Weight loss may be an early indicator of Alzheimer’s disease in people with Down syndrome

Unintentional weight loss in people with Down syndrome may predict the onset of Alzheimer’s disease long before typical cognitive symptoms such as memory loss and dementia appear.

Up to 90% of people with Down syndrome experience Alzheimer’s symptoms by the time they reach the age of 65, but the brain changes associated with the disease appear decades earlier. A study recently published by researchers from the University of Wisconsin-Madison in Alzheimer’s Disease Journal shows that unintentional weight loss beginning in the mid-to-late 30s coincides with hallmarks of early Alzheimer’s disease in people with Down syndrome. The results suggest that weight loss may be a useful predictor of disease before the onset of the cognitive problems that often lead to a diagnosis.

“It may be possible to track weight loss as a way to make an early diagnosis of Alzheimer’s disease,” says Victoria Fleming, PhD student in human development and family studies and first author of the study. “Measuring weight change is convenient and low-cost to track, as opposed to screening for early disease pathology through blood tests, imaging scans, or cerebrospinal fluid tests.”

The higher incidence of Alzheimer’s disease in Down syndrome is due to the characteristic triple duplication of Down’s chromosome 21. This chromosome carries one of the genes responsible for regulating the production of amyloid beta, a short chain of amino acids that can build up in the brain and interfere with brain function, leading to the cognitive impairments seen in Alzheimer’s disease.

For people without Down syndrome, being overweight or obese in middle age increases the risk of developing Alzheimer’s disease. Fleming’s primary interest was to look at this association in people with Down syndrome. However, the results were surprising.

“We were really intrigued, because when we looked at the data and the time course over which weight was changing, we actually saw a stronger story of unintentional weight loss associated with early Alzheimer’s pathology in the brain,” says Sigan Hartley, UW-Madison Professor of Human Development and Family Studies and senior The authors of the new study.

The study looked at data on 261 adults with Down syndrome, ages 25-65, who were weighed at first and again about 18 months later. At both points, they also completed a battery of cognitive tests and underwent brain scans to measure levels of amyloid beta and tau, the proteins associated with Alzheimer’s disease.

The people with Down syndrome in the study began showing unintentional weight loss in their mid-30s, around the same time that amyloid buildup was forming. Moreover, people with Down syndrome who lost the most weight had the highest accumulations of these proteins.

“The finding that unintentional weight loss appears to coincide in time with the accumulation of these proteins could indicate that these processes are linked or share causal pathways. This is something we will explore next,” says Hartley.

The results lead to what Hartley calls the weight paradox.

“In middle age, a higher BMI may put you at risk for Alzheimer’s disease. But Alzheimer’s disease may actually be related to weight loss. So, in fact, both could be true,” says Hartley.

Scientists can only speculate on the biological causes of this connection between unintentional weight loss and Alzheimer’s pathology. One hypothesis is that amyloid buildup causes a shift in the brain’s metabolism and hormone balance that leads to a loss of fat and muscle.

The following Fleming studies will focus on how unintentional weight loss occurs, and on teasing out the weight paradox by looking at midlife BMI and the trajectory of unintentional weight loss across multiple time points in Down syndrome.

“We don’t have a lot of good clinical signs that someone might be approaching the cusp of cognitive decline in Alzheimer’s disease,” says Hartley. “Our results are exciting, as they suggest that there may be some non-cognitive signs — including unintentional weight loss — that can help us predict who may be on the verge of developing dementia sooner or later.”