Scientists have revealed new insights into how Alzheimer's disease risk genes contribute to the disease

A new study has found a link between a known Alzheimer's disease risk gene and alterations at the level of a molecule in the blood called lactoceramide, providing new insights into the underlying mechanisms of the disease and potentially new targets for future drug discovery
.

UK Institute of Dementia

Researchers have discovered a new biological pathway that may be linked to Alzheimer's disease, led by Professor
Paul Elliott of the UK Institute of Dementia Research (UK DRI) at Imperial College London 。 The findings, published in the Proceedings of the National Academy of Sciences (PNAS), provide new insights into the underlying mechanisms of the disease and may provide new targets for future drug discovery
.

The study was published on October 21, 2022 in the journal Proceedings of the National Academy of Sciences (latest impact factor: 12.
779).

Large-scale genetic studies have provided us with reliable information about the different genes associated with an increased risk of developing Alzheimer's disease, but there is currently limited
understanding of how these genes contribute to the disease.
In this study, Professor Elliott and his team sought to investigate this
by looking for links between genes known to be involved in Alzheimer's disease and small molecules in the blood involved in intracellular chemical reactions.

They analyzed blood samples from 2,600 people and found a link between ABCA7, a known Alzheimer's disease risk gene, and changes at the molecular level of a
type of lactoceramide called lactosylceramide in the blood.
Lactose ceramide is a special type of fat of the ceramide family (not to be confused with the fat we consume in food) that can be found in the membranes of certain types of cells and is involved in important biological pathways
in the body.

Lead author Dr Abbas Dehghan, Chief Scientist at Imperial College Eri's UK DRI, explains:

From genetic studies, we know that the ABCA7 gene is associated with an increased risk of Alzheimer's disease, but until now we didn't know why
.
Our study shows that genetic variation in this gene is associated with
alterations at the level of a molecule called lactoceramide in the blood.
This suggests that lactose ceramide and the pathways it is involved in may be one
of the missing links between the ABCA7 gene and an increased risk of Alzheimer's disease.
”

Through further analysis, the researchers found a potential causal relationship between lactose ceramide levels in the blood and an increased risk of developing Alzheimer's disease, suggesting that the ceramide pathway increases the risk of
developing the disease.

Since the blood-brain barrier separates blood from the brain, the researchers also wanted to test whether their findings could be replicated
within the brain.
To investigate this, they used mouse models in which the ABCA7 gene was deleted to help understand its role
.
They found changes in lactoceramide levels in the brains of mice, suggesting that ABCA7 is involved in regulating lactoceramide levels
in the brain and blood.

Professor Paul Elliott, Head of the DRI Research Group at Imperial College UK, Head of the Department of Epidemiology and Biostatistics at Imperial College London and leader of the study, said:

Our goal is to gain new knowledge about environmental, lifestyle, genetic and metabolic risk factors associated with the development of dementia so that we can identify and recommend effective and practical clinical and lifestyle interventions and preventive measures that ultimately lead to improvements in diagnosis, quality of life and life expectancy

"The number of people affected by Alzheimer's disease is increasing as the population ages, but unfortunately, treatment options are very limited
at the moment.
Our research is an important step towards understanding the underlying mechanisms of Alzheimer's disease, which may help develop new drugs
to treat the disease.
" ”

"With this new information about the potential role of lactose ceramide in Alzheimer's disease, we plan to conduct further investigations to try to understand how changes in this and other pathways contribute to the development of
the disease.
"

Professor Jules Griffin, director of the Rowett Institute at the University of Aberdeen and co-author of the study, said:

"Our research is important for two reasons
.
First, we outline why people with altered ABCA7 gene sequences are predisposed to Alzheimer's disease
.
Second, the work highlights that ceramides, a special fat, or lipid, are important for our cells to function properly and may play a key role
in the development of Alzheimer's disease.
If we can better understand this, we can develop new treatments and lifestyle interventions to reduce the impact of
this disease.

"This study clarifies the role of lactose ceramide and highlights the importance of this pathway in Alzheimer's disease, which until now has been largely overlooked
.
"