Research finds lysophosphatidylcholines either promote or protect against disease depending on APOE ε4 gene status, with implications for personalized treatments.
New research reveals that compounds responsible for transporting fatty acids to the brain either increase or decrease Alzheimer’s disease risk depending on a person’s genetic makeup, potentially opening pathways for personalized treatment approaches.
The study, published in Nature Aging, examined lysophosphatidylcholines (LPCs) across three diverse patient cohorts totaling 1,068 participants, including 250 Alzheimer’s patients and 818 healthy controls. Researchers from Columbia University Mailman School of Public Health and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain led the work with collaborators in the Dominican Republic.
“How the brain transports and uses healthy fats is a key early event in Alzheimer’s, but whether these fats are good or bad for you depends on your genes. This finding, which is consistent across three diverse cohorts, opens up exciting new possibilities for early detection and personalized treatments,” says first author Vrinda Kalia, PhD, associate research scientist in environmental health sciences at Columbia Mailman School, in a release.
Genetic Variation Determines LPC Effects
The research team discovered that in people carrying the APOE ε4 gene—a known Alzheimer’s risk factor present in approximately 25% of Americans—certain LPCs appear harmful and increase disease risk. However, in people without this gene variant, the same LPCs seem protective against the disease.
More than half of reported Alzheimer’s patients carry at least one copy of the APOE ε4 gene, making this genetic distinction particularly relevant for potential therapeutic development. The findings suggest future treatments could include supplements formulated with LPCs and omega-3 fatty acids tailored to individual genetic profiles.
The researchers used untargeted metabolomics to analyze biosamples from three data sources: the EFIGA cohort of Caribbean Hispanic participants from the Dominican Republic, the WHICAP cohort of multi-ethnic participants from Washington Heights and Inwood, and the ROSMAP post-mortem brain tissue collection.
Blood Test Confirmation Critical for LPC Association
A notable aspect of the findings involved the method of Alzheimer’s diagnosis. The LPC relationship appeared only in patients whose Alzheimer’s diagnosis was confirmed using blood tests for pTau217 and pTau181 biomarkers. The association was not observed in patients with symptoms-based diagnoses unconfirmed by blood testing.
“Our findings support the value of the pTau biomarker test since we only saw the LPC connection in Alzheimer’s patients whose diagnosis was confirmed with the test. Patients whose diagnosis was unconfirmed likely have another non-Alzheimer’s variety of dementia,” says study co-author Gary Miller, PhD, professor of environmental health sciences and director of the Center for Innovative Exposomics at Columbia Mailman School, in a release.
The US Food and Drug Administration cleared a pTau217 blood test for clinical use in May, adding clinical relevance to these research findings.
Historical Context and Future Applications
The research builds on observations dating back more than a century. “Over a century ago, Alois Alzheimer observed unusual fat deposits in the brains of dementia patients. We’ve now found the early warning system: blood metabolites that reveal this fat transport breakdown decades before symptoms appear,” says senior author Badri N. Vardarajan, PhD, associate professor of neurological science at Columbia University Vagelos College of Physicians and Surgeons, in a release.
Beyond LPCs, the study identified other compounds linked to Alzheimer’s, including metabolites of tryptophan and tyrosine. Tryptophan helps produce serotonin and melatonin, while tyrosine serves as a building block for neurotransmitters including dopamine and norepinephrine.
The research team is continuing work to determine when exactly during disease progression LPCs begin playing a role in disease onset. They are also examining molecular differences between study participants with clinical Alzheimer’s diagnoses who tested negative versus positive for pTau217, expanding their analysis to include environmental chemicals and epigenetic factors.
The research received support from the National Institute on Aging and National Institutes of Health through multiple grants. The authors reported no conflicts of interest.
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