A team from the Sant Pau Research Institute (IR Sant Pau), in collaboration with the Catalan Down Syndrome Foundation, has published in the journal Annals of Neurology the largest study to date on brain metabolism—measured through fluorodeoxyglucose positron emission tomography (FDG-PET)—in adults with Down syndrome. The results prove that Alzheimer’s-related neurodegeneration, as measured by FDG-PET, begins many years before the first symptoms appear and can already be detected from age 35.
“In this study, we analyzed how brain metabolism changes in people with Down syndrome throughout the different stages of Alzheimer’s disease: from those who show no symptoms yet, through a prodromal stage where cognitive symptoms begin to appear without affecting functionality, all the way to the dementia stage,” explains Dr. José Enrique Arriola-Infante, first author of the study, who conducted the research at IR Sant Pau and currently works at the Torrecárdenas University Hospital (Almería, Spain).
People with Down syndrome have a unique genetic predisposition: overexpression of the APP gene due to the triplication of chromosome 21 leads to overproduction of beta-amyloid protein, making them a natural genetic model for Alzheimer’s. It is estimated that over 90% of this population will develop the disease over their lifetime.
“The age at which boys and girls with Down syndrome start showing reduced brain metabolism is much earlier than in healthy controls. From age 35, we already see significant differences,” Dr. Arriola points out. “From a very young age, even before symptoms appear, they already show brain hypometabolism in regions typically affected by Alzheimer’s disease: the parietal and temporal lobes.”
The study is part of the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI), an internationally recognized cohort. A total of 105 adults with Down syndrome in different clinical stages of Alzheimer’s disease—asymptomatic, prodromal, and with dementia—were included, along with a group of 71 healthy controls without intellectual disability.
All participants underwent an FDG-PET scan, which visualizes glucose consumption as a marker of brain activity. Structural MRI scans were also performed, along with cerebrospinal fluid extractions to analyze key biomarkers such as beta-amyloid, phosphorylated tau, and neurofilament light chain (NfL), the latter being an indicator of axonal damage.
Images were analyzed using advanced voxelwise statistical techniques, which allow researchers to detect abnormalities at each point in the brain without needing to predefine specific regions. “This analysis allows us to skip any a priori assumptions about anatomical regions and explore where in the brain the effects are occurring. It helps detect the areas where changes emerge earliest,” explains Dr. Alexandre Bejanin, neuroscientist with the Neurobiology of Dementia group at IR Sant Pau and senior author of the paper. “This method is more sensitive than regional analyses, where signals might be missed. It lets us map the exact topography of hypometabolism.”
Beyond brain metabolism, the team also examined how variables such as sex or the degree of intellectual disability might influence outcomes. The findings were clear: the only truly significant factor was age. “Sex did not significantly affect brain metabolism, nor did the degree of intellectual disability,” summarizes Dr. Arriola. “What we did see is that age is directly related to metabolic decline. The older the person, the closer their pattern is to typical Alzheimer’s.”
Dr. Bejanin adds: “The effect of age is stronger in people with Down syndrome than in the general population. That’s because they are essentially all genetically predisposed to develop Alzheimer’s. So, age functions like a marker of the silent progression of the disease.”
One of the most important findings was the strong association between brain hypometabolism and biomarker levels in cerebrospinal fluid. In particular, neurofilament light chain (NfL), a marker of axonal damage, was found to be the most closely associated with metabolic loss.
“What we’ve seen is that the biomarker most related to metabolism is NfL, which also measures neurodegeneration,” explains Dr. Bejanin. “This confirms that the hypometabolism detected by PET is a highly reliable reflection of the disease process.”
The study also found associations with beta-amyloid (Aβ42/40) and phosphorylated tau (p-tau 181) levels, reinforcing the interpretation of hypometabolism as an indicator of Alzheimer’s-related degeneration.
Although FDG-PET is a technique with some logistical limitations—such as requiring the injection of a radioactive tracer—the study highlights its usefulness as a tool for early diagnosis in people with Down syndrome. “What our work shows is that this test’s ability to detect neurodegeneration is strong even in the earliest stages, when individuals are still asymptomatic,” says Dr. Arriola. “This can help us better select participants for clinical trials of treatments aimed at modifying the course of the disease.”
Dr. Bejanin also emphasizes its clinical value. “We already knew this technique is sensitive for detecting neurodegeneration in sporadic Alzheimer’s. What we’re showing now is that it’s also effective in a genetic form like the one seen in Down syndrome.”
The team is already working on complementary research lines. “We’re comparing FDG-PET with other neuroimaging techniques such as structural MRI and cerebral perfusion imaging. This will help us determine which is more sensitive for detecting neurodegeneration in the very early stages,” says Dr. Bejanin. These MRI-based techniques would also be less invasive, as they don’t require injection of radioactive tracers.
Arriola-Infante JE, Morcillo-Nieto AO, Zsadanyi SE, Franquesa-Mullerat M, Vaqué-Alcázar L, Rozalem-Aranha M, Arranz J, Rodríguez-Baz Í, Maure-Blesa L, Videla L, Barroeta I, Del Hoyo Soriano L, Benejam B, Fernández S, Sanjuan-Hernández A, Giménez S, Alcolea D, Belbin O, Flotats A, Camacho V, Lleó A, Carmona-Iragui M, Fortea J, Bejanin A. Regional brain metabolism across the Alzheimer’s disease continuum in Down syndrome. Ann Neurol 2025. https://doi.org/10.1002/ana.27226
