Illustration of amyloid plaques, which build up around brain cells in Alzheimer’s disease
JUAN GAERTNER/SCIENCE PHOTO LIBRARY/Alamy
The biggest genetic study of Alzheimer’s disease so far has identified 127 gene locations that are associated with the condition, of which 48 are new. The study also pinpoints several genes that could be prioritised as drug targets and cell types linked to a higher genetic risk of the condition.
“It’s an exciting time for Alzheimer’s genetics,” says Rudolph Tanzi at Massachusetts General Hospital, who provided evidence of the first Alzheimer’s-linked gene, APP, in 1987.
Alzheimer’s disease, the most common cause of dementia, is highly heritable, with twin studies showing genetics can account for about 60 to 80 per cent of a person’s risk. Many genes have been found to play a role, chief among which is APOE. Inheriting one copy of a variant of this, known as APOE4, from a parent makes someone two or three times as likely to develop Alzheimer’s as someone without the variant, and getting a copy of APOE4 from both parents can increase risk up to 12-fold.
But health and lifestyle also play a big part and even people who seem genetically destined to develop Alzheimer’s sometimes avoid it. “There are people who have those two risk variants and never develop Alzheimer’s,” says Danielle Posthuma at the Free University of Amsterdam.
To get a better handle on the genetics, she and her colleagues have analysed genome data from almost 110,000 people diagnosed with Alzheimer’s, plus about 74,000 people with at least one parent who had the condition but were too young to have developed it themselves. They compared this with data from about 2.6 million people without Alzheimer’s to pinpoint the genetic activity that was stronger in the condition.
This revealed 127 genes associated with Alzheimer’s, of which 48 haven’t been linked to the condition before.
These newly identified genes offer clues to the mechanisms behind Alzheimer’s, which are still poorly understood. The disease features an abnormal build-up of the proteins amyloid-beta and tau in the brain. Immune cells, including a type called microglia, also move to the area, at first helping to clear the protein accumulations, but leading to inflammation as the disease progresses.
Posthuma’s team saw that Alzheimer’s risk variants may lead to heightened expression of microglia genes and reduced expression of neuronal genes, which fits with previous reports of inflammation and reduced neuronal functions 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 team identified three types of neurons that express genes more weakly when people have Alzheimer’s-linked variants of those genes, compared with other variants. “These are some of the first neurons to disappear in the Alzheimer’s brain,” says Posthuma, although she can’t say whether the disappearance is a cause or effect of Alzheimer’s.
Posthuma and her colleagues highlight five potential drug targets among the newly flagged genes. Three of these are known to be involved in the immune response.
“Maybe we should be thinking more about drugs that target the immune system, rather than just anti-amyloid, which is where most of the funding has gone previously,” says Shea Andrews at the University of California, San Francisco.
The other two targets they flag are UBE2V1 and SPATA2, which seem to be relevant to multiple neurodegenerative conditions.
Andrews thinks a multi-drug approach will be needed to treat Alzheimer’s, with some drugs targeting amyloid, some tau and others the immune system, with all used alongside healthy lifestyle choices to prevent cognitive decline.
“This work shows that risk for Alzheimer’s disease is multifaceted and there isn’t just one biology or cell type at play,” says Rebecca Sims at Cardiff University, UK. “It also suggests that we need to be using more sophisticated models such as co-cultures [growing several cell types together in the lab] or organoids to explore the cell interplay in disease.”
About 90 per cent of the people in the study were of European ancestry, but the study encompasses a multiethnic design so it is a step towards research that is representative of a wide range of ancestries, says Sims.
Genetic tests currently have limited power to predict people’s Alzheimer’s risk, but Andrews says research like this might make them more useful. Improved tests could identify people with a slightly higher risk who could be screened more regularly or encouraged to develop a lifestyle to try to offset that risk. “We don’t want to be too deterministic about it because the increase in risk is not determinative,” he says.
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