Dementia Risk Increased in Those With Down Syndrome

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People with Down syndrome face an increased risk of early-onset dementia due to a defect in a regulatory enzyme that also malfunctions in Alzheimer’s disease.

Domenico Praticò, MD, of the Lewis Katz School of Medicine at Temple University in Philadelphia, and colleagues examined tissues from the brains of deceased Down syndrome patients. When they compared the tissue to postmortem brains of healthy patients, they noticed that the tissue from the Down patients had higher levels of γ-secretase activating protein (GSAP), which is involved in the formation of beta-amyloid plaque and is found in the brains of Alzheimer's disease patients, the researchers reported in the journal Annals of Neurology.

The research demonstrates connection between GSAP hyperactivity and excess processing of the amyloid-beta precursor protein (APP), which is responsible for the the final formation of beta amyloid, in Down syndrome. In Down syndrome, APP overexpression is extremely high, about four to five times higher than normal.

“The higher levels of APP in Down syndrome patients causes increased formation of amyloid beta peptides which then precipitate in the amyloid plaques in the brain much earlier in life,” Praticò said in a statement. “We've shown that GSAP inhibition reduces amyloid production, and because GSAP is specific to the formation of amyloid, without affecting other pathways, it should be a safe alternative to other strategies of a direct γ-secretase inhibition.”

Dementia Risk Increased in Those With Down Syndrome
Postmortem brain tissue from the Down patients had higher levels of an enzyme involved in the formation of beta-amyloid plaque.

Individuals with Down syndrome who survive into adulthood face the additional challenge of early-onset dementia, in which toxic amyloid plaques build up in the brain. The condition is strikingly similar to Alzheimer's disease, and as new work led by researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) shows, dementia in Down syndrome involves defects in a regulatory enzyme known as γ-secretase activating protein (GSAP), which also happens to malfunction in Alzheimer's disease.

The study, which appeared online in the Annals of Neurology, is the first to draw a connection between GSAP hyperactivity and excess processing of the Aβ precursor protein (APP) — the protein responsible for the final formation of amyloid beta — in Down syndrome.

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