Gearing Up for Down’s Syndrome Clinical Trials

Part 2 of two

For years, researchers have been paving the way for Down’s syndrome treatment studies by carrying out longitudinal observation studies. These have identified imaging, fluid biomarker, and cognitive measures that could serve as selection or outcome measures. In parallel, clinicians have identified people with Down’s who are willing to take part in trials. Hundreds are expected to join trial-ready cohorts this year. Encouraged by the completion of AC Immune’s Phase 1 trial of an anti-amyloid vaccine in people with Down’s (see Part 1 ), researchers hope to test several other anti-amyloid treatments in these cohorts within the next few years.

“It is truly amazing how much work has happened in the last five years,” Michael Rafii, University of Southern California, Los Angeles, told Alzforum. Juan Fortea, Hospital of Sant Pau, Barcelona, Spain, agreed. “It is a very exciting time for DS research, which benefits from a dramatic increase in attention and funding,” he wrote.

Natural History Studies
Efforts to characterize clinical and biomarker changes during AD progression in people with DS have gained momentum ( Rafii et al., 2021 ). At present, at least nine cohorts in six countries are collecting biomarker data (see sidebar). Six cohorts in the EU are part of the European Horizon 21 Consortium, which tracks AD biomarkers and cognitive changes in more than 1,000 Down’s syndrome volunteers. In the U.S., The Alzheimer’s Disease in Down Syndrome (ADDS) and Neurodegeneration in Aging Down Syndrome (NiAD) cohorts recently merged to create the National Institute on Aging’s Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) ( Handen et al., 2020 ). In this cohort, scientists have collected imaging, fluid, and cognitive biomarkers from more than 400 people with DS age 25 and older. “The planned enrollment is just over 700, and there is a particular focus on increasing diversity,” Laurie Ryan, NIA, Bethesda, Maryland, told Alzforum. The scientists will compare how AD biomarkers change in DS relative to sporadic AD, search for genes that modify AD risk in DS, and apply what they learn to precision medicine approaches and clinical trials.

Also in the U.S., the LIFE-DSR natural history study aims to follow 270 people with DS aged 25 and older for 32 months, measuring plasma AD biomarkers, cognition, and behavior. It recruits using the U.S. Down Syndrome Clinical Trials Network (DS-CTN), which includes 11 clinic sites in nine states.

Biomarkers: Similar in Alzheimer’s and Down’s
What have researchers learned so far about how biomarkers change in Down’s?

Markers begin shifting in a similar way, but at a much earlier age than in AD. In one cross-sectional study, Fortea and colleagues correlated memory, imaging, and fluid biomarker measures with age in 388 people with DS from the DABNI and DiDS cohorts ( Fortea et al., 2020 ). They found that cerebrospinal fluid Aβ42/40 ratios fell and plasma neurofilament light (NfL) concentrations crept up in people’s 20s. Amyloid PET ligand uptake and CSF phospho-tau181 (p-tau181) began rising, while brain glucose metabolism started waning, by the 30s. The hippocampus atrophied and memory declined in people’s 40s. All this culminated in an AD diagnosis at an average age of 54.

In short, Fortea found almost identical AD biomarker trajectories in DS as did researchers led by Randall Bateman, Washington University, St. Louis, in autosomal-dominant AD (see image below and Bateman et al., 2012 ). “There is nothing to suggest that AD is categorically different in DS than in the general population,” Bradley Christian, University of Wisconsin, Madison, told Alzforum.

Likewise, researchers led by Dominic Walsh, then at Harvard Medical School, saw plasma Aβ42 fall, NfL rise, and the N-terminal tau fragment NT1 fall, then rise, in people with DS as they aged. Change was fastest in the 20s to 40s ( Mengel et al., 2020 ). Striking Similarity . Biomarkers and memory decline track similarly in familial AD (left) and DS (right). Most begin to change 15 to 20 years before age of symptom onset (dashed vertical line). For CDR-SOB and Cambridge Cognitive Examination – Down Syndrome ( CAMCOG-DS), higher and lower scores, respectively, indicate worsening. CAMCOG-DS measures seven cognitive domains: orientation, language understanding and production, memory, attention, praxis, abstraction, and visual construction. [Courtesy of Bateman et al., NEJM, 2012 (left) , and Fortea et al., Lancet, 2020 . ]

Tracking Plaques and Tangles
How can this biomarker information be used in clinical trials of DS?

In the case of Aβ, the data suggest it might help select the right candidates for trials. Christian and colleagues grouped people from the ABC-DS cohort by how fast their PET amyloid load changed ( Zammit et al., 2021 ). Three groups emerged: “Aβ-negatives,” “Aβ-positives,” and a group deemed “converters” (see image below). Negatives had a low plaque load at baseline, which grew slowly. Positives had a high baseline plaque load, which grew quickly. Converters had a negative scan at baseline but accumulated plaques as fast as did positives. All About Speed. People with DS, grouped by how fast plaques deposit in their brains over two to four measurement time points. [Courtesy of Zammit et al., NeuroImage, 2021.] Christian proposed that lowering the amyloid-positivity threshold might catch some of the converters, and thus identify a group of people with DS who are at the earliest point of amyloid accumulation, irrespective of their age. He believes this might be a good group to test in trials of anti-amyloid therapies.

Similarly, scientists led by Ira Lott, University of California, Irvine, have identified a pattern of plaque accumulation that might indicate imminent dementia in DS. They took five PET scans over four years in 19 DS adults 40 years old or older without dementia at baseline. In five volunteers who developed dementia during the study, plaques built up in the same brain regions that typically accumulate amyloid in AD, including the inferior parietal cortex and temporal lobes. Buildup in the prefrontal and superior frontal cortices and posterior cingulate best predicted transition to dementia ( Keator et al., 2020 ).

Focusing on change in specific regions of the brain might offer a […]

Read more at www.alzforum.org