Dr Lotte Knudsen began her scientific career researching laundry detergent that would keep red dyes from ruining white clothes.
Decades later, she is the scientist behind semaglutide, the active ingredient in the blockbuster weight-loss drugs Ozempic and Wegovy – and now, she is hoping to harness the drug to prevent dementia.
The self-professed socialist from a small town outside Copenhagen, who relinquished intellectual property rights to semaglutide and didn’t cash in on its massive success like Novo Nordisk executives, spearheaded the development of Ozempic, which was initially designed to treat type 2 diabetes.
The Danish scientist, pioneered research into the drug’s predecessors, culminating in groundbreaking findings about their ability to reduce cognitive decline in dementia patients.
Several studies she co-authored have uncovered compelling evidence that Ozempic-like drugs can prevent hallmark symptoms such as memory loss before causing permanent brain damage.
Dr Knudsen believes they can do even more.
Of the roughly seven million Americans with Alzheimer’s today, around 81 percent are estimated to have type 2 diabetes. The metabolic condition is known to raise the risk of developing the memory-robbing disease by up to 77 percent.
Dr Lotte Knudsen pioneered research into semaglutide and its older cousins, which gave the world Ozempic and Wegovy, breakthrough drugs have have helped around five million people lose weight
The compound she spent years investigating is GLP-1, which mimics a hormone in the brain that regulates appetite and makes people feel full.
Dr. Knudsen helped develop liraglutide, a synthetic version of GLP-1.
Since natural GLP-1 doesn’t last long in the body, Knudsen and her team added a ‘spacer’ to increase its ability to dissolve in the body and help it attach to a protein called albumin. This allowed it to stay in the body longer.
Building on the foundational work done with liraglutide, Dr Knudsen and her team focused on creating a next-generation GLP-1 analog that would offer improvements, including a longer duration of action.
Thus, semaglutide, the active ingredient in Ozempic and Wegovy, was born.
Today, semaglutide has been linked to better outcomes for people with heart disease and heart failure, high blood pressure, and dementia.
Marketed as Ozempic, it is approved to treat Type 2 diabetes but is often prescribed off-label for weight loss.
Wegovy is a higher-dose version that’s approved for weight loss in people who have a body mass index of at least 30, or in overweight people with a BMI of 27 or greater, who also have a medical condition caused by their weight.
The search for a dementia cure has not been going well. Part of this is due to a general lack of understanding of what exactly in the brain causes signature cognitive decline.
Most research, including that which has led to controversial, expensive treatments, has focused almost exclusively on a protein called beta-amyloid. This protein creates the sticky buildup that clogs up the spaces around brain cells.
But scientists are now coming to terms with the notion that they set their sights on the wrong target. A growing body of evidence posits that twisted fibers that build up inside brain cells called tau tangles could be behind the dementia.
A 2015 study published in the journal Journal of Alzheimer’s Disease co-authored by Dr Knudsen investigated how mice given a semaglutide-like compound would be better able to stave off cognitive decline.
They followed the mice for four months. All of them had a predisposition to Alzheimer’s.
The mice given the drug liraglutide for four months had more neurons in a key area of the brain (the hippocampus) associated with memory, suggesting that the drug might help preserve brain cells and improve memory function.
Dr Knudsen said last Spring: ‘The effectiveness against Alzheimer’s has not yet been proven, but it is a hypothesis that we are investigating.’
Still conducting research into liraglutide’s applications, she co-authored a study in 2016 that revealed mice with a genetic tendency to develop tau tangles in their brains and movement issues showed better survival when given liraglutide, semaglutide’s older cousin.
Mice treated with the drug showed a 62 percent reduction in tau tangles compared to the untreated mice.
A few years later, in a study published in the journal Alzheimer’s & Dementia, Dr Knudsen and colleagues sampled nearly 16,000 people and gave one group a drug in the same class as Ozempic while not giving the other group anything.
After three and a half years, they found that the risk of developing dementia was 53 percent lower in the experimental group.
In studies in both humans and mice, those given the class of drug that includes Ozempic had slower rates of cognitive decline linked to fewer deposits of harmful proteins in the brain
In that same study, they looked at a national cohort of more than 120,000 people with diabetes. Dr Knudsen and fellow scientists followed them for seven years and four months and found that people using these drugs over a long period of time had a lower risk of developing dementia.
In addition to the compelling evidence pointing to diabetes’ links to Alzheimer’s, obesity is a known risk factor.
Research has shown a relationship between body mass index (BMI) and brain size in people around the age of 60, finding that the higher someone’s BMI, the smaller their brain is.
Research indicates that brain regions that shrink in Alzheimer’s disease also do so in obese individuals.
Obesity can reduce resilience to Alzheimer’s-related brain damage, worsening symptoms and accelerating disease progression. It can also cause chronic inflammation, negatively affecting the brain by overstimulating immune cells and damaging nerve cells, linking it to dementia.
Ozempic and Wegovy, meanwhile, have been shown to reduce a person’s body weight by five to twenty percent. At this point, between five and seven million people are taking one of these drugs or similar ones from Eli Lilly, and there are early signs that obesity rates may have decreased in the US for the first time.
A CDC report released in September found that 40 percent of US adults were obese from 2021 to 2023, down from 42 percent from 2017 to 2020.
When asked by Pharma Times what her goal for the future of these drugs was, Dr Knudsen said: ‘Building new innovation in cognitive impairment (dementia).
‘Getting GLP-1 properly tested in neurodegenerative disease because a lot of science supports its potential utility there.’
There are purported downsides to semaglutide though. Hundreds of Americans have joined a class-action lawsuit alleging that Novo Nordisk, the maker of Ozempic and Wegovy, failed to warn its millions of eager customers about the very real risk of severe gastrointestinal injury, including stomach paralysis, gallbladder issues, colon removal, and more, as well as making misleading statements about the drugs’ safety.
It’s also not clear yet, because the drugs haven’t been around long enough for researchers to have gathered long-term data, whether people who stop taking one of the blockbuster drugs will quickly regain all of the weight they’ve lost.
Dr Knuden’s research focus has changed drastically over the years. Before changing the landscape of obesity treatment, she was studying at the Technical University of Denmark.
She began working with Danish pharmaceutical company Novo on a project to uncover enzymes that improve how clothes detergent works to both prevent color bleeding and pilling in clothes.
A research mishap during her investigation into the prevention of dye bleeding, which resulted in a stink bomb-like explosion in a lab refrigerator, coincided with Novo’s acquisition of Nordisk, an insulin-making giant.
This transition shifted industrial products to a new division, Novozymes, while Knudsen’s boss became head of a small research group focused on type 2 diabetes. Dr Knudsen was then brought into the fold.
She became a diabetes researcher by chance. Repeated efforts to develop compounds that activated GLP-1 receptors failed.
But Dr Knudsen’s determination pushed the project forward, laying the groundwork for later advancements that became a critical breakthroughs.
