New Window on Leading Genetic Cause of Alzheimer’s

Researchers found that the particles in our nervous system, molecular cousins of the well-known HDL, or “good cholesterol” particles in our bloodstream, are much more diverse than previously thought. Researchers detected more than 300 different proteins associated with the particles, far more than the 16 known previously, that fall into at least 10 different families. These particles are rich in proteins that affect wound healing, the immune response, and the creation and nurturing of brain cells called neurons that are important for cognitive function.

The most common protein on the particles is apolipoprotein E, better known as APOE. Of the three commonly studied forms of APOE, the form known as APOE4 puts people at higher risk of Alzheimer’s disease. One copy of the APOE4 gene makes a person approximately four times as likely to develop dementia; a person with two copies is about 12 times more vulnerable.

“We’ve known for a long time that in the nervous system, APOE is the primary protein on these particles calling the shots. But we don’t know much more beyond that. Our technology opens the door to learning more,” said the leader of the study, John Melchior.

“What the heck is APOE4 doing? That’s the big question. Why does one form translate to less risk for dementia while a slightly different form confers significant risk? Our technology brings us one step toward more answers,” he added.

Lipoproteins in the nervous system are much smaller, present at less than 1 percent of the concentration in blood. Their actions, even their presence, in the nervous system have been a mystery. 

On the particles in the central nervous system, APOE reigns supreme, serving as a scaffold to hold lipids and other proteins together. The proteins are specialized tools that can do things like repair cells, turn genes on or off, or regulate amyloid beta processing, a well-known molecule related to the development of dementia. The work suggests that APOE may bring these tools together on different particles to deliver them where needed.

But something is more likely to go wrong in people with one or two copies of APOE4, leading to dementia. Scientists don’t know what.

Scientists suspect APOE4 of playing a role in other neurologic conditions such as Parkinson’s and Huntington’s diseases, multiple sclerosis, amyotrophic lateral sclerosis and even traumatic brain injury.

Because lipoproteins are less common in the nervous system, researchers either need an impossibly large amount of the cerebrospinal fluid to study them — or scientists develop a new way to detect the rare molecules. That’s what Melchior’s team did, creating a new fluorescent technology to tag lipoproteins in spinal fluid.

The team studied just one-third of a milliliter of spinal fluid — much less fluid than in a raindrop — and discovered 303 different proteins across the particle families using mass spectrometry. Most had never been detected on these particles in the nervous system before.

“Now comes the fun part,” said Melchior. “We want to open up our technology to clinicians to learn more about what’s happening in Alzheimer’s disease and possibly other conditions like multiple sclerosis and Parkinson’s disease.


Nathaniel J. Merrill, W. Sean Davidson, Yi He, Ivo Díaz Ludovico, Snigdha Sarkar, Madelyn R. Berger, Jason E. McDermott, Linda J. Van Eldik, Donna M. Wilcock, Matthew E. Monroe, Jennifer E. Kyle, Kimberley D. Bruce, Jay W. Heinecke, Tomas Vaisar, Jacob Raber, Joseph F. Quinn, John T. Melchior. Human cerebrospinal fluid contains diverse lipoprotein subspecies enriched in proteins implicated in central nervous system health. Science Advances, 2023; 9 (35) DOI: 10.1126/sciadv.adi5571

DOE/Pacific Northwest National Laboratory. “New window on leading genetic cause of Alzheimer’s.” ScienceDaily. ScienceDaily, 12 September 2023. <>.

Materials provided by DOE/Pacific Northwest National Laboratory. Original written by Tom Rickey. Note: Content may be edited for style and length.

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Photo by Randy Fath