Part 1 - written in your genes? How cholesterol and inheritance are linked to ALS
Higher cholesterol has been linked to a slightly greater chance of developing amyotrophic lateral sclerosis (ALS), and studies of our genes suggest the link may be more than coincidence. Yet some of the genes that set our cholesterol levels point in surprising directions. So what do blood fats look like in the years before an ALS diagnosis, and how much of the story is inherited?
A two-minute guide to the fats in your blood
Before we get started on a deep dive into cholesterol and ALS, let's first discuss what we mean when we talk about cholesterol, LDL and HDL.
Pour cooking oil into a glass of water and it floats in a separate layer. Blood is mostly water, and the fats it carries behave in much the same way. So the body packs them into tiny protein-wrapped parcels called lipoproteins (a word that simply means fat plus protein) (Alves-Bezerra & Cohen, 2017; Sniderman et al., 2019). Picture these lipoproteins as delivery vans on a motorway. The vans are not the cargo; they carry it.
The two main cargoes are cholesterol and triglycerides. Cholesterol is building material: it forms part of the outer wall of every cell and is the raw material for steroid hormones and vitamin D (Schade et al., 2020). Triglycerides are fuel: they are the main form in which the body stores fat and moves it around in the blood (Alves-Bezerra & Cohen, 2017). The vans themselves come in several types:
• Very low-density lipoprotein (VLDL) leaves the liver loaded mainly with triglycerides, ready to drop fuel off at muscles and fat stores (Alves-Bezerra & Cohen, 2017).
• Low-density lipoprotein (LDL) is what is left once a VLDL van has unloaded most of its fuel. It carries mostly cholesterol, which it delivers to cells around the body (Sniderman et al., 2019). High LDL over many years is a well-established cause of heart disease (Ference et al., 2017).
• High-density lipoprotein (HDL) works in the opposite direction, like a recycling lorry, collecting surplus cholesterol from tissues and returning it to the liver. Its main protein is called apolipoprotein A1, or ApoA1 (Rader & Hovingh, 2014).
• Apolipoprotein B (ApoB) is a protein found exactly once on every VLDL and LDL particle. It works like a number plate: count the plates and you know how many vans are on the road, rather than how much cargo they carry (Sniderman et al., 2019).
In ALS research, all of these have been measured, and so have the balances between them: LDL against HDL, and ApoB against ApoA1. Those balances come up again and again (Dupuis et al., 2008; Mariosa et al., 2017).
Your nerves keep their own private supply
The brain and spinal cord make up only about 2% of body weight, yet they hold nearly a quarter of all the cholesterol in the body (Dietschy & Turley, 2004). Most of it sits in myelin, the fatty sheath that wraps around nerve fibres like the insulation on an electrical cable (Björkhem & Meaney, 2004). The nervous system makes almost all of this cholesterol itself, and the blood-brain barrier, a tightly sealed lining around its blood vessels, largely keeps the cholesterol in the bloodstream out (Björkhem & Meaney, 2004; Dietschy & Turley, 2004). Think of it as a walled garden that grows its own supply.
So a blood cholesterol result is not a direct window into the nerves. Yet the two worlds are connected: a protein called TDP-43, which clumps abnormally inside nerve cells in most people with ALS, also helps control how cells make cholesterol (Egawa et al., 2022; Ho et al., 2021). Blood fats may therefore be one visible sign of a wider change in how the body handles fat, a thread picked up in Part 2 of this 3-part series.
A Paris clinic, a cholesterol test and a result nobody expected
In 2008, doctors at a specialist clinic in Paris compared the blood fats of 369 people with ALS, with those of 286 people without it. Raised cholesterol was twice as common in the ALS group. More surprising still, people with ALS who had a higher ratio of LDL cholesterol to HDL cholesterol (both explained below) lived, on average, more than a year longer (Dupuis et al., 2008).
Decades of heart research had taught doctors to see high LDL as harmful (Ference et al., 2017), so a pattern linking it to longer survival in ALS challenged expectations about how to read cholesterol results in this illness. Later studies examined stored blood samples from hundreds of thousands of people, many of them tested decades before anyone was diagnosed. These are discussed below (Mariosa et al., 2017; Thompson et al., 2022; Vaage et al., 2024). More recently, researchers have turned to our genes, to ask whether cholesterol might play a part in ALS or simply travel alongside it (Chalitsios et al., 2024; Xia et al., 2026).
These findings help researchers investigate the biology of ALS. They cannot currently predict any one person’s ALS risk from a cholesterol test or a gene result. With that boundary in place, the research has a great deal to say, and it starts with what a cholesterol test actually measures.
What the largest studies found
The biggest studies of blood fats and ALS follow very large groups of healthy people for decades and record who is later diagnosed.
• Sweden: more than 636,000 people had blood tests between 1985 and 1996. Higher LDL and ApoB, and higher ratios of LDL to HDL and of ApoB to ApoA1, were each linked to a higher chance of developing ALS over the following two decades (Mariosa et al., 2017).
• Norway: in a study of 640,000 people, each 1 mmol/L higher LDL (mmol/L is the unit used on UK blood tests) was linked to a 6% higher relative risk of developing ALS, and the link could be seen more than 40 years before diagnosis. Taking account of weight, smoking and physical activity did not change the result. HDL showed no link (Vaage et al., 2024).
• UK Biobank: among more than 500,000 adults, people with higher HDL and ApoA1
were less likely to develop ALS, while a higher ratio of total cholesterol to HDL was linked to higher risk. When several blood markers were considered together, higher LDL or ApoB was also linked to higher risk (Thompson et al., 2022).
• UK GP records: a 2026 study of routine blood tests, including up to 2,695 people later diagnosed with ALS, found that higher LDL and total cholesterol were each linked to a modestly higher risk. For total cholesterol, the link was stronger in people aged 60 and over (Chalitsios et al., 2026).
When an Oxford team pooled the large population studies, higher LDL and lower HDL were both linked to a higher risk of ALS (Chalitsios et al., 2024). The LDL finding is the most consistent. The HDL picture is less settled, since Norway found no link where the UK did (Thompson et al., 2022; Vaage et al., 2024).
These are small shifts across very large groups of people, and they do not mean that anyone’s cholesterol caused their ALS. In the Norwegian study, fewer than 1 in 600 participants were diagnosed with ALS during the years they were followed (Vaage et al., 2024).
How much of your cholesterol is written in your genes?
Cholesterol levels are shaped by diet, weight, activity and age, and also by the genes we inherit. At one extreme, rare genetic changes that weaken the LDL receptor, the loading bay on the surface of cells that pulls LDL out of the blood, lead to markedly higher LDL from birth (Ference et al., 2017). Most of us, though, inherit a mix of common gene versions, each linked to a small nudge up or down in our blood fats (Voight et al., 2012).
A Dutch study of 1,324 people with ALS gives a sense of how this works in practice. Researchers built genetic scores to predict each person’s blood fats, and these particular scores explained only part of the variation in blood fat levels at diagnosis, between about 1% and 13% (Janse van Mantgem et al., 2023). That does not measure the full contribution of inheritance, since any score captures only some of the genes involved, but it is a reminder that genes are one influence among several.
That partial influence is exactly what makes genes so useful to researchers. Because the genes we inherit do not change with lifestyle or illness, they can help test whether cholesterol plays a part in ALS, or simply appears alongside it.
Genes enter this story in three different ways, and it helps to keep them apart. Some influence ordinary cholesterol levels. Some affect the same targets as cholesterol-lowering medicines, which lets researchers test those pathways. And a few, such as C9orf72 and SOD1, are linked directly to ALS itself. These are related questions, but they are not interchangeable: inherited high cholesterol and inherited ALS are not versions of the same problem.
Nature’s coin toss: using genes to test cause and effect
A link between LDL and ALS does not prove that LDL plays a part. People with higher LDL might also differ in diet, exercise or other ways. One way to test this is a method called Mendelian randomisation. Each of us inherits a random shuffle of gene versions at conception, rather like a coin toss, and those genes are not altered by lifestyle or illness (Voight et al., 2012). Comparing people who happened to inherit gene versions that raise a blood fat with those who did not works like a natural experiment running from birth.
The method can strengthen the case for cause and effect, but it rests on assumptions. A gene version might influence ALS through another biological route as well as through cholesterol. Genetic studies also reflect the effect of a lifetime of slightly higher or lower levels, which builds up over decades (Ference et al., 2017). They tell us about the chance of developing ALS, not about what happens after diagnosis or what starting a medicine later in life would do.
What our genes reveal about cholesterol and ALS risk
Using this approach, an Oxford team found that people whose genes predicted higher LDL, higher total cholesterol or higher ApoB had a modestly higher risk of ALS (Chalitsios et al., 2024). Genetically higher ApoB was also linked to a higher risk of frontotemporal dementia, a condition that overlaps with ALS (Chalitsios et al., 2024).
HDL is less clear-cut. A 2026 Chinese study found that ALS and HDL, and ALS and ApoA1, share a surprising number of genetic regions (Xia et al., 2026). Sharing genes suggests overlapping biology, but it does not show that one causes the other.
The genes behind cholesterol-lowering medicines
Some gene versions affect exactly the same target as a cholesterol-lowering medicine, so they act like a gentle, lifelong version of that medicine. Studying them lets researchers ask what lowering cholesterol by a particular route might do, decades before anyone takes a tablet:
• The ApoB route: gene versions that lower LDL by reducing ApoB were linked to a lower ALS risk, by around 16% (Chalitsios et al., 2024). A separate study reached a similar conclusion for ApoB, and also found that higher activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the enzyme that statins block and the main machine in the body’s cholesterol factory, was linked to higher risk (Li et al., 2024).
• The PCSK9 route: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that breaks down the LDL loading bays on cells, so medicines that block it leave more bays free to clear LDL from the blood (J. D. J. Wang et al., 2026). Gene versions that mimic these medicines were linked to a slightly lower ALS risk (Huang et al., 2024), and a 2026 study found protective links for gene versions affecting both PCSK9 and a second drug target, adenosine triphosphate citrate lyase (ACLY) (Xia et al., 2026).
• A note on statins: genes that predict being prescribed a statin are not the same as genes that mimic blocking the statin target, because the first group may also reflect why someone needed treatment. One study found that a genetic tendency to be prescribed statins was linked to a higher ALS risk, and that once those gene versions were set aside, the link between LDL and ALS was no longer statistically significant (W. Wang et al., 2023). Another team found the same prescribing link but thought the conditions that lead people to take statins were the more likely explanation (Li et al., 2024).
Real-world data add another layer. In a Norwegian study of more than 425,000 people, taking a statin for five years or more was associated with a possibly lower risk of developing ALS, a link that was clearer in men (Nakken et al., 2025). A 2026 review concluded that statins are generally not linked to increased ALS risk in human studies (Farè et al., 2026).
Put together, the genetic evidence hints that a lifetime of lower LDL and ApoB may slightly lower the chance of developing ALS, while the statin findings are harder to interpret. None of this is a reason to start, stop or change a medicine, especially after diagnosis, which is a different question altogether.
APOE: the gene behind the brain’s own cholesterol carrier
Inside the walled garden, the brain uses its own lipoprotein particles. Apolipoprotein E (ApoE) is the main protein that carries fats and cholesterol around the brain and spinal cord, and the APOE gene that makes it comes in three common versions, called ε2, ε3 and ε4. The ε4 version is one of the strongest known genetic risk factors for late-onset Alzheimer’s disease (Fernández-Calle et al., 2022). Researchers have naturally asked whether it shapes ALS risk too.
The answers so far differ. A 2014 analysis that pooled studies of 4,249 people with ALS and 10,397 without found no clear association between APOE versions and ALS risk (Govone et al., 2014). In a study of 683 people with ALS in China, 21% carried at least one copy of the ε4 version, compared with 16% of people without ALS, although ε4 was not linked to the type of ALS people had (He et al., 2022). A 2025 study found that people with two copies of ε2 were less likely to have ALS, while two copies of ε4 were linked to an earlier start (Ashford et al., 2025).
With results that vary between studies and populations, APOE cannot currently tell an individual much about their own ALS risk. It is, however, a clear example of how a cholesterol-handling gene in the nervous system has become part of the ALS story.
Genes that cause ALS, and the mark they may leave on metabolism
Some people with ALS carry a gene change that raises their risk directly. One of the most common is in a gene called C9orf72 (Gao et al., 2025); another well-known example is in a gene called SOD1 (Xia et al., 2023).
A German and Chinese team measured blood fats and other markers in 60 people who carried a range of ALS-linked gene changes, including C9orf72 and SOD1, but had no symptoms, and compared them with 70 relatives without these changes. When all the carriers were analysed together, there were no differences from their relatives. Differences only appeared when the carriers were grouped by gene: those with the C9orf72 change tended to have a lower body mass index, lower blood pressure, lower blood sugar and higher HDL, while those with SOD1 changes showed the opposite pattern of a higher body mass index, higher blood sugar and lower HDL (Xia et al., 2023).
The subgroups were small and the study was a single snapshot, so it cannot show how metabolism changes on the way to diagnosis. It does suggest that the gene involved may shape the body’s metabolism long before symptoms appear. For families who know about a gene change, it is also worth knowing that carrying one does not make ALS certain. A UK Biobank study estimated that some C9orf72 carriers remain free of diagnosed ALS or dementia into older age, although individual risk varies and these population estimates cannot predict what will happen to any one person (Gao et al., 2025).
When ALS itself starts to change the numbers
Some blood fat changes appear only shortly before diagnosis. In the Norwegian study, higher triglycerides and total cholesterol were linked to ALS only within the last six to seven years, which led the authors to suggest these rises are more likely a consequence of the illness than a cause (Vaage et al., 2024). The Swedish study found that LDL, HDL, ApoB and
ApoA1 all rose during the ten years before diagnosis (Mariosa et al., 2017), and an Oxford study of routine GP blood tests found that cholesterol levels changed direction several years before diagnosis in a way not seen in people who stayed well (Thompson et al., 2023).
Scientists call this reverse causation: the illness, quietly under way, changing the test result rather than the test result shaping the illness. The Norwegian statin study shows how easily it can mislead. People who had started a statin within the previous year appeared to have a much higher risk of ALS, but the researchers concluded this was most likely because rising cholesterol and early symptoms were bringing people to their doctor just before diagnosis (Nakken et al., 2025).
This is one reason genetic studies are so valuable. A gene inherited at conception cannot be changed by an illness that begins decades later.
Can diet make a difference before diagnosis? Two intriguing clues
Not all fats do the same job. Omega-3 fats are built into the fatty membranes of the brain and help regulate oxidative stress and inflammation (Fitzgerald et al., 2014). In five large US studies involving more than one million people, those who ate the most omega-3, from both plant sources and oily fish, had about a third lower risk of developing ALS than those who ate the least. Omega-6 intake showed no link (Fitzgerald et al., 2014).
Antioxidants offer a second clue. In a 2026 analysis of four US studies, including 154 people later diagnosed with ALS, women with higher blood levels of beta-carotene and beta-cryptoxanthin (plant pigments found in orange and yellow fruits and vegetables) had a lower risk, while in men a form of vitamin E showed only a borderline link. The analysis took cholesterol levels into account (O’Reilly et al., 2026).
Both were observational studies about the risk of developing ALS. The carotenoid study measured levels in the blood, which reflect more than diet alone, and most of the compounds it measured showed no clear link (O’Reilly et al., 2026). These findings warrant further study, but they do not establish a diet or supplement strategy that prevents ALS.
What this could mean for you and your family
• If ALS runs in your family: questions about genetic testing and counselling are best raised with a neurologist or genetics service. Carrying an ALS-linked gene change does not make the illness certain (Gao et al., 2025).
• Your heart health still counts: high LDL remains a proven cause of heart disease (Ference et al., 2017), and nothing in the ALS research suggests ignoring it.
• Food choices: omega-3 intake and some blood antioxidant levels have been linked with a lower ALS risk in observational studies (Fitzgerald et al., 2014; O’Reilly et al., 2026). These are clues for further research rather than a proven prevention plan, though omega-3-rich foods fit well with wider healthy eating.
A diagnosis changes the questions. After diagnosis, studies find that some blood fats are linked with longer survival and others with shorter, and in one large study the genetic scores that predicted blood fats were not linked to survival (Janse van Mantgem et al., 2023). Part 2 looks at why, at the body’s energy needs in ALS, at what the diet trials found, and at what is happening to fats inside the nerve cells themselves.
Supporting MND and ALS at You Nutrition Clinic
If this article has left you with questions about your own cholesterol or blood fat results, or those of someone you care for, you do not have to work them out alone. Dr Kirstie Lawton, PhD, MSc, FBANT, founder and Clinical Director of You Nutrition Clinic, leads a dedicated multidisciplinary team supporting people living with motor neurone disease (MND), amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Kirstie heads up the MND/ALS/PLS team alongside Kerry (RNTP), Deborah (RD) and Rachael (RN), with further support from Rae, our breath and movement practitioner.
Together, the team brings clinical nutrition, dietetics, nursing and movement support under one roof, with specialist experience in the particular nutritional and functional challenges that MND/ALS presents. That includes looking at what blood test results such as cholesterol and triglycerides may mean in the context of ALS, alongside weight, energy needs and your wider health. Get in touch to find out how the team can support you.
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Disclaimer: This article is for informational and educational purposes only and does not constitute medical advice. Always consult with a qualified, registered medical doctor (MD) for diagnosis and treatment decisions.
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