"Our work found that, just like in sporadic and other genetic forms of the disease, APOE-e4 was associated with earlier clinical symptoms of AD and earlier changes in biomarkers of amyloid, tau, glucose metabolism and hippocampal volume, but not with neurofilament light chain (NfL)," Drs. Alexandre Bejanin and Maria Florencia Iulita of Universitat Autònoma de Barcelona told Reuters Health by email on behalf of the authors.
"Researchers and drug developers should be aware of these results," they said, "particularly for preventive clinical trials of AD if drugs that target amyloid or that use MRI as an efficacy marker are tested, since we now know that these endpoints can be affected by APOE genotype, in sporadic and genetic forms alike."
As reported in JAMA Neurology, the dual-center cohort study included 464 adults with DS in Barcelona, Spain, and in Cambridge, UK, from 2009-2020. Participants underwent neurological and neuropsychological assessments, and a subset of participants had biomarker measurements.
Overall, 464 adults were included in the analyses; 20.9% were APOE-e4 allele carriers. No differences between carriers and non-carriers were observed by age (median 45.9 vs. 43.7) or sex (52.6% vs.54.2%). Notably, no individuals with DS older than age 60 were found in the e4 allele carrier group, a finding the authors say is consistent with previous studies that associated the e4 allele with lower life expectancy.
Carriers presented with AD symptoms at a younger age (mean, 50.7 vs. 52.7) and showed earlier cognitive decline.
Further analyses showed between-group differences in biomarker trajectories with age. Specifically, carriers had lower levels of the CSF Abeta1-42 to Abeta1-40 ratio until age 40; earlier increases in amyloid PET and plasma pTau181; and earlier loss of cortical metabolism and hippocampal volume.
No differences were seen in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed that carriers had lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume.
Drs. Bejanin and Iulita said, "We are continuing this research by exploring the impact of other non-modifiable risk factors of AD, such as the effect of biological sex on biomarkers and clinical symptoms."
"Our work did not allow the investigation of differences between each of the APOE isoforms," they noted. "This is something that would be interesting to explore - particularly, the protective effect of the e2 alleles versus the negative effects of the e4 haplotype."
"Unfortunately, few trials have been conducted in people with DS, and we urge that this changes," they noted. "People with DS are perfectly capable of undergoing all the procedures required in a trial, and the benefits of including them can also help people suffering from AD in the general population."
Dr. Cynthia Lemere of Brigham and Women's Hospital in Boston, coauthor of a related editorial, told Reuters Health by email, "Many of the early Alzheimer's-related changes in biomarkers are similar between people with DS, autosomal-dominant AD and sporadic AD, and can be used to predict the onset of dementia. In particular, APOE-e4 carriers are at increased risk and develop dementia earlier in all three populations. Thus, these similarities suggest that mutual benefits may be achieved by inclusion of people with DS in Alzheimer's clinical trials."
"Going forward, longitudinal studies are needed to track cerebral spinal fluid and blood biomarkers, brain imaging and cognitive testing on a regular basis within individual young and middle-aged adults with DS to allow a more precise estimation of the age of conversion to dementia," she said. "Depending on the disease stage, a precision medicine approach could be used to help prevent or stave off dementia, possibly by targeting amyloid or ApoE or facilitating a healthy lifestyle."
SOURCE: https://bit.ly/3xJzrUk and https://bit.ly/3wCNcTv JAMA Neurology, online July 6, 2021.
By Marilynn Larkin
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