The liver may hold the key to the Alzheimer’s puzzle

In Sweden, around 15,000 people develop Alzheimer’s disease each year, and approximately 100,000 Swedes have the diagnosis. At the same time, the number of undiagnosed cases is very high, with many cases remaining unidentified, particularly in the early stages. In the Western world, Alzheimer’s disease is overall the third most common cause of death, after cancer and cardiovascular disease.

Focus on a high-risk group

One group with a significantly higher risk of developing Alzheimer’s disease is people with the so-called APOE4 gene. In Sweden, they account for around 25 percent of the population. Depending on whether a person has one or two copies of this gene variant, the risk of developing Alzheimer’s increases by between five and 15 times.

Henrietta Nielsen, a senior lecturer in neurochemistry and molecular neurobiology, is studying why this may be the case. Her research points to an unexpected possible explanation – namely, the liver.

“We think that the liver in APOE4 carriers secretes a particular profile of substances that affects the blood–brain barrier, which in turn has negative effects on the brain. At the same time, only some carriers develop the disease, so there must also be some kind of counteracting factor that provides protection. Our goal is to determine what the risk profile looks like and understand how different factors are connected and influence one another.”

Working against the current

What is interesting, and partly controversial, about Henrietta Nielsen’s research is that it challenges the traditional view of Alzheimer’s disease as a condition linked exclusively to processes within the brain.

Historically, processes occurring in the body outside the brain have not been considered relevant because the body and brain are separated by the blood–brain barrier. However, the various studies conducted by her research group (see fact box) clearly point towards Alzheimer’s disease – at least in APOE4 carriers – having a metabolic component, in which hepatic apoE production, lipid metabolism and potentially liver function more broadly can influence disease risk and progression.

“Very little Alzheimer’s research has focused on this perspective, and we have often had to work against the prevailing view. But now a number of studies, in addition to our own, are beginning to indicate that the peripheral system and the body as a whole – and not just the brain – play a role in neurodegenerative diseases. So it feels as though the timing is right; we are beginning to gain momentum.”

New treatment may be possible

Taken together, Henrietta Nielsen’s research shows that although liver-produced apoE does not physically reach the brain, its levels nevertheless appear to affect the brain indirectly – through metabolism, inflammation, vascular health and other pathways. This opens up the possibility that systemic metabolic health, including liver health, could be a modifiable factor specifically in APOE4 carriers.

“If, in the long term, we can determine how a person’s overall metabolic health interacts with the genetic risk associated with APOE4, this would create entirely new opportunities for treating Alzheimer’s disease. Just as we prescribe statins to people with high cholesterol to reduce their risk of cardiovascular disease, we could potentially provide some form of preventive treatment to people who carry the APOE4 gene. The positive aspect is that it is much easier to medicate or otherwise treat something outside the blood–brain barrier than it is to treat the brain itself.”

From mice to humans

Recently, Henrietta Nielsen’s research group was awarded funding from the Swedish Brain Foundation (Hjärnfonden) for a major new study involving liver transplant recipients. The study will hopefully provide further important insights into the role of the liver in relation to Alzheimer’s disease.

The transition from studies in mice – which have primarily been conducted so far – to studies in humans is significant, says Henrietta Nielsen.

The research is being conducted together with Carl Jorns and Ewa Ellis at Karolinska Institutet and will follow 1,500 people who have received a new liver and consequently have a different APOE profile from the one they had before transplantation. The aim is to investigate how this change affects the body and the brain.

“We can examine the effects of such a change over a long period of time by measuring plasma biomarkers after transplantation. The goal is to understand what happens in the body and, in the long term, to identify a treatment that can reduce the risk of Alzheimer’s disease.”