How an ABCA7 Gene Deletion Affects Lipid Metabolism in Alzheimer’s Disease
A rare, ancestry‑specific deletion in the ABCA7 gene alters lipid handling and mitochondrial function in neurons, offering new insight into Alzheimer’s disease risk.
Alzheimer’s disease is often explained by the buildup of amyloid plaques and tau tangles in the brain. But long before those changes appear, more basic problems can begin inside brain cells. Two of the most important involve disruptions in lipid regulation and impairments in cellular energy production.
A new study by John P. Hussman Institute for Human Genomics researchers sheds light on those early changes. The research shows how a specific genetic deletion in the ABCA7 gene disrupts lipid metabolism and impairs mitochondrial function in neurons. These two processes are increasingly linked to Alzheimer’s disease risk.
The research team included:
• Juan Young, Ph.D., associate professor in the Dr. John T Macdonald Foundation Department of Human Genetics
• Jeffery Vance, M.D., Ph.D., founding chair of the Dr. John T. Macdonald Foundation Department of Human Genetics
• YounJi Nam, Ph.D., a Hussman Institute assistant scientist
• Margaret Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Professor of Human Genetics
ABCA7 encodes a transporter involved in lipid homeostasis, and certain ABCA7 variants are associated with increased Alzheimer’s disease risk.
It is a 44‑base‑pair deletion (rs142076058) identified as a strong Alzheimer’s disease risk factor in African ancestry populations; it is predicted to produce a truncated ABCA7 protein.
Neurons carrying the deletion—especially homozygous deletion neurons—showed increased lipid droplet accumulation after lipid stress and reduced mitochondrial membrane potential.
Lipid droplets reflect how cells store and manage lipids, and abnormal accumulation can indicate disrupted lipid handling that may contribute to neuronal stress and downstream neurodegenerative processes by promoting neuroinflammation and altering apoE (apolipoprotein E) lipidation, a key genetic modifier in Alzheimer’s disease.
The African-specific ABCA7 44-bp deletion appears to increase Alzheimer’s disease risk by disrupting lipid and mitochondrial homeostasis in neurons, providing a clearer mechanistic link between this ancestry-specific genetic variant and disease biology.
Why ABCA7 is an Important Alzheimer’s Risk Gene
ABCA7 helps cells transport and regulate lipids, which are essential for healthy brain function. The study focuses on a 44‑base‑pair deletion in the ABCA7 gene that is found primarily in individuals of African ancestry and is rare or absent in people of European ancestry.
“The 44‑bp ABCA7 deletion is enriched in African‑American populations but rare or absent in non‑Hispanic White populations,” said Dr. Pericak-Vance. “This deletion confers a substantially increased risk for Alzheimer’s disease. Studying this variant is critical for understanding Alzheimer’s disease risk in African ancestry populations and uncovering mechanisms that may not be apparent in populations lacking this deletion.”
Despite the strong genetic link, scientists have not fully understood how this deletion affects cells.
A Key Discovery: The Shortened Protein Remains Stable in Cells
Many genetic deletions produce unstable proteins that are rapidly degraded. In this study, however, the researchers observed an unexpected outcome. The African-specific 44-bp deletion in ABCA7 produces a shortened protein that remains stable and reaches the same cellular locations as the full-length ABCA7 protein.
“Unlike most nonsense or frameshift mutations, which are degraded, the truncated ABCA7 protein produced by the deletion is stable and correctly trafficked to the endoplasmic reticulum and plasma membrane,” said Dr. Young. “This suggests that the mutation does not simply cause a loss of ABCA7 expression, but instead may produce a protein with altered function.”
The researchers next examined how cells respond to excess fats. In laboratory cell models, cells carrying the ABCA7 deletion accumulated more lipid droplets than cells with the normal gene. Lipid droplets are organelle-like structures that store lipids, and their excessive buildup can indicate a disruption in lipid balance.
Why Neurons are Central to the Findings
ABCA7 is expressed at higher levels in neurons than in many other brain cell types, making neurons particularly relevant for studying how the African-specific 44-bp deletion in ABCA7 influences Alzheimer’s disease risk.
In neurons derived from stem cells, those carrying two copies of the ABCA7 44-bp deletion consistently accumulated lipid droplets when exposed to fatty acids. This pattern was observed across multiple genetically matched neuron lines.
Dr. Nam, an assistant scientist in the John P. Hussman Institute for Human Genomics and first author of the paper, connected these changes to broader Alzheimer’s biology.
“Lipid metabolism and mitochondrial health are tightly linked in neurons, as proper lipid composition is essential for membrane integrity, energy production and synaptic signaling,” Dr. Nam said. “The African-specific 44-bp deletion in ABCA7 appears to impair lipid metabolism and mitochondrial health in neurons, which can compromise neuronal function and contribute to an increased risk of Alzheimer’s disease.”
What the Findings Mean for Alzheimer’s Research
Together, these results point to a clear biological pathway. The ABCA7 deletion produces a shortened but stable protein that disrupts lipid transport, causes excess lipid accumulation in neurons and is linked to reduced mitochondrial function. Each of these processes is increasingly recognized as a contributor to Alzheimer’s disease.
The study also highlights the importance of ancestry-informed research. Genetic risk factors differ across genetic ancestries. Understanding ancestry-specific variants is crucial for improving disease models and developing more equitable therapeutic strategies.
“Our findings open future research on understanding the lipid dysregulation from ABCA7, and future studies will test strategies that restore ABCA7 function and rebalance lipid pathways, which can improve our model,” said Dr. Pericak-Vance.
More from the Hussman Institute
Miller School researchers at AD/PD 2026 highlighted why APOE is now a leading genetic target for Alzheimer’s treatment.
A new Miller School study explores how two genes influence the age at onset of Alzheimer’s disease in individuals of African ancestry.
The Miller Schhol’s Hussman Institute for Human Genomics and Department of Neurology played a prominent role at the AAIC.
Miller School researchers presented on the biology of Alzheimer’s disease at the Alzheimer’s Disease/Parkinson’s Disease annual meeting.
Tags: Alzheimer's disease, APOE gene, cognitive decline, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Margaret Pericak-Vance, genetics, genomics, John P. Hussman Institute for Human Genomics