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A new understanding of Alzheimer’s disease suggests that the root cause involves a build-up of fat droplets in brain cells.

Targeting these droplets could lead to more effective treatments than the current strategy of drugs that target proteins, says at the University of Pennsylvania. “This opens up a new avenue for therapeutic development,” he says.

The commonest explanation for Alzheimer’s disease is that it is caused by a build-up of a protein called beta-amyloid in plaques between nerve cells. Another suspect is a build-up of tangles made of a different protein, called tau, stored inside nerve cells.

Arguments over which of these two proteins is the key culprit have gone on for decades. The amyloid hypothesis is currently in the lead, as some antibody treatments that rid the brain of it have recently shown modest effectiveness at slowing memory loss in people with Alzheimer’s.

But this debate ignores the fact that fat droplets can also be seen in the brains of people who have died from the disease, says Haney. These were first described by Alois Alzheimer, a German doctor who gave his name to the condition in the early 20th century, when he noted amyloid plaques, tau tangles and fat droplets present in the brains of people who had Alzheimer’s. But for decades the fat was mostly overlooked.

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In the latest study, Haney was investigating the biggest genetic risk factor for Alzheimer’s disease: a gene called APOE. The protein it encodes helps transport fat into and out of cells.

People have different variants of this gene, called APOE2, 3 and 4. Of these, APOE2 brings the least risk of developing Alzheimer’s, while APOE4 brings the most – although until now, it wasn’t clear why.

To shed more light, Haney and his colleagues carried out a series of experiments while he was working at Stanford University in California. First, the team used a relatively recent technique called single-cell RNA sequencing to identify which proteins were being made in individual cells. They applied this to tissue samples from people who had died from Alzheimer’s disease, who had either two copies of the APOE4 variant or two copies of APOE3.

This showed that the key difference in the people with APOE4 is that immune cells in their brain had higher levels of a certain enzyme, the effect of which was to boost fat droplets in those cells.

In a further experiment, the team grew this kind of brain immune cell – called microglia – in a dish, using cells from living people with either the APOE4 or APOE3 variant. Applying amyloid to the cells made them accumulate fat, especially if they had the APOE4 variant.

The team concluded that in Alzheimer’s, a build-up of amyloid triggers fat accumulation. This then leads to the build-up of tau inside neurons, which causes cell death, and so leads to the symptoms of memory loss and confusion.

Previous studies have found that other genes that raise Alzheimer’s risk, but to a lesser extent than APOE4, tend to be involved in , which further supports their hypothesis, says Haney.

at Aston University in Birmingham, UK, who wasn’t involved in the work, says previous studies have suggested fat metabolism in other kinds of brain cells could also be playing a role. “The common thing tying all these [findings] is involvement of lipid [fat] metabolism,” she says. “But this is a very interesting paper.”

The finding comes as separate research suggests harmful APOE gene variants are behind more than three-quarters of Alzheimer’s cases. That work, by at University College London and his colleagues, was based on a population study called UK Biobank, which recorded the APOE variant people had and tracked their health records.

Compared with people who have two copies of the least-risk variant, APOE2, those with either one or two copies of the other variants were nearly four times more likely to get Alzheimer’s disease, they reported in a .

This means that about 75 per cent of people who get Alzheimer’s wouldn’t do so if we could somehow intervene in this molecular pathway, says Williams. “Given that we’re in a rare position where differences in this one protein seem to be responsible for a large majority of the disease burden, if we design drugs where we could somehow mitigate that risk, we would expect to prevent most disease.”