By Ana Gorelova
Alzheimer’s disease is a devastating neurological condition that affects millions of people globally. It robs individuals of years of independent living, strains relationships and challenges health care workers—and its burden is especially felt by individuals with Down syndrome.
More than 90% of adults with Down syndrome will develop Alzheimer’s disease by their early- to mid-60s, a stark contrast to the estimated 10% lifetime risk in the general population. This increased risk is partly attributed to the extra 21st chromosome that people with Down syndrome are born with. It carries additional copies of genes that produce amyloid-beta and promote the formation of tau tangles—two hallmark pathologies of Alzheimer’s disease in the brain.
However, until a pair of papers published in July in Alzheimer’s & Dementia, the genetic landscape of Alzheimer’s disease in Down syndrome remained incomplete. The studies, led by investigators at the University of Pittsburgh, identified new genetic signatures of the disease that are unique to Down syndrome.
By analyzing genetic samples collected by the Alzheimer’s Biomarker Consortium–Down Syndrome (ABC-DS), a team of researchers led by Ilyas Kamboh, a professor of human genetics and of epidemiology at Pitt’s School of Public Health, discovered several distinct gene regions associated with adverse levels of amyloid and clumping-prone tau in the blood.
Despite similar patterns of plaques and tangles in the brain, the studies found minimal overlap in the genes driving these changes between Down syndrome patients and people with Alzheimer’s disease in the general population. Even the well-known Alzheimer’s risk gene APOE4, which is one of the most impactful genetic risk factors for dementia in the general population, did not conform to the expected pattern. APOE4 carriers with Down syndrome did not exhibit greater levels of amyloid and tau biomarkers than those without this genetic risk factor, challenging the established understanding of Alzheimer’s risk.
Unlike in the general population, the combined effect of minor genetic variations on the probability of Alzheimer’s-associated cognitive decline—called the polygenic risk score—was not predictive of Alzheimer’s-associated dementia in Down syndrome patients. Furthermore, APOE4 showed only a modest association with dementia risk in Down syndrome.
“This tells us that the extra chromosome in Down syndrome may create a unique genetic environment that influences how Alzheimer’s develops,” said Kamboh. “These are not just early versions of typical Alzheimer’s; it’s a distinct biological process.”
The newly identified associations between genetic traits and blood and imaging biomarkers pave the way for personalized treatments that target previously unknown molecular pathways contributing to Alzheimer’s pathology in this patient population.
“We’re trying to understand what’s happening biologically years before symptoms appear,” Kamboh added. “That’s how we’ll find opportunities to intervene early.”