New Research Shows How Fat Transport Molecules and Genetics May Shape the Earliest Stages of Alzheimer’s Disease

A newly published scientific study is shedding important light on how the brain’s handling of fats may influence the very early development of Alzheimer’s disease. Researchers have found that specific fat-transport molecules in the blood, known as lysophosphatidylcholines (LPCs), can either increase the risk of Alzheimer’s or potentially protect against it—depending largely on a person’s genetic makeup.

The study was led by scientists from Columbia University’s Mailman School of Public Health and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, with key collaborators working in the Dominican Republic. Their findings were published in the peer-reviewed journal Nature Aging, marking one of the most detailed investigations so far into how lipid metabolism, genetics, and modern blood biomarkers intersect in Alzheimer’s disease.

What Are LPCs and Why Do They Matter?

Lysophosphatidylcholines are molecules that play a crucial role in transporting healthy fatty acids—including omega-3 fats—from the bloodstream into the brain. These fats are essential for normal brain function. They help reduce inflammation, support neuron survival, and maintain cognitive abilities such as memory and learning.

For years, scientists have suspected that disruptions in fat metabolism might be involved in Alzheimer’s. More than a century ago, Alois Alzheimer himself observed abnormal fat deposits in the brains of dementia patients. This new study builds on that long-standing observation by identifying specific blood-based fat molecules that appear to reflect early brain changes long before symptoms appear.

The Role of the APOE ε4 Gene

A central finding of the study involves the APOE ε4 gene, which is the strongest known genetic risk factor for late-onset Alzheimer’s disease. About 25 percent of Americans carry at least one copy of this gene, yet more than half of all Alzheimer’s patients are carriers.

The researchers found that LPCs behave very differently depending on whether someone carries the APOE ε4 gene:

• In APOE ε4 carriers, certain LPCs were associated with a higher risk of Alzheimer’s disease.
• In people without the APOE ε4 gene, those same LPCs appeared to have a protective effect.

This gene-dependent switch is one of the most striking aspects of the research. It suggests that fats that are beneficial for one group of people could potentially be harmful for another, depending on genetics.

How the Study Was Conducted

To reach these conclusions, the researchers used a powerful approach called untargeted metabolomics. This method allows scientists to measure and analyze thousands of small molecules in blood and tissue samples without preselecting which molecules to study. In other words, it casts a very wide net.

The analysis included samples from 1,068 participants, divided into 250 people with Alzheimer’s disease and 818 healthy controls. Data came from three major sources:

• The EFIGA cohort, consisting of Caribbean Hispanic participants recruited in the Dominican Republic
• The WHICAP cohort, which includes a multi-ethnic population from Washington Heights and Inwood in New York City
• The ROSMAP study, which provided post-mortem brain tissue samples for validation

This combination allowed the researchers to examine both blood-based markers and actual brain tissue, strengthening the reliability of their findings.

Why Blood Biomarkers Made a Big Difference

One of the most important aspects of the study is that the LPC connection to Alzheimer’s only appeared clearly when the disease diagnosis was confirmed using modern blood biomarkers.

Specifically, the researchers used blood tests for pTau217 and pTau181, which are biomarkers linked to tau protein abnormalities in the brain—one of the hallmarks of Alzheimer’s disease. The relationship between LPCs and Alzheimer’s was not seen in patients whose diagnosis was based only on symptoms and not confirmed by these blood tests.

This distinction is critical. It suggests that some people diagnosed with Alzheimer’s based on symptoms alone may actually have other forms of dementia, which could explain why many Alzheimer’s drug trials have failed in the past.

Notably, the FDA approved a pTau217 blood test for clinical use in May, making this approach increasingly relevant for real-world diagnosis and research.

What Else the Researchers Found

Beyond LPCs, the study identified several other metabolic changes associated with Alzheimer’s disease:

• Tryptophan metabolites, linked to the production of serotonin and melatonin
• Tyrosine-related compounds, which are involved in producing neurotransmitters like dopamine and norepinephrine

Previous research has shown that tyrosine supplementation can improve memory and cognitive function in healthy individuals, making these findings particularly interesting.

The researchers also confirmed that LPCs carrying omega-3 fatty acids, such as DHA and EPA, were closely related to levels of these fats in the brain, reinforcing the idea that LPCs act as critical transport vehicles.

Why This Matters for Future Treatments

The study’s findings open the door to personalized approaches to Alzheimer’s prevention and treatment. Instead of a one-size-fits-all strategy, future therapies might:

• Target the LPC transport system directly
• Be customized based on APOE ε4 genetic status
• Focus on early detection, decades before symptoms appear

This approach could help explain why treatments targeting symptoms alone may be too late to alter the disease’s underlying biology.

Ongoing and Future Research

The research team is now working to answer several important follow-up questions:

• When exactly during disease progression do LPC changes begin?
• What molecular differences exist between people who test positive or negative for pTau biomarkers, despite having similar clinical diagnoses?
• How do environmental exposures and epigenetic factors interact with fat metabolism and Alzheimer’s risk?

To explore these questions, the researchers are expanding their metabolomics work to include a wider range of environmental chemicals and repeated samples collected over time from the same individuals.

A Step Toward Earlier Detection

Overall, this study provides some of the strongest evidence yet that fat transport breakdown in the brain is an early and measurable event in Alzheimer’s disease. By identifying blood-based metabolic signals linked to genetics and confirmed disease biology, scientists are moving closer to detecting Alzheimer’s years or even decades before symptoms appear.

While this research does not mean people should start taking supplements on their own, it does highlight the importance of understanding how genes, fats, and brain health are deeply interconnected—and how precision medicine could change the future of Alzheimer’s care.

Research paper:
https://www.nature.com/articles/s43587-025-01025-7