Should adults with Down syndrome be part of Alzheimer’s clinical trials?

The order and timing of Alzheimer’s disease biomarker changes in Down syndrome patients closely paralleled those seen in sporadic and early-onset forms of Alzheimer’s, a population based cross-sectional study found.

Alzheimer’s disease prevalence reached 90–100% by the seventh decade of life in Down syndrome patients, and median ages for diagnosis of prodromal disease and Alzheimer’s dementia were 50.2 and 53.7 years, respectively, reported Juan Fortea, PhD, of the Hospital de la Santa Creu i Sant Pau in Barcelona, and coauthors, in Lancet.

Biomarker data for Down syndrome patients showed:

  • In the third decade of life, CSF Aβ1–42/1–40 decreased and plasma NFL increased.
  • In the fourth decade, amyloid PET uptake increased; ¹⁸F-fluorodeoxyglucose PET-reflected metabolic decline and CSF p-tau accumulation increased.
  • In the fifth decade, hippocampal atrophy reflecting neurodegeneration occurred.

“Alzheimer disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades,” Fortea and colleagues wrote. “The similarities with sporadic and autosomal dominant Alzheimer disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer disease preventive treatments.”

“Clinical trials in this population have obvious advantages: the ultra-high risk for developing symptomatic Alzheimer disease and, as we showed here, a predictable sequence of events make this population ideal for preventive trials in Alzheimer disease, together with individuals with its autosomal dominant form,” they added. “Notably, Down syndrome is much more common than autosomal dominant Alzheimer disease.”

In an accompanying editorial, Elizabeth Head, PhD, of University of California Irvine, and Beau Ances, MD, PhD, of Washington University St Louis, wrote,”Fortea and colleagues noted similarities between biomarkers reflecting Alzheimer disease pathogenesis in individuals with Down syndrome and individuals with late onset and autosomal dominant Alzheimer disease. These results provide strong evidence that studies of people with Down syndrome can inform research on late-onset and autosomal dominant Alzheimer disease.”

The widely-used A/T/N framework for late-onset and the much less common (<1%) autosomal dominant forms of Alzheimer’s disease posits early amyloid β (Aβ) deposition (A), followed by hyperphosphorylated tau protein accumulation (T), then neurodegeneration (N). These changes begin in a preclinical phase 15 or more years before evident cognitive symptoms appear.

Down syndrome is associated with increased risk of developing early-onset Alzheimer disease, primarily because of the overexpression of the Aβ precursor (APP) gene on chromosome 21. Duplication of the gene, as occurs in Down syndrome (trisomy 21) with a 1.5-fold increase in expression, can cause dementia with Alzheimer’s neuropathology.

The age range for the onset of cognitive decline in Down syndrome varies considerably, though—from <50 years to >70 years—and how biomarkers change over this time in this population is not well known.

To establish the order and timing of changes in biomarkers of Alzheimer disease in adults with Down syndrome, researchers enrolled 388 participants (45% women) with Down syndrome (66% asymptomatic, median age about 38; 12% with prodromal Alzheimer’s disease, median age about 50; and 21% with Alzheimer’s dementia, median age about 54) between June 2009 and June 2019. The cross-sectional study used available follow-up data which included annual evaluations with a cognitive test battery adapted for Down syndrome in a subset of participants.

Fortea and colleagues included participants with mild or moderate intellectual disability who had at least one of the following: APOE allele status; plasma concentrations of amyloid β peptides 1–42 and 1–40 and their ratio (Aβ1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with ¹⁸F-fluorodeoxyglucose, PET with amyloid tracers including ¹¹C-Pittsburgh compound B and ¹⁸F-florbetapir, or MRI.

Down syndrome participants were compared with 242 cognitively health euploid controls with no biomarker abnormalities (67% women, median age 56.6).

Differences between Down syndrome participants and controls included plasma Aβ1–42 concentrations (58% higher in Down syndrome than controls across the Down syndrome age range) and hippocampal atrophy (Down syndrome participants had smaller hippocampi across their life spans than did controls).

Not all findings in Down syndrome mirrored both autosomal dominant and late-onset disease: the group also found features of Alzheimer disease in individuals with Down syndrome that were “more similar to those of autosomal dominant Alzheimer disease than those of late-onset Alzheimer disease, such as early striatal Pittsburgh compound B binding,” the editorialists wrote. “It will be crucial to characterize not only similarities of Alzheimer disease in people with Down syndrome to late-onset Alzheimer disease, but also important differences that might also guide future clinical trials.”

“Biomarker research in people with Down syndrome has important contributions and implications for the general population, especially for individuals with late-onset Alzheimer disease,” they added, noting that biomarker criteria could be used to streamline recruitment of people with Down syndrome for clinical trials.

Limitations of the study include its cross-sectional design and different sample sizes for the different components of the evaluations.

“Regrettably, individuals with Down syndrome have yet to be included in preventive clinical trials,” Fortea and co-authors wrote. “Such trials would, admittedly, pose additional challenges compared with those done in the general population regarding informed consent and concerns about the feasibility of completing all assessments. However, our study shows that a substantial proportion of adults with Down syndrome are capable and willing to do all the multimodal studies required in a trial.”

  1. The order and timing of Alzheimer’s disease biomarker changes in Down syndrome patients closely paralleled those seen in sporadic and early-onset forms of Alzheimer’s, a population based cross-sectional study found.

  2. Though individuals with Down syndrome have yet to be included in Alzheimer’s prevention clinical trials, the researchers suggest a substantial proportion of adults with Down syndrome are capable and willing to do all the multimodal studies required in a trial.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was funded by Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical ResearchCouncil, and National Institutes of Health.

Fortea reports grants from Instituto de Salud Carlos III, Generalitat de Catalunya, National Institute on Aging of the US National Institutes of Health, and Fundació La Marató de TV3, during the conduct of the study; personal fees from AC Immune, Merck, and Novartis, outside the submitted work; and a patent about markers of synaptopathy in neurodegenerative disease.

The editorialists had no disclosures.

Cat ID: 33

Topic ID: 82,33,730,33,138,192,925