Huge study of Alzheimer’s genetics identifies new drug targets

The most extensive genetic study of Alzheimer’s disease to date has uncovered 127 gene locations associated with the disease, with 48 being newly identified. The research also highlights several genes that could be targeted for drug development and identifies cell types linked to an increased genetic risk of Alzheimer’s.

“It’s an exciting time for Alzheimer’s genetics,” says Rudolph Tanzi at Massachusetts General Hospital, who first provided evidence of an Alzheimer’s-linked gene, APP, in 1987.

Alzheimer’s disease, the leading cause of dementia, is highly heritable. Twin studies indicate that genetics can account for around 60 to 80 percent of a person’s risk. Numerous genes have been implicated, with APOE being one of the most significant. Inheriting one copy of the APOE4 variant from a parent increases the likelihood of developing Alzheimer’s two to three times compared to those without it. Having two copies can increase the risk up to 12 times.

However, health and lifestyle factors also play a crucial role, and some individuals with a genetic predisposition to Alzheimer’s do not develop the disease. “There are people who have those two risk variants and never develop Alzheimer’s,” says Danielle Posthuma at the Free University of Amsterdam.

To better understand the genetics of Alzheimer’s, Posthuma and her team analyzed genome data from nearly 110,000 individuals diagnosed with the disease, along with approximately 74,000 people with at least one parent who had Alzheimer’s but were too young to have developed it themselves. They compared this with data from about 2.6 million people without Alzheimer’s to identify genetic activity more prevalent in those with the condition.

This analysis revealed 127 genes associated with Alzheimer’s, 48 of which had not been previously linked to the disease.

The newly identified genes provide insights into the mechanisms underlying Alzheimer’s, which remain poorly understood. The disease is characterized by the abnormal accumulation of proteins amyloid-beta and tau in the brain. Immune cells, such as microglia, initially work to clear these protein deposits but can lead to inflammation as the disease advances.

Posthuma’s team discovered that Alzheimer’s risk variants might enhance the expression of microglia genes while reducing the expression of neuronal genes, consistent with previous findings of inflammation and reduced neuronal function in Alzheimer’s.

“While the first four Alzheimer’s genes discovered all pointed to amyloid-beta deposition, many still implicate amyloid, but the majority of the new genes implicate the roles of immunity and neuroinflammation,” says Tanzi.

The researchers identified three types of neurons that express genes less strongly in individuals with Alzheimer’s-linked variants compared to other variants. “These are some of the first neurons to disappear in the Alzheimer’s brain,” says Posthuma, though she cannot determine whether their disappearance is a cause or effect of the disease.

Posthuma and her team highlighted five potential drug targets among the newly identified genes, three of which are involved in the immune response.

“Perhaps we should consider drugs that target the immune system, rather than focusing solely on anti-amyloid, which has received most of the funding in the past,” says Shea Andrews at the University of California, San Francisco.

The other two targets identified are UBE2V1 and SPATA2, which appear to be relevant to multiple neurodegenerative diseases.

Andrews believes a multi-drug approach will be necessary to treat Alzheimer’s, with some drugs targeting amyloid, others focusing on tau, and additional treatments addressing the immune system, all complemented by healthy lifestyle choices to prevent cognitive decline.

“This research demonstrates that the risk for Alzheimer’s disease is complex, with no single biology or cell type in play,” says Rebecca Sims at Cardiff University, UK. “It also suggests the need for more advanced models, such as co-cultures or organoids, to explore cell interactions in the disease.”

Approximately 90 percent of study participants were of European ancestry, but the research employs a multiethnic design, marking a step toward more representative research across diverse ancestries, according to Sims.

Genetic tests currently have limited ability to predict Alzheimer’s risk, but Andrews suggests that research like this could enhance their usefulness. Improved tests might identify individuals with a slightly higher risk, allowing for more frequent screening or encouraging lifestyle changes to mitigate that risk. “We don’t want to be too deterministic about it because the increase in risk is not determinative,” Andrews says.