlights

The USC Center for Personalized Brain Health’s pursuit of end-to-end disease impact begins with basic and clinical research. Ongoing, dedicated research in the lab drives critical insights and understanding about the mechanisms of Alzheimer’s Disease and the role of modifiable and non-modifiable risk factors in disease progression and intervention.

We invite you to explore examples of our work below.  Please visit yassinelab.org for additional information about our research or or sign up for our newsletter to stay current with our work.

Development of potent, selective cPLA2 inhibitors for targeting neuroinflammation in Alzheimer’s disease and other neurodegenerative disorders

Chronic neuroinflammation plays a key role in the progression of Alzheimer’s disease (AD), and the cytosolic calcium-dependent phospholipase A₂ (cPLA₂) enzyme is a critical mediator of inflammatory lipid signaling pathways. We investigated the therapeutic potential of novel cPLA₂ inhibitors in modulating neuroinflammation in AD. In vivo studies revealed favorable brain-to-plasma ratios, highlighting the ability of BRI-50460 to penetrate the central nervous system, modulating neuroinflammatory pathways, and restoring lipid homeostasis. Our results support that small molecule inhibitors of cPLA₂ can modulate the downstream inflammatory signaling, offering a promising therapeutic strategy for neurodegenerative diseases.

Associations of APOE ε4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness

The aim of this study was to  identify the effect of APOE ε4 and DHA lipid species on the entorhinal cortex (EC). EC refers to a part of the brain that is affected early in Alzheimer’s disease (AD) and is rich in DHA. In the study, plasma and cerebrospinal fluid (CSF) were analyzed for lipid content. Findings demonstrated that there is an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species, with APOE having the strongest effect on DHA-containing triglycerides. 

Nutritional metabolism and cerebral bioenergetics in Alzheimer’s disease and related dementias

If the brain is unable to meet its energy demands, the risk for synaptic loss, neurodegeneration and cognitive decline may increase. This study suggests that nutritional and metabolic interventions may help treat and prevent AD. The study specifically investigates the mechanisms of cerebral bioenergetic breakdown and the consequences of disturbed bioenergetics. Novel therapeutic nutrition approaches integrating studies of the gut microbiome, neuroimaging and other biomarkers are provided. 

Can the gut microbiome inform the effects of omega-3 fatty acid supplementation trials on cognition? 

The purpose of this review was to determine whether the gut microbiome can help elucidate the inconsistent findings regarding omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation. The study concluded that a high-saturated-fat Western diet, obesity and lack of exercise can strain the gut microbiome. By contrast, a plant-based diet yielded beneficial effects even when deficient in n-3 PUFAs. It was concluded that the composition of the gut microbiome can help define the effects of n-3 PUFA supplementation on the brain and increase personalized nutritional interventions. 

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease 

This study highlights a current public health issue: type 2 diabetes mellitus (T2DM). T2DM is common and increasing in prevalence worldwide, leading to serious consequences. Recent data support the presence of brain insulin resistance (BIR) in the aging brain and found that BIR may contribute to AD and cognitive impairment. The review highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia. 

Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers

While observational studies have associated ω-3 intake, including DHA, with a reduced risk for incident AD, randomized clinical trials have yielded mixed and inconsistent results. This literature review incorporated various study results in order to understand these mixed results. It was concluded that high-dose DHA supplementation in APOE ε4 carriers before the onset of AD can be a promising approach to decrease the incidence of AD. Considering the safety profile, availability and affordability of DHA supplements, researchers suggest that refining an ω-3 intervention in APOE ε4 carriers is warranted.