Alzheimer’s disease starts earlier and progresses faster in people with Down syndrome

Almost all adults with Down syndrome develop symptoms of Alzheimer’s disease by late middle age, and a new study from researchers at Washington University School of Medicine in St. Louis finds that the disease begins earlier and progresses more quickly in people with Down syndrome. a discovery that could have important implications for the treatment and care of this vulnerable group of patients.

The findings are part of a study published in the journal Lancet Neurology that compares the development and progression of Alzheimer’s disease in two genetic forms of the disease: a familial form known as autosomal dominant Alzheimer’s disease and Alzheimer’s disease associated with Down syndrome.

“There are currently no treatments for Alzheimer’s disease for people with Down syndrome,” says co-author Beau Ances, MD, professor of neurology, who cares for Down syndrome patients and explains that they have historically been excluded from the population of people with it. syndrome. disability from developing clinical trials for Alzheimer’s disease. “It’s a tragedy because people with Down syndrome need this treatment just like everyone else,” he continues.

Down syndrome is caused by the presence of an extra 21 chromosome. This extra chromosome carries a copy of the APP (amyloid precursor protein) gene, meaning that people with Down syndrome develop much more amyloid deposits in their brains than normal. Amyloid accumulation is the first stage of Alzheimer’s disease. In people with Down syndrome, cognitive decline usually occurs by age 50.

People with autosomal dominant Alzheimer’s disease also have a predictable pattern of cognitive decline. These patients inherit mutations in one of three specific genes: PSEN1, PSEN2 or APP. They typically develop cognitive symptoms at the same age as their parents: 50, 40, or even 30.

“Because these two groups develop the disease at a relatively early age, they do not exhibit the age-related changes seen in most patients with Alzheimer’s disease, who are typically over 65 years of age,” explains study author Julie Wisch, Ph.D., chief neuroimaging engineer. in the Ances laboratory. “This, combined with the clearly defined age of onset of both conditions, gives us a rare opportunity to disentangle the effects of Alzheimer’s disease from normal aging and expand our understanding of the pathology of the disease,” he adds.

In this study, scientists mapped the development of tau tangles, the second stage of Alzheimer’s disease. Using positron emission tomography (PET) scans of 137 participants with Down syndrome and 49 with autosomal dominant Alzheimer’s disease, the researchers looked at when tau tangles appeared in relation to amyloid plaques and which parts of the brain were affected.

The study found that amyloid plaques and tau tangles—protein abnormalities that precede cognitive decline in Alzheimer’s disease—accumulated in the same areas of the brain and in the same sequence in both groups. However, in people with Down syndrome, this process occurs earlier and faster, and the levels of tau are higher for a given level of amyloid.

“The typical progression of Alzheimer’s disease is that you see amyloid and then tau comes in—and this happens five to seven years apart—and then neurodegeneration,” explains Wish. “In Down syndrome, amyloid and tau accumulate almost simultaneously,” he adds.

There is currently only one FDA-approved treatment for Alzheimer’s disease that has been shown to be effective in modifying the course of the disease: lecanemab, which targets amyloid. Because amyloid accumulation is the first stage of the disease, lecanemab is recommended for people in the early stages of Alzheimer’s disease with very mild or mild symptoms. Tau-targeted therapies are also being developed to target people in later stages of the disease, when tau pathology plays a more prominent role.

“Given that people with Alzheimer’s disease associated with Down syndrome have compression of the amyloid and tau phases of the disease, we will have to focus on both the amyloid and tau phases,” explains Ances. “We may have to come up with different approaches for this population,” he notes.