In a small set of brain tissue drawn from a decades-long study of aging minds, researchers at MIT found a quiet fault line running through a rare gene. Carriers of certain variants in ABCA7, a protein that ferries fats across cell membranes, face roughly double the odds of Alzheimer's, and the lab work now suggests that when this ferrying falters, neurons struggle to manage their fats, their energy, and their stress. The discovery sits among a larger human effort to understand how the brain's chemistry frays with age, and in cultured cells and organoids the researchers saw that restoring a mol
Rare ABCA7 Gene Variants Linked to Alzheimer's Risk Through Disrupted Lipid Metabolism
A variant once thought harmless showed the same lipid changes
Mark
What's the central finding here?
Mimi
That losing ABCA7 function disturbs how neurons handle a membrane lipid called phosphatidylcholine, and that sets off stress, hyperexcitability and extra amyloid beta.
Mark
And the choline part?
Mimi
Treating the cells with CDP-choline, a precursor, restored mitochondrial membrane potential, cut oxidative stress, and brought amyloid levels in organoids back to normal.
Luke
Before anyone reaches for supplements, how much is that worth? This was cells and organoids.
Mimi
Fair. Nothing here shows it works in people with ABCA7 variants.
Mark
Tsai does say supplements may help many people reduce risk.
Luke
That's her view, and it leans on her APOE4 work in mice. The trial underway is in APOE4 carriers, not ABCA7 carriers.
Mark
How solid is the patient-tissue side?
Luke
Thin in numbers: 12 carriers out of about 1,200 samples. It's a start, not a large cohort.
Mimi
Though the stem-cell neurons echoed those gene changes, which strengthens the link.
Mark
And the 18% common variant?
Luke
Von Maydell herself says more work is needed. It's a suggestion, not a finding about risk.
Le Pouls
- Rare ABCA7 variants, carried by a very small share of people, roughly double the odds of Alzheimer's, creating urgency around a gene few had examined closely.
- Inside neurons, the faulty protein disrupts phosphatidylcholine metabolism, stiffening membranes and letting mitochondria falter as oxidative stress rises.
- Amyloid beta accumulates and neurons grow hyperexcitable in lab models, pressing researchers to find a way to interrupt the cascade.
- CDP-choline restored membrane potential, eased oxidative stress, and normalized amyloid levels in cells and organoids, while a clinical trial in APOE4 carriers is now underway.
- A more common ABCA7 variant, once thought harmless, shows similar lipid disruptions, hinting the concern may extend to a far larger population than the rare carriers.
In a small set of brain tissue drawn from a decades-long study of aging minds, researchers at MIT found a quiet fault line running through a rare gene. Carriers of certain variants in ABCA7, a protein that ferries fats across cell membranes, face roughly double the odds of Alzheimer's, and the lab work now suggests that when this ferrying falters, neurons struggle to manage their fats, their energy, and their stress. The discovery sits among a larger human effort to understand how the brain's chemistry frays with age, and in cultured cells and organoids the researchers saw that restoring a molecule called choline could mend some of the damage. Whether that mending will reach people remains an open question, as the work so far lives in tissue, dishes, and small clusters of grown neurons.
The study began with a modest collection of brain tissue from the Religious Orders Study and Memory and Aging Project, which has tracked older adults since 1994. Of roughly 1,200 samples with genetic data, only 12 carried a rare variant of ABCA7. That scarcity mattered less than what the variant did: people whose ABCA7 produces less working protein face about double the risk of Alzheimer's, and the gene's job of moving lipids across membranes overlaps with the territory of APOE4, the more common risk factor that Li-Huei Tsai's lab has studied for years.
Led by graduate student Djuna von Maydell and senior author Tsai at MIT's Picower Institute, the team sequenced single cells from the carriers and found the strongest shifts in genes governing lipid metabolism, DNA damage, and cellular energy production. Neurons engineered with the variants reproduced those changes. Their mitochondrial safety valve grew sluggish, free radicals built up, and phosphatidylcholine metabolism went awry, leaving membranes stiff and mitochondria struggling.
When the researchers gave these neurons CDP-choline, a precursor to phosphatidylcholine, the cells began rebuilding the molecule, their mitochondria recovered, and oxidative stress eased. In three-dimensional organoids, amyloid beta levels and hyperexcitability returned toward normal. Tsai sees this as part of a pattern, since her earlier work showed similar effects against APOE4 in mice, and she is now collaborating on a human trial of choline supplements in APOE4 carriers. Choline occurs naturally in eggs, meat, fish, and some beans and nuts.
The story may extend further. A more common ABCA7 variant, carried by about 18 percent of people, appeared to share many of the same lipid disruptions. Von Maydell cautions that more work is needed, and that all these results so far come from tissue, cultured cells, and organoids rather than people with the variants.
The starting point for this study was a small set of brain tissue samples. Researchers at MIT drew them from the Religious Orders Study/Memory and Aging Project, known as ROSMAP, which has followed memory, motor function and other age-related changes in older people since 1994. About 1,200 samples in that dataset came with genetic information. Only 12 came from people who carried a rare variant of a gene called ABCA7.
Those variants matter. Genomic studies of Alzheimer's patients have found that people whose ABCA7 variants produce reduced levels of working ABCA7 protein have roughly double the odds of developing the disease compared with people who lack them. The variants are found in a very small share of the population. The gene encodes a protein that moves lipids across cell membranes, and lipid metabolism is also the main target of APOE4, a more common Alzheimer's risk factor. Li-Huei Tsai's lab has previously shown that APOE4, found in about half of all Alzheimer's patients, impairs brain cells' ability to metabolize lipids and respond to stress.
The new paper, published in Nature, was led by MIT graduate student Djuna von Maydell. Tsai, who directs MIT's Picower Institute for Learning and Memory and is the Picower Professor in the Department of Brain and Cognitive Sciences, is senior author. The team ran single-cell RNA sequencing on neurons from the 12 carriers to see which other genes shift when ABCA7 function is lost. The most strongly affected genes grouped into three clusters: lipid metabolism, DNA damage, and oxidative phosphorylation, the process cells use to capture energy as ATP.
To probe the effects further, the researchers introduced ABCA7 variants into neurons derived from induced pluripotent stem cells. Those cells showed many of the same gene expression changes seen in the patient samples, especially among oxidative phosphorylation genes. The mitochondrial "safety valve" that normally limits excess buildup of electrical charge was less active, which can lead to oxidative stress, a state in which damaging free radicals accumulate. The engineered cells also showed altered metabolism of phosphatidylcholine, a molecule that may lead to stiffer membranes and could explain why the mitochondrial membranes failed to work normally.
That pointed to a test. The team treated neurons carrying ABCA7 mutations with CDP-choline, a precursor of phosphatidylcholine. The cells began making new phosphatidylcholine, in both saturated and unsaturated forms, their mitochondrial membrane potentials returned to normal, and oxidative stress fell. Three-dimensional organoids built from variant-carrying neurons developed higher levels of amyloid beta, the protein that forms plaques in Alzheimer's brains. Those levels returned to normal with CDP-choline, and the treatment also reduced the neurons' hyperexcitability. Von Maydell said the team found "pretty strikingly" that many transcriptional defects reversed with choline.
This fits a pattern in Tsai's earlier work. A 2021 paper from her lab found that CDP-choline reversed many effects of APOE4 in mice. She is now working with researchers at the University of Texas and MD Anderson Cancer Center on a clinical trial of how choline supplements affect people who carry APOE4. Choline occurs naturally in eggs, meat, fish, and some beans and nuts. Tsai says boosting intake with supplements may offer many people a way to reduce their risk, and describes her lab's findings as showing that disrupted lipid homeostasis leads to Alzheimer's-related pathology and that restoring it can ease those effects.
The work may also reach beyond rare carriers. A more common ABCA7 variant, present in about 18% of the population, was thought to be harmless. The MIT team found that cells with it showed many of the same lipid metabolism alterations as cells with the rare variants. Von Maydell said more work is needed, but it suggests ABCA7 dysfunction could matter for a much larger part of the population. The results so far come from patient tissue, cultured cells and organoids; the human trial under way concerns APOE4 carriers, not ABCA7.
Citations marquantes
This suggests ABCA7 dysfunction might play an important role in a much larger part of the population than just people who carry the rare variants.— Djuna von Maydell, MIT graduate student and lead author
Restoring lipid homeostasis, such as through choline supplementation, can ameliorate these pathological phenotypes.— Li-Huei Tsai, senior author, MIT
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