Breakthrough Large-Scale Study Uncovers New Genetic Drug Targets for Alzheimer’s Disease

The most extensive genetic study on Alzheimer’s disease has pinpointed a total of 127 gene locations linked to the disorder, with 48 of these genes being previously undiscovered. This research has also highlighted specific genes that may be prioritized as drug targets, along with identifying cell types associated with an elevated genetic risk for Alzheimer’s.

“It’s a pivotal moment for Alzheimer’s disease genetics,” says Rudolph Tanzi of Massachusetts General Hospital, referencing the landmark study from 1987.

Alzheimer’s disease, the most prevalent cause of dementia, exhibits strong heritability; a twin study indicates that genetics may account for 60% to 80% of an individual’s risk. Key genes, such as ApoE, play a significant role. Individuals inheriting one copy of the APOE4 variant from their parents face a two to three times greater likelihood of developing Alzheimer’s than those without the mutation. Importantly, parental genetic influence can increase risk up to 12 times.

However, health and lifestyle factors are equally crucial, as some genetically predisposed individuals manage to evade the disease. “Some can possess these risk variants yet remain unaffected,” comments Daniel Posthuma from Vrije Universiteit Amsterdam.

To deepen the understanding of genetic influences, her team analyzed genomic data from approximately 110,000 diagnosed Alzheimer’s patients and around 74,000 individuals who had at least one parent with the condition. This was compared to data from 2.6 million individuals without Alzheimer’s, revealing heightened gene activity in the affected population.

This research unveiled 127 genes associated with Alzheimer’s, with 48 newly identified connections. Such findings could elucidate mechanisms underlying the poorly understood disease, which is typified by abnormal protein accumulations of amyloid beta and tau. Immune cells, especially microglia, respond to this buildup by initially attempting to mitigate protein accumulation, but later contribute to inflammation as the disease progresses.

Posthuma’s team suggests that mutations linked to Alzheimer’s may enhance microglial gene expression while diminishing neuronal gene activity, aligning with past reports on neuroinflammation and functional deterioration in Alzheimer’s disease.

“While the initial Alzheimer’s genes suggested amyloid-beta deposition, the majority of the novel genes are related to immune response and neuroinflammation,” asserts Tanzi.

Researchers identified three neuron types with diminished gene expression in individuals carrying Alzheimer’s-related genetic mutations. “These neurons are among the first to decline in Alzheimer’s brains,” states Posthuma, who notes that it remains uncertain whether this neuronal loss is a cause or consequence of the disease.

Posthuma and colleagues have flagged five promising drug targets among the newly identified genes, three of which are involved in immune processes.

“We should consider targeting the immune system in treatment, rather than focusing solely on anti-amyloid drugs, which have dominated funding,” suggests Shea Andrews of the University of California, San Francisco.

The additional two targets identified—UBE2V1 and SPATA2—are thought to be involved in multiple neurodegenerative diseases.

According to Andrews, effective Alzheimer’s treatment will necessitate a multidrug strategy that targets amyloid, tau, and the immune response, in conjunction with healthy lifestyle adjustments to combat cognitive decline.

“The study reveals the multifaceted nature of Alzheimer’s risk, signifying that there isn’t a one-size-fits-all biological or cellular pathway,” remarks Rebecca Sims from Cardiff University, UK. “It indicates the need for advanced models such as co-culture or organoids to study cellular interactions in disease.”

Approximately 90% of participants in the study were of European descent, although Sims notes that this research is a stride towards encompassing a more diverse genetic representation due to its multi-ethnic design.

Presently, genetic tests have limited efficacy in predicting Alzheimer’s risk, but research of this nature could enhance their predictive capabilities, Andrews explains. Improved testing could help identify individuals at slightly increased risk, potentially allowing for more frequent evaluations or encouraging proactive lifestyle changes. “I wouldn’t want to make any definitive claims since the augmented risk is not conclusive,” he adds.