Ask the Expert

Q. Why are people with Down syndrome more vulnerable to Alzheimer disease than others?

A. People with Down syndrome are more vulnerable to the development of Alzheimer disease, and at an earlier age, than people without Down syndrome.  The main reason for this is that there are several genes on chromosome 21, present in triplicate in people with Down syndrome, which are involved with the development of Alzheimer disease.  These genes, and there are several, are translated into proteins at higher levels than usual, leading to enhanced risk of Alzheimer disease in people with Down syndrome.

One of the key genes involved with developing Alzheimer disease in people with Down syndrome is the amyloid precursor protein gene, or APP.  APP is cut into smaller pieces into a protein called beta-amyloid.  Beta-amyloid is a small protein (only 40-42 amino acids long) that is toxic to the cells in the brain, accumulates into clumps or senile plaques, which we see in the brains of all people with Alzheimer disease.  For people with Down syndrome, we see senile plaques beginning to form while people are in their 30’s and with increasing age, we see progressively more and more of these senile plaques.  The more senile plaques a person has in their brain, the higher the likelihood that people will develop Alzheimer disease.

Usually by the time a person with Down syndrome is in their 40’s, they will have both senile plaques and another kind of Alzheimer disease pathology called neurofibrillary tangles in their brains.  Tangles are made of a protein called tau, which develops abnormalities and begins to collect up in twisted tangles inside of brain cells important for thinking and learning.  When you have lots of senile plaques and neurofibrillary tangles, a diagnosis of Alzheimer disease is made.  It is fascinating to note that most times, people with Down syndrome may not shows signs of dementia (losses in learning and memory ability) until they are in their 50’s, almost a decade later!  It may be that other genes on chromosome 21, which leads to more proteins being made, help protect the brain for all those years. 

The best news, however, is that we are seeing more people with Down syndrome reach their 50’s and 60’s without signs of dementia.  When we learn more why these people do not develop dementia even with Alzheimer disease in their brains, we may be able to develop new therapeutics that will help everyone with Down syndrome. Reasons why a person with Down syndrome may stay cognitively intact with age include environmental contributions (e.g. exercise, social enrichment, good diet) or genetic contributions (other genes on chromosome 21 that are made in excess that are good for the brain).

There is a great deal of active research by academic institutions (supported by the National Institutes on Health) and by pharmaceutical companies, to find ways to either prevent beta-amyloid protein from collecting up in the brain or to find ways to clear the protein out of the brain.  All of these lines of research may have significant benefits in future for preventing Alzheimer disease in people with Down syndrome.  Recently, the NIH launched a new funding initiative called  “INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE).  The project aims to understand critical health and quality-of-life needs for individuals with Down syndrome, with the aim of yielding scientific discoveries to improve the health, well-being, and neurodevelopment of individuals with Down syndrome..”. We are excited about this initiative and the impact we believe it will have for people with Down syndrome and their families.

Here at the University of Kentucky, the goal of our research is to follow people with Down syndrome as they get older.  This will help us to understand why and who will develop dementia. Importantly, if we follow people who do not develop dementia we may be able to learn how to prevent this from occurring in others. The Down syndrome aging study is now in its second cycle of funding and will allow us to follow people with Down syndrome as they age to learn more about the challenges they might face.

Website for INCLUDE: https://www.nichd.nih.gov/health/topics/downsyndrome

Website for our study at the University of Kentucky:  https://www.uky.edu/dsaging/

Elizabeth Head, M.A., PhD., Professor and Associate Director of Education, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY.