French actor Maurice Chevalier once said, “Old age isn't so bad when you consider the alternative.” Would we feel differently if “old age” was synonymous with Alzheimer's disease? For people with Down syndrome, that is their reality.
Down syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of an additional copy of chromosome 21 that results in physical developmental delays and intellectual disability. Because of this extra chromosome, virtually every person with Down syndrome age 40 and older has Alzheimer's disease. 1,2 That is to say, they have a progressive neurodegenerative disorder that causes them to accumulate beta-amyloid plaques and neurofibrillary tangles of tau protein in their brain. 3 Down syndrome happens to be one of the most common genetic disorders in the world, occurring in roughly 1 in 700 births in the U.S. 4 The global population of people with Down syndrome is estimated to be over 5 million, 5 making it the largest group of individuals in the world with a genetically determined form of Alzheimer's disease.
Many people with Down syndrome eventually develop dementia, a set of symptoms that may include memory loss and difficulties with thinking, problem-solving, or language. Dementia prevalence increases with age and is estimated to be as high as 77% in individuals over 60 years old. 6 Living to a ripe old age is a relatively recent possibility for a person with Down syndrome. In the early 1980s, the average life expectancy of a person with Down syndrome in the US was only 25 years. 7 Since then, it has increased to 60 years largely due to increased access to better health care and ending the practice of institutionalization. Improved longevity is a double-edged sword for people with Down syndrome since it comes with an increased risk of dementia.
The data are clear. A disproportionate burden of Alzheimer's disease falls on people with Down syndrome. So why is it that so few people are aware of the increased risk of Alzheimer's faced by this group? Worse, why is it that only four out of more than 500 active clinical trials on Alzheimer's disease and related dementias involve people with Down syndrome? 8 In the era of equity and inclusion, this looks like injustice. The way Alzheimer's disease manifests in people with Down syndrome may differ from the general population. That means treatments that work for the neurotypical individuals may not work for individuals with Down syndrome.
But there is hope. In recent years, research efforts dedicated to studying Alzheimer's disease in people with Down syndrome have grown rapidly due to increased funding. The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project, was established in 2018 as a critical health and quality-of-life research initiative for people with Down syndrome. In 2020, the NIH budget for Down syndrome research was $111 million, with $60 million coming from INCLUDE. 9 That may sound like a lot of money, but it pales in comparison to the $2.8 billion budgeted solely to research on Alzheimer's disease and related dementias that same year. 10 It is imperative that the federal government continue to fund INCLUDE and raise its budget commensurate with the funding allotted to Alzheimer's research in neurotypical individuals.
Down syndrome is an ideal condition in which to study Alzheimer's disease. The strong age- dependent progression of Alzheimer's disease and dementia in people with Down syndrome enables more precise tracking of the timing and sequence of neurobiological changes preceding Alzheimer's-related cognitive decline. Because dementia is more predictable—though not fully determined—in Down syndrome than in the general population, people with Down syndrome who have Alzheimer's pathology but do not have dementia are an ideal control group to compare against those with dementia. Brain changes that distinguish these two groups may be associated with risk and resilience to cognitive impairment in spite of pathology. These data can be used to diagnose at-risk individuals earlier in the disease course, add new targets for therapeutic intervention, and enable clinical trials in Down syndrome before Alzheimer's symptom onset. 11 These discoveries may also have high translational value, informing diagnosis and treatment of Alzheimer's disease in the general population.
For all its advantages, there are some limitations to studying Alzheimer's disease in people with Down syndrome. It may be difficult to determine whether the brain changes observed in adults with Down syndrome are specific to Alzheimer's disease. There are developmental differences in brain structure, function, and metabolism researchers must consider when comparing people with Down syndrome to neurotypical individuals with Alzheimer's disease. 11 However, this issue can be mitigated by instead comparing results within Down syndrome groups to control for developmental confounds. Cognitive impairments secondary to intellectual disability can confound the detection of Alzheimer's-related cognitive decline in those with Down syndrome. For example, verbal memory deficits are often found in people with Down syndrome of all ages but are also frequently used as an outcome measure indicating early cognitive impairment in Alzheimer's disease in the general population. To combat this, standard neuropsychological assessments used to detect dementia in typically-developing individuals have been adapted and validated to detect dementia in Down syndrome. 12 Perhaps most importantly, people with Down syndrome represent a vulnerable population that requires additional protections in order to ensure their safe and ethical participation in research. 13 Input from caregivers and clinicians is crucial when designing a study involving individuals with Down syndrome so as to establish trust between participants and researchers and to avoid overburdening participants.
The work is not done. Not even close. We should continue to spread awareness of and fund research on the relationship between Down syndrome and Alzheimer's disease. We must find a cure for Alzheimer's that works for people with Down syndrome. They deserve to look forward to old age, just like anyone else.
References
1. Coyle JT, Oster-Granite ML, Gearhart JD. The neurobiologic consequences of Down syndrome. Brain Res Bull. 1986;16(6):773-787. doi:10.1016/0361-9230(86)90074-2
2. Mann DM. Alzheimer's disease and Down's syndrome. Histopathology. 1988;13(2):125-137. doi:10.1111/j.1365-2559.1988.tb02018.x
3. LaFerla FM, Oddo S. Alzheimer's disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005;11(4):170-176. doi:10.1016/j.molmed.2005.02.009
4. Mai CT, Isenburg JL, Canfield MA, et al. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 2019;111(18):1420-1435. doi:10.1002/bdr2.1589
5. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 [published correction appears in Lancet. 2017 Jan 7;389(10064):e1. doi: 10.1016/S0140-6736(16)32606- X]. Lancet. 2016;388(10053):1545-1602. doi:10.1016/S0140-6736(16)31678-6
6. Head E, Powell D, Gold BT, Schmitt FA. Alzheimer's Disease in Down Syndrome. Eur J Neurodegener Dis. 2012;1(3):353-364.
7. Presson AP, Partyka G, Jensen KM, et al. Current estimate of Down Syndrome population prevalence in the United States. J Pediatr. 2013;163(4):1163-1168. doi:10.1016/j.jpeds.2013.06.013
8. NIA-Funded Active Alzheimer's and Related Dementias Clinical Trials and Studies. National Institute on Aging. Accessed July 1, 2024. https://www.nia.nih.gov/research/ongoing-AD-trials
9. INCLUDE Project/Down Syndrome Research Plan. National Institute of Health. Accessed July 1, 2024. https://www.nih.gov/include-project/include-project-down-syndrome-ds-research- plan
10. May 2020 Director's Status Report. National Institute on Aging. Accessed July 1, 2024. https://www.nia.nih.gov/about/naca/may-2020-directors-status-report
11. Lott IT, Head E. Down syndrome and Alzheimer's disease: a link between development and aging. Ment Retard Dev Disabil Res Rev. 2001;7(3):172-178. doi:10.1002/mrdd.1025
12. Krinsky-McHale SJ, Silverman W. Dementia and mild cognitive impairment in adults with intellectual disability: issues of diagnosis. Dev Disabil Res Rev. 2013;18(1):31-42. doi:10.1002/ddrr.1126
13. Shivayogi P. Vulnerable population and methods for their safeguard. Perspect Clin Res. 2013;4(1):53-57. doi:10.4103/2229-3485.106389