The biggest risk factor in the development of Alzheimer’s disease (AD) is one that can’t be controlled: the act of aging itself. But there are other risk factors that lay the groundwork for the disease earlier in life that can be changed — like obesity during midlife. The presence of obesity in middle age can mean up to a 74 percent increased risk of developing dementia, clearly signaling a key relationship between excess adipose tissue and neurodegeneration in the brain. Yet, the biological mechanisms linking the two have remained a mystery.
Now, researchers led by Stephen Wong of the Houston Methodist Academic Institute and Weill Cornell Medicine revealed an answer. The team found that a lipid molecule called phosphatidylethanolamine (PE) travels into the brain and disrupts cell membrane dynamics and lipid homeostasis, and wreaks havoc on neuroimmune communication. These changes to the structural environment create direct consequences — like increased amyloidogenic processing in excitatory neurons — that encourages AD progression.
“One of the most surprising findings was how broadly a single lipid class could influence communication among distinct brain cell types,” Wong told DDN. “We initially thought PE might affect metabolism in a more limited or indirect way. Instead, the data suggested that excess PE can reshape the membrane system itself, altering the structural environment in which immune and neuronal signaling occurs.”
The new work was published in Molecular Neurodegeneration in collaboration with Xianlin Han at the University of Texas at San Antonio, Willa Hsueh at The Ohio State University, Weiming Xia at Boston University, and key Wong lab members, Li Yang and Jianting Sheng.
Because obesity is modifiable, Wong emphasized that studying the lipid-mediated pathways that influence brain health could be important in identifying earlier timepoints to intervene and prevent disease. “Our hope is that defining this PE-driven adipose–brain–neuroimmune axis will help open new strategies to delay or reduce Alzheimer’s progression in metabolically at-risk populations,” he said.
Restoring lipid homeostasis to heal the brain
Wong’s team made their integral discovery about PE using integrative lipidomics, single-nucleus RNA sequencing, proteomics, high-resolution imaging, extracellular vesicle models, and mouse models of AD. Their work showed that excess PE in the brain has many detrimental effects, including the accumulation of ectopic lipid droplets, impaired microglial identity and signaling that affects the communication between neurons and microglia, T-cell functional exhaustion, and altered membrane organization that leads to increased amyloidogenic processing in excitatory neurons.
Fortunately, the team also showed that these processes can be ameliorated using a drug compound, ebselen, known to have glutathione peroxidase (GPx) mimetic antioxidant activity. In this study, however, the team uncovered a previously unrecognized mechanism: Ebselen appears to restore PE lipid homeostasis, improve neuroimmune function, and reduce AD-related pathology, in part through regulation of PE metabolism rather than only through general antioxidant effects. To identify ebselen, they performed in silico screening of more than 2,400 compounds and tested candidates into 96-well human neuron-based AD assays and specifically looked to see whether any could normalize PE homeostasis.
Treating AD mouse models with ebselen resulted in the successful restoration of PE homeostasis in the brain and neuroimmune function, decreased lipid dysregulation, and boosted cognitive performance.
Our hope is that defining this PE-driven adipose–brain–neuroimmune axis will help open new strategies to delay or reduce Alzheimer’s progression in metabolically at-risk populations.
—Stephen Wong, Houston Methodist Academic Institute and Weill Cornell Medicine
“In mice, the results were encouraging,” said Wong. “Based on our current data, it is still too early to say whether ebselen itself could be used as a standalone preventive treatment for Alzheimer’s disease in people with obesity. What our study provides is preclinical evidence that restoring lipid homeostasis may be an important therapeutic direction for this high-risk population.”
A novel precision medicine approach
From a drug discovery standpoint, Wong said their new study shows that “metabolic balance, especially lipid homeostasis, should not be treated only as a downstream readout. It should become a design principle for therapeutic discovery.” The researchers are actively incorporating metabolic homeostasis into their AI-guided prediction framework as a result.
The new work also shines a light on the potential need for treatments that target the restoration of lipid homeostasis as a precision medicine approach for individuals at high risk of AD due to obesity. This could include medications like ebselen that target lipid homeostasis, GLP-1 receptor agonists already used for weight loss and diabetes, or a combination of both. While the recent results from Novo Nordisk’s Phase 3 trial testing semaglutide in the treatment of AD were disappointing, the new work suggests that the real benefit of GLP-1s could be in earlier treatment in midlife — and perhaps only for individuals who are metabolically vulnerable.
“Rather than treating Alzheimer’s disease as a one-size-fits-all condition, our findings suggest that tailoring treatment to metabolic status could potentially lead to better outcomes,” said Wong.
Wong also went a step further to suggest that the field of AD research needs to look beyond the brain. “Our findings suggest that Alzheimer’s disease should not be viewed only as a brain-intrinsic disorder,” he said. “We hope this work shifts part of the Alzheimer’s field toward recognizing that brain health and systemic metabolism are deeply interconnected.”
