Shedding New Light on Dementia in Down Syndrome

By combining data from several sources, including the National Alzheimer’s Coordinating Center (NACC) database, researchers at the University of Texas Southwestern Medical Center (UTSW) have compiled the most comprehensive analysis to date of Alzheimer’s disease neuropathologic changes in the brains of patients with Down syndrome. The work, published in the Journal of Alzheimer’s Disease, provides new insight into the neuropathology of dementia, and suggests that Down syndrome patients could benefit from new amyloid-targeting therapies. 

Down syndrome occurs in people who inherit an extra copy of chromosome 21. In addition to cognitive and behavioral delays, this triplication can also drive early-onset dementia. “Starting in the 1950s, it was recognized that these patients developed dementia much earlier than usual,” says Fatih Canan, MD, a neuropathology fellow at UTSW and lead author on the new paper. Geneticists have even found the likely mechanism; chromosome 21 carries the amyloid precursor protein gene, so an extra copy of it increases the amount of amyloid-beta protein available to form plaques in the brain. 

In 2012, though, the National Institute on Aging released new diagnostic criteria for Alzheimer’s disease, and only a few studies have looked at the condition in Down syndrome using those guidelines. “The other problem with previous studies was that none of them actually mentioned race as a variable and only a handful included children,” says Canan. To address that gap, he wanted to analyze a large, diverse sample of brains from Down syndrome patients who had died at different ages. 

Building a Large, Diverse Neuropathology Cohort

UTSW has a collection of 34 brains from Black, Hispanic, and White Down syndrome patients. Looking to expand the sample size, Canan heard about the NACC dataset from colleagues. “I requested the data, and they were so quick and fast and helpful,” he says. Amid the NACC’s tens of thousands of patients, he found 29 with Down syndrome. Only six of those cases had the accompanying neuropathology records that he needed, but they nonetheless expanded his initial sample. 

To make the analysis as broad as possible, Canan, along with colleagues at UTSW, the University of Alabama at Birmingham, and the Icahn School of Medicine at Mount Sinai in New York, also included data from the four published studies that had used the current diagnostic criteria. That produced a total sample of 160 patients. “As far as I know, it’s the largest neuropathological dataset from people with Down syndrome published so far,” says Canan. 

Early and Distinct Patterns of Alzheimer’s Pathology

Many of the results confirmed previous findings, showing that the Down syndrome patients did indeed develop Alzheimer’s disease neuropathology early in life -occurring much earlier than in typical, 'sporadic' cases of the disease. But the new paper emphasizes just how early that can happen. “The main surprising finding … was the youngest patient we found to have diffuse plaques in the frontal lobe, was an 11-year-old kid,” says Canan. 

Another surprise was the trajectory of neuropathology in Down syndrome. Sporadic Alzheimer’s disease tends to start with the accumulation of tangles of Tau protein, followed by the development of amyloid plaques. In Down syndrome, however, Canan and his colleagues saw that amyloid plaques develop first,  and Tau tangles only arise a few decades later. 

Other forms of neurodegenerative disorders were infrequent in Down syndrome patients. “In sporadic Alzheimer’s, comorbid pathologies are almost always the rule; we usually see other pathologies like Lewy body disease and aging-related tau astrogliopathy,” says Canan, adding that “we also evaluated those proteinopathies in these Down syndrome patients, and they’re relatively rare.” In the few cases where other forms of neurodegenerative disorders occurred, the patients were in their sixties or seventies, long past the point when their Alzheimer’s disease pathology had started. 

Implications for Treatment and Future Research

Down syndrome neuropathology also helps illuminate the pathogenesis of sporadic Alzheimer’s disease. In particular, Canan points to the beta-amyloid cascade hypothesis, which is that amyloid-beta plaque formation is the primary cause of Alzheimer’s disease. “It seems like that’s fitting more with the Down syndrome patients, but not with the sporadic Alzheimer’s disease patients, so that can be worked on to see what the difference is,” he says. 

The researchers are now extending their work to use image analysis and machine learning to examine whether amyloid plaque morphology differs between sporadic Alzheimer’s disease and Down syndrome-associated Alzheimer’s disease. “Our goal is to apply AI-based methods to see whether these plaques show distinct morphological patterns in the two conditions,” says Dr. Canan. He’s especially excited about plans by the NACC to include more imaging data, which could provide a larger pool of pathology data for both sporadic and Down syndrome-associated Alzheimer’s disease cases.

Canan F, Wick N, Raisanen JM, Burns DK, Hatanpaa KJ, Richardson TE, White CL 3rd, Daoud EV. Characterization of neurodegenerative pathologies in adult and pediatric subjects with Down syndrome. J Alzheimers Dis. 2025 Sep;107(2):835-856. doi: 10.1177/13872877251362762. Epub 2025 Sep 1. PMID: 40785271; PMCID: PMC12417618.