Using genetic data from 21,982 Alzheimer’s disease patients and 41,944 controls, the authors found that higher levels of a particular lipoprotein – a molecule that carries fat throughout the body – found in LDL, or “bad” cholesterol – may increase the risk of developing Alzheimer’s disease. Their findings were published in Nature’s Communications Biology.

“The method that we used, Mendelian randomization, removes many of the problems that happen in correlational research,” said Charleen Adams, a lead scientist at the Harvard T.H. Chan School of Public Health. “For instance, using Mendelian randomization reduced the chance that something else was responsible for the signal we saw between higher apolipoprotein and Alzheimer’s.”

Every year, more than 10 million new cases of Alzheimer’s disease, the most prevalent form of dementia, are diagnosed. That equates to about one new diagnosis every three seconds. Despite its prevalence, the causes of the degenerative disease remain unclear.

The lipoprotein at the heart of the study – apolipoprotein B-100, often referred to as APOB – is a key player in metabolism and has been linked to cardiovascular disease.

Studying the possible association is difficult because researchers cannot easily modify the level of APOB in study participants, said Brian Boutwell, UM associate professor of population health science and co-author of the report.

“Generally speaking, we can’t randomly assign people to have different levels of APOB in order to see what the effects would be on Alzheimer’s disease,” Boutwell said.

“When classical experiments aren’t really an option, it requires us to use other techniques to try and unpack whether one variable exerts any causal effect on another. In the case of APOB, it could be that the two correlate – higher levels of APOB tend to occur in patients with Alzheimer’s – but not necessarily because one is causing the other. There could be a third factor that causes both.

“Instead, we used a technique called Mendelian randomization – a way to try to do what a traditional experiment does very elegantly.”

Mendelian randomization is a method of using genetic data to strengthen inferences when a traditional study is not an option.

“We know correlation is not necessarily causation,” Adams said. “Mendelian randomization uses genetics to make inferences stronger. It can take care of the problem of there being something else explaining the signal.”

The research is still a long way from being truly convincing that elevated levels of APOB can increase the risk of Alzheimer’s, Boutwell said.

“One thing I think we should make as clear as we can is that our study should not be seen as fundamental, incontrovertible proof of APOB causing Alzheimer’s,” he said. “It’s so tempting when you have interesting findings like ours to latch on to them as more than they are, especially because Alzheimer’s is such a prevalent and devastating disease.”

Adams and Boutwell agreed on the next steps for the research.

“We need five, 10, 15 more studies that line up with what our results show,” Boutwell said. “That’s the nature of science.”

“The second thing, and some of this is already underway at various universities, is the need to clarify the mechanism that causes Alzheimer’s risk to go up.”

Adams agreed: “How do you prove causation? You discover the mechanism that is causing the problem.”

Until then, Boutwell cautioned against vilifying APOB, noting that, in general, lipids help to perform necessary functions in the body, such as transporting fats and cholesterol around the body, which is necessary to create new cells.

“An important point to make about lipoproteins in general is we’re often tempted to only think about them in a negative connotation, but cholesterol is vital to life, not only in our species but in many others as well,” the Ole Miss researcher said. “Cholesterol is so essential in your body that it manufactures it – and that’s a good thing, because there would be very negative consequences otherwise.”

Much more work must be done before definitively saying high APOB levels cause Alzheimer’s disease, but Adams and Boutwell said they hope this study will spark other researchers’ interest topic.

“I found the results very exciting, but it remains important to fight against an impulse to be too excited,” Boutwell said. “Still, if in the coming years and decades, our findings are consistently replicated, it could mean we have a new tool in our toolkit that might help us stave off Alzheimer’s.

“We’re not there yet, but I think most folks would agree that it’s a goal very much worth pursuing.”

This material is based upon work supported by the National Institute of Environmental Health Sciences award no. R01ES031657, the National Institutes of Health award no. T32HL007118 and the Harvard T.H. Chan School of Public Health Dean’s Award.