For years, scientists have contemplated the link between the risk of developing Alzheimer's disease and a metabolic gene called TOMM40, which affects the function of mitochondria, the components inside cells that provide them with energy. Studies have produced mixed results, giving rise to much frustration. However, a new study now finds that a third factor, family history of Alzheimer's, may be the missing link. It shows that having a family history of Alzheimer's disease appears to alter the behavior of TOMM40.

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Researchers have deduced that having a family history of Alzheimer's disease can change the behavior of the gene TOMM40.

The study - led by researchers at Iowa State University (ISU) in Ames - is shortly to be published in the journal Alzheimer's & Dementia.

There are around 5 million people in the United States living with Alzheimer's disease - the most common form of dementia in older adults. This figure is expected to rise to 14 million by 2050.

Alzheimer's disease affects the parts of the brain that deal with memory, thinking, and language.

An internal hallmark of Alzheimer's is the presence of abnormal deposits of amyloid beta and tau proteins in the brain. As these deposits increase, brain cells stop working, lose connections with each other, and perish.

Outward symptoms begin with mild memory loss and progress so that it becomes increasingly difficult to hold a conversation and carry out daily activities.

Although scientists are discovering more and more clues every day, the exact causes of Alzheimer's disease are still not fully understood. They suspect that there are several factors, with some affecting different people in different ways, as this study reveals.

Study explores how family history alters TOMM40

Lead author and study leader Auriel Willette, an assistant professor of food science and human nutrition at ISU, says that the researcher who first came across TOMM40 (Translocase of Outer Mitochondrial Membrane-40kD) found evidence that linked it to a raised risk of Alzheimer's disease. However, as other researchers found that they could not replicate those findings, they dismissed them.

Therefore, Prof. Willette and colleagues decided to investigate other factors that might be producing the mixed findings. They chose to focus on family history of Alzheimer's disease, the definition of which they confined to having parents who developed the disease.

They designed the study to explore the extent to which family history modulated the effects of TOMM40 on symptoms of Alzheimer's disease, such as memory loss and thinking.

The researchers used data from two large studies of Alzheimer's disease. One set of data came from 912 participants in the Wisconsin Registry for Alzheimer's Prevention, which is following middle-aged people at risk for Alzheimer's and tracking changes in memory loss and cognitive function, based on assessments carried out every 2 years for up to a decade.

The other set of data for the study came from 365 participants in the Alzheimer's Disease Neuroimaging Initiative, which is monitoring similar changes in older people with and without Alzheimer's.

Family history influences gene depending on its length

The team found that having a family history of Alzheimer's disease appears to make a big difference to how TOMM40 affects memory and thinking, and that the difference depends on the length of a particular portion of the gene, as Prof. Willette explains:

"It was kind of a shot in the dark, but we found if you don't have a family history of Alzheimer's disease, then having a longer version of the gene is a good thing."

He and his colleagues found that having the longer version of the gene, together with no family history of Alzheimer's, was linked to around a one-fifth lower risk of developing Alzheimer's disease and better memory up to 10 years later.

"However, if your mom or dad has Alzheimer's," says Prof. Willette, "then having a long version is bad. It's a complete polar opposite."

The researchers also found that TOMM40, family history of Alzheimer's disease, and mitochondrial function are also linked.

In other work, the team is also investigating other factors that affect how the body makes and uses energy, such as insulin resistance, as well as proteins and enzymes that affect energy regulation.

Such studies are helping to make sense of what happens to thinking and memory when there is not enough energy for brain cells to perform properly. Prof. Willette describes what the work feels like for researchers:

"It's like trying to solve The New York Times Saturday crossword puzzle, which can be incredibly frustrating. But by finding the correct answer to one question, you can begin to fill in other answers. My hope is we're providing the answer to that crossword and other researchers can find additional answers based off this one."

In the following video from ISU, Prof. Willette explains the study findings and their significance:

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