Lysophosphatidylcholines show gene-dependent effects in early Alzheimer’s disease

A new study presents robust evidence on the role of lysophosphatidylcholines (LPCs) in the onset of Alzheimer's disease. Researchers discovered that LPCs-compounds that transport a variety of healthy fatty acids to the brain-either promote Alzheimer's or protect against it, depending on a person's genetics. Researchers at Columbia University Mailman School of Public Health and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia's College of Physicians and Surgeons led the study with collaborators in the Dominican Republic. Their findings are published in the journal Nature Aging.

Fat transport molecules interact with Alzheimer's gene

In people with the APOE ε4 gene, a known risk factor for Alzheimer's, certain LPCs appear to be harmful and increase the risk of disease. In people without the gene, these same LPCs seem to be protective. As many as a quarter of all Americans carry at least one copy of the APOE-e4 gene, but more than half of reported Alzheimer's disease patients are carriers of the gene. The new findings could help tailor future treatments, potentially including supplements formulated with LPCs and omega-3 fatty acids. Omega-3s are critical to the health function of the brain and help reduce inflammation in the brain, promote neuron survival, and support cognitive functions like memory and learning.

"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'21, MPH'15, associate research scientist in environmental health sciences at Columbia Mailman School.

The researchers performed untargeted metabolomics, a technique that casts a wide net to uncover patterns of molecular metabolites-to analyze biosamples collected from three data sources and a total of 1,068 participants, including 250 Alzheimer's patients and 818 healthy controls: (1) the EFIGA cohort of Caribbean Hispanic participants recruited in the Dominican Republic; (2) the WHICAP cohort of multi-ethnic participants recruited in Washington Heights and Inwood; and (3) the ROSMAP post-mortem brain tissue collection.

Evidence identifies early changes in Alzheimer's disease pathology using pTau blood tests

In their analysis of thousands of molecules, researchers discovered strong evidence for LPCs in early-stage Alzheimer's across the two cohorts-but notably only in patients whose Alzheimer's diagnosis was confirmed using blood tests for the pTau217 and pTau181 biomarkers. The relationship was not seen in patients with a symptoms-based diagnosis that was unconfirmed with the blood tests. (The FDA approved a pTau217 blood test for clinical use in May.)

"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. "One possible reason so many Alzheimer's drug trials have so far been unsuccessful is that they target the onset of clinical symptoms, which might be too late to alter neurodegeneration pathology that starts decades earlier."

"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. By targeting the lysophosphatidylcholine transport system that ferries protective fats into the brain and tailoring interventions to APOE ε4 genetic status, we could prevent or treat the disease, translating his discovery into preventive therapy," says the study's senior author, Badri N. Vardarajan, PhD, associate professor of neurological science (in Neurology and the Gertrude H. Sergievsky Center and the Taub Institute) at Columbia University Irving Medical Center (CUIMC).

The new paper identifies several other compounds linked to Alzheimer's, including metabolites of tryptophan, an essential amino acid that helps produce serotonin and melatonin, and tyrosine, a building block for proteins used to produce several important chemicals, including neurotransmitters like dopamine and norepinephrine (the paper cites research in healthy people which found that administering tyrosine orally can enhance memory and cognitive function).

The researchers also cite previous research on the protective and neurotoxic effects of LPCs and their potential to be a biomarker for Alzheimer's.

Future research directions

Ongoing research by the team aims to shed light on when exactly, during the progression of the disease, LPCs begin to play a role in disease onset. Separately, they are looking to uncover molecular differences in study participants with a clinical Alzheimer's diagnosis who tested negative for pTau217 from those who tested positive. To do this, they are examining a greater number of samples, including those taken at different time points from the same patients. They are also expanding their metabolomics analysis to include more environmental chemicals and measuring levels of molecules that determine how various genes function (epigenetics).

Additional study authors include Dolly Reyes-Dumeyer, Saurabh Dubey, Hanisha Udhani, Renu Nandakumar, Annie J. Lee, Diones Rivera, Lawrence S. Honig, and Richard Mayeux at CUIMC; Rafael Lantigua at Pontificia Universidad Católica Madre y Maestra in the Dominican Republic; and Martin Medrano at CEDIMAT hospital in the Dominican Republic.

Support for the research was provided by the National Institute on Aging (NIA) and by the National Institutes of Health (NIH) (grants AG063908, AG067501, AG015473). WHICAP is funded by the NIA and NIH (AG072474, AG066107). ROSMAP is supported by the NIH (AG10161, AG72975, AG15819, AG17917, AG46152, AG61356). The metabolomics core that generated the metabolomics data for the project is supported by the National Center for Advancing Translational Sciences grant (5UL1TR001873).