![\"\"](\"https:\/\/images.newscientist.com\/wp-content\/uploads\/2024\/03\/13145907\/SEI_195864515.jpg?width=1200\")
<\/div>Various changes are seen in the brains of people with Alzheimer\u2019s, but the exact cause of the disease is unclear<\/p>\n
Science Photo Library\/Alamy<\/p>\n<\/div>\n<\/figcaption><\/figure>\n<\/p>\n
A new understanding of Alzheimer\u2019s disease suggests that the root cause involves a build-up of fat droplets in brain cells.<\/p>\n
Targeting these droplets could lead to more effective treatments than the current strategy of drugs that target proteins, says Michael Haney<\/a> at the University of Pennsylvania. \u201cThis opens up a new avenue for therapeutic development,\u201d he says.<\/p>\n The commonest explanation for Alzheimer\u2019s disease is that it is caused by a build-up of a protein called beta-amyloid in plaques between nerve cells<\/a>. Another suspect is a build-up of tangles made of a different protein, called tau, stored inside nerve cells.<\/p>\n 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<\/a> that rid the brain of it have recently shown modest effectiveness at slowing memory loss in people with Alzheimer\u2019s.<\/p>\n <\/p>\n 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\u2019s. But for decades the fat was mostly overlooked.<\/p>\n In the latest study, Haney was investigating the biggest genetic risk factor for Alzheimer\u2019s disease: a gene called APOE<\/a><\/em>. The protein it encodes helps transport fat into and out of cells.<\/p>\n People have different variants of this gene, called APOE2<\/em>, 3<\/em> and 4<\/em>. Of these, APOE2<\/em> brings the least risk of developing Alzheimer\u2019s, while APOE4<\/em> brings the most \u2013 although until now, it wasn\u2019t clear why.<\/p>\n 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\u2019s disease, who had either two copies of the APOE4<\/em> variant or two copies of APOE3<\/em>.<\/p>\n This showed that the key difference in the people with APOE4<\/em> 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.<\/p>\n In a further experiment, the team grew this kind of brain immune cell \u2013 called microglia \u2013 in a dish, using cells from living people with either the APOE4<\/em> or APOE3<\/em> variant. Applying amyloid to the cells made them accumulate fat, especially if they had the APOE4<\/em> variant.<\/p>\n The team concluded that in Alzheimer\u2019s, 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.<\/p>\n Previous studies have found that other genes that raise Alzheimer\u2019s risk, but to a lesser extent than APOE4<\/em>, tend to be involved in fat metabolism or the immune system<\/a>, which further supports their hypothesis, says Haney.<\/p>\n Irundika Dias<\/a> at Aston University in Birmingham, UK, who wasn\u2019t involved in the work, says previous studies have suggested fat metabolism in other kinds of brain cells could also be playing a role. \u201cThe common thing tying all these [findings] is involvement of lipid [fat] metabolism,\u201d she says. \u201cBut this is a very interesting paper.\u201d<\/p>\n The finding comes as separate research suggests harmful APOE<\/em> gene variants are behind more than three-quarters of Alzheimer\u2019s cases. That work, by Dylan Williams<\/a> at University College London and his colleagues, was based on a population study called UK Biobank, which recorded the APOE<\/em> variant people had and tracked their health records.<\/p>\n Compared with people who have two copies of the least-risk variant, APOE2<\/em>, those with either one or two copies of the other variants were nearly four times more likely to get Alzheimer\u2019s disease, they reported in a paper posted online<\/a>.<\/p>\n This means that about 75 per cent of people who get Alzheimer\u2019s wouldn\u2019t do so if we could somehow intervene in this molecular pathway, says Williams. \u201cGiven that we\u2019re 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.\u201d<\/p>\n Topics:<\/p>\n<\/section><\/div>\n