A recent study published in Molecular Psychiatry has identified a series of molecular events that may contribute to the development of Alzheimer’s disease. The research, conducted by scientists at Baylor College of Medicine, Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and other institutions, combined gene expression analysis from postmortem human brains with laboratory studies using fruit flies.
The team aimed to clarify how common changes in the brains of people with Alzheimer’s—such as amyloid plaques and tau tangles—lead to neurodegeneration and cognitive decline. Their cross-species approach found that some molecular pathways might worsen the disease while others could offer protection.
“One important way to investigate the molecular cascade leading to cognitive decline is to study brain gene expression changes from individuals with Alzheimer’s disease when compared with those from healthy brains,” said Dr. Joshua Shulman, professor at Baylor College of Medicine and co-director of the Duncan NRI. “The Accelerating Medicines Partnership (AMP)-AD target discovery consortium, which we are a part of, analyzed about 2,000 postmortem brain tissue samples and identified 30 AD-associated gene expression networks. The association with Alzheimer’s was particularly robust for genes involved in immune and synaptic, or neuron communication, regulatory mechanisms.”
Shulman explained that an important question remained: which gene expression changes cause the disease and which are simply present without contributing? “Our role in the consortium was to try to answer that question,” he said. “We used the fruit fly as a model system to test hundreds of different genes whose expression was altered in human brains with Alzheimer's disease and try to sort out which genes might play a causal role. We also wanted to know which genes promote versus protect against disease.”
Fruit flies provided an efficient way for researchers to test many genes quickly. According to Shulman, “In the fruit fly we can test many different genes in a relatively short time. We manipulate the genes in the fly to resemble the change in human brains and determine which genes enhance or suppress neurodegeneration in the flies or have no effect.”
Researchers studied 344 genes whose activity changed in Alzheimer’s-affected human brains. They focused on immune response genes that showed increased activity; activating these same genes in fruit flies led to more neurodegeneration, suggesting these may play a direct role in Alzheimer’s.
Unexpectedly, when they examined synaptic regulation genes—which show reduced activity in Alzheimer’s—they found silencing these genes protected brain cells from death in fruit flies. Shulman noted: “We thought at the beginning that this reduction in activity was a consequence of the death of brain cells that comes with the disease. But our experiments with fruit flies showed us something surprising.” He added: “Prior published work suggests that brain cells may become abnormally hyperactive in Alzheimer’s disease. Our results suggest that the reduced expression of synaptic genes may in fact represent a compensatory response to the damaging brain cell hyperactivity.”
Based on their findings, researchers proposed a two-stage model for how cause-effect events unfold during Alzheimer’s progression: early on, amyloid plaques increase synaptic gene activity leading to harmful hyperactivity; later, tau tangles reduce this activity as a protective response—though not enough to prevent further decline.
“Our new understanding of the molecular cascade and gene expression networks causing Alzheimer’s disease pinpoints specific driver genes and pathways worthy of further study as potential therapeutic targets,” Shulman said.
Other contributors included Pinghan Zhao, Omar El Fadel, Anh Le, Carl Grant Mangleburg, Justin Dhindsa, Timothy Wu, Jinghan Zhao, Meichen Huang, Bismark Amoh, Aditi Sai Marella, Yarong Li, Zhandong Liu, Ismael Al-Ramahi and Juan Botas—all affiliated with Baylor College of Medicine or Duncan NRI—as well as Nicholas T. Seyfried and Allan I. Levey from Emory University.
Baylor College of Medicine is recognized for its commitment to community service as one of its core missions according to its official website. The institution operates independently but maintains clinical partnerships while advancing research across various health sciences fields (source). Paul Klotman serves as president and chief executive officer (source). Since relocating to Houston's Texas Medical Center in 1943 after its founding in 1900,Baylor has focused on education across medicine-related schools, biomedical research advancement,patient care through partnerships, community support efforts,and integrated health sciences development.
This research received funding from several National Institutes of Health grants along with support from private foundations such as The Florence and William K. McGee Jr., Huffington Foundation,
Southern Star Medical Research Foundation,
The Effie Marie Caine Endowed Chair for Alzheimer’s Research,
CPRIT,
and additional NIH programs.
The Religious Orders Study
and Rush Memory
and Aging Project were also supported by multiple grants.
