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New research shows a genetic variant previously associated with Alzheimer’s is also linked to Lewy body and frontotemporal dementia. Ekaterina Demidova/Getty Images
  • Dementia cases are rising fast globally, yet there is little understanding of the exact causes of different types of dementia. They are thought to be both environmental and genetic.
  • Much of the focus of research into genetic risk factors of dementia has been on Alzheimer’s disease.
  • New research has identified a number of genetic variants linked to other forms of dementia.
  • The findings show a specific genetic variant that’s been associated with Alzheimer’s is also linked to Lewy body and frontotemporal dementia.

Every year there are over 10 million new cases of dementia, around two-thirds of which are diagnosed as Alzheimer’s disease (AD).

As such, a significant amount of research focus has been on Alzheimer’s disease and its potential causes.

In 2022, a study in Nature Genetics identified 75 genetic variants linked to an increased risk of developing Alzheimer’s.

One genetic risk factor — a variant of the APOE gene — is widely understood. In fact, it was the subject of a media frenzy in late 2022 when actor Chris Hemsworth discovered he had an 8 to 10 times greater risk of developing the condition after genetic testing showed he had two copies of the variant.

In contrast, research into genetic risk factors that affect other types of dementia including Lewy body dementia and frontotemporal dementia, have received less attention. This is despite the fact that it is possible to have more than one type of dementia at once.

To gain greater insight into the genetic structural variants that could be linked to Lewy body and frontotemporal dementia, researchers from the National Institutes of Health (NIH) recently carried out whole genome sequencing on 5,213 individuals with these types of dementia, and compared them to 4,132 controls who did not have dementia.

The results show that a genetic variant previously associated with Alzheimer’s is also linked to other forms of dementia. The results are published in Cell Genomics.

Scientists used a type of whole genome sequencing called short read sequencing which involves chopping up the genome into shorter chunks, sequencing them, and putting them in order.

They were looking specifically for genetic variants known as structural variants, which occur when large chunks of the genome feature changes due to events such as duplications or translocation.

This is in contrast to genetic variants which have smaller variations, such as a single nucleotide change.

While both types of variants can cause or increase the risk of certain diseases, it is particularly important to look at this type of variant as structural variants have been implicated in many other neurological conditions.

Dr. David A. Merrill, adult and geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center in Santa Monica, CA, told Medical News Today:

“These are all neurodegenerative syndromes that lead to functionally impairing cognitive and memory loss. The difference is the underlying pathologic process for each.”

Researchers looked specifically at 50 genes on the genome already known to be linked to inherited neurodegenerative disease and used machine learning-based algorithms to discover 83 structural variants linked to Lewy body dementia and 81 linked to frontotemporal dementia.

This analysis identified variants at three points on the genome already implicated in the risk of dementia.

Researchers discovered one variant of the gene TCPN1, in which more than 300 nucleotides were deleted, was found in patients with Lewy body dementia.

This is the first time the TCPN1 gene has been linked to Lewy body dementia, having previously been linked to genetic risk factors for Alzheimer’s disease.

“Alzheimer’s disease is typically amyloid plaques along with tau tangles,” Dr. Merrill said.

“Frontotemporal dementia is predominantly tau tangle based with or without plaques. Lewy body dementia is a Parkinson’s spectrum disease that involves misfolding of a protein called alpha-synuclein. The symptoms differ for the different diseases based on where in the brain the pathology develops.”

– Dr. David A. Merrill, adult and geriatric psychiatrist

A limitation of short read sequencing is that it’s considered better at detecting smaller variants, rather than more complex structural variants, as were investigated in the current study.

In addition, all of the study participants were of European ancestry, which means the results cannot be extrapolated to individuals with other ancestries.

Previous research into the genetic determinants of dementia has shown that people of African ancestry with the APOE gene variant linked to increased Alzheimer’s risk are actually less likely than people of European ancestry with the same variant to develop the condition.

It’s thought this could be due to differences in the epigenetics at the site of the gene, affecting the ability of the cell machinery to access, read and transcribe it, highlighting the importance of considering ancestry in relation to genetic risk factors.

The results of this study were unlikely to change how dementia is diagnosed, said Dr. Hana Patel, general practitioner and GP Expert Witness and Honorary Lecturer, University of Kent. She noted to MNT:

“There’s not a different pathway to all the different forms of dementia, you generally go into the memory assessment clinic and then once we get the results of the test to make sure there’s no kind of underlying, for example, thyroid issues or folic acid deficiency issues, then the consultant, geriatrician, or psychiatrist, will refer patients for a CT scan, or some sort of imaging their head and maybe do more than in-depth history taking. The brain scans we do — usually, it’s an MRI — will help confirm the diagnosis of dementia and the type of disease that’s causing the dementia.”

Dr Merrill added that genetics “help us stratify patients into higher versus lower risk.”

In the vast majority of cases, genes are not your destiny when it comes to neurodegenerative disorders. What we do to optimize and maintain our health makes a huge difference in how well our brains age,” Dr. Merrill said.