Understanding the History Behind Down Syndrome and Dementia

Down syndrome, caused by trisomy 21, is the most common chromosomal condition associated with intellectual disability, affecting approximately 1 in 700 live births in the United States.¹ Improvements in medical care over the past several decades have led to a steady increase in life expectancy, with many individuals now living well into adulthood. As a result, the clinical landscape of Down syndrome has shifted, with neurologists increasingly encountering age-related neurological considerations in this growing population.

Alongside these demographic changes, there has been a renewed focus on better understanding the neurological profile of Down syndrome across the lifespan, including how underlying biology may influence later-life cognitive outcomes. Ongoing research efforts have begun to reshape how clinicians think about disease risk, monitoring, and long-term care in this population, setting the stage for a deeper exploration of the relationship between Down syndrome and neurodegeneration.

Down Syndrome & Dementia

By the late 1800s and early 1900s, prior to the formal description of Alzheimer disease (AD) itself, physicians began reporting the first cases of premature senility or dementia in adults with Down syndrome. Despite the increased discussion, the relationship between Down syndrome and AD remained poorly understood for decades.²

In 1959, researchers identified trisomy 21–an extra copy of chromosome 21–as the genetic cause of Down syndrome, thus shifting the conversation from descriptive medicine to molecule and genetic neuroscience.³ At the time, researchers then began to investigate how gene dosage on chromosome 21 affects brain development, which would then set the stage for later work linking Down syndrome to neurodegeneration.

The discovery of the link between Down syndrome and amyloid pathology in the 1980s further accelerated the conversation and interest in this area. Through a number of research works, experts in the field found amyloid-ß plaques in the brain of individuals with Down syndrome, similar to those seen in AD. Shortly after, scientists discovered the amyloid precursor protein (APP) gene on chromosome 21, which helped explain why AD pathology is common in this population.^4,5

It turned out that because people with Down syndrome have 3 copies of chromosome 21, they produce excess APP, increasing amyloid-ß accumulation in the brain. This was significant, as Down syndrome was thought to be more of a natural genetic model for AD, and it contributed to the development of the amyloid hypothesis in AD research. Currently, people with Down syndrome who have suspected AD confirmed through PET are also eligible for anti-amyloid therapies, which are considered more targeted, potentially disease-altering options.

Over the past 2 decades, as life expectancy for individuals with Down syndrome has improved, so has the recognition for the high risk of AD. Research has shown that nearly all adults with Down syndrome develop Alzheimer pathology by late middle age, with some estimates suggesting a 75-90% lifetime risk of symptomatic AD in this population.⁶ Over time, the conversation started to shift toward more lifespan neurology, early detection, and neurodegeneration in genetic syndromes.

Within the last few years, there has been an influx of longitudinal studies that have provided more insights on the connection between neurology and Down syndrome. Data has revealed that amyloid-ß deposition can begin in the third or fourth decade of life, with tau pathology and cognitive decline following in the years after. In addition, conversion to mild cognitive impairment in this patient population may occur about 7 years after amyloid positivity, with dementia developing roughly 12-13 years later.⁶

These insights have led to research programs such as the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) and the NIH INCLUDE, more biomarker-driven clinical trial designs, and greater inclusion of people with Down syndrome in AD therapy studies. Currently, there are a number of ongoing trials and study programs investigating AD in Down syndrome:

• ALADDIN study – a double-blind, placebo-controlled trial that tests anti-amyloid donanemab (Kisulna; Eli Lilly), one of 2 FDA-approved treatments for AD, in individuals with Down syndrome.
• HERO study – a clinical trial testing ION269 (Ionis Pharmaceuticals), an antisense oligonucleotide designed to reduce production of amyloid plaques by targeting APP expression. The study enrolled adults with Down syndrome who have biomarker evidence of amyloid deposition.
• ELND005 trial – a previously completed study that investigated whether ELND005 could reduce amyloid accumulation and improve working memory in people with Down syndrome. It was considered one of the earlier pharmacologic trials exploring AD-related mechanisms in this patient population.

REFERENCES
1. 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
2. Down Syndrome Research and Medical Care Timeline. Global Down Syndrome Foundation. Accessed March 29, 2026. https://www.globaldownsyndrome.org/about-down-syndrome/history-of-down-syndrome/research-and-medical-care-timeline/
3. Wallace RA, Dalton AJ. What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population? Alzheimers Res Ther. 2011;3(2):13. doi:10.1186/alzrt72
4. Koch L. 1987: Finding the first Alzheimer’s gene Mutations in the gene encoding APP, the precursor to amyloid-β, are found to underpin some cases of familial Alzheimer’s disease. Nature. Published online September 24, 2024. https://www.nature.com/articles/d41586-024-02884-7
5. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. Characterization and Chromosomal Localization of a cDNA Encoding Brain Amyloid of Alzheimer's Disease. Science. 1987;235(4791):877-880. doi:10.1126/science.3810169
6. Schworer EK, Zammit MD, Wang J, et al. Timeline to symptomatic Alzheimer’s disease in people with Down syndrome as assessed by amyloid-PET and tau-PET: a longitudinal cohort study. Lancet Neurol. 2024;23(12):1214-1224. doi:10.1016/S1474-4422(24)00426-5