A recent study published in eBioMedicine has identified genetic mosaicism as a potential factor influencing the risk of Alzheimer’s disease (AD) in adults with Down syndrome (DS). This research sheds light on amyloid biomarkers and their implications for both DS individuals and the broader population.
The study utilized biomarker and neuropsychological data from two large-scale studies on Down syndrome to explore the relationship between mosaicism and the onset of Alzheimer’s disease. Findings revealed that mosaicism, a rare genetic condition present in approximately 1.3 to 5% of individuals with Down syndrome, modifies typical DS characteristics, leading to a significant reduction in AD risk. Additionally, mosaicism was linked to less severe congenital heart disease and a delay in cognitive decline.
Down syndrome, or trisomy 21, occurs when an individual has three copies of chromosome 21, resulting in three copies of the amyloid precursor protein (APP) gene rather than the usual two. This genetic condition is common and is associated with cognitive decline and various comorbidities, including congenital heart disease and an increased risk of Alzheimer’s disease.
A small subset of individuals with Down syndrome exhibit mosaicism, where some of their cells have the typical two copies of the APP gene. Observational evidence suggests that those with mosaicism tend to live longer and experience less cognitive decline compared to their non-mosaic counterparts.
The study aimed to fill existing knowledge gaps regarding the role of mosaicism in the relationship between Down syndrome and Alzheimer’s disease. Researchers analyzed data from two independent cohorts: the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) with 357 participants and a legacy cohort from a long-term aging and dementia study in New York with 468 participants. The ABC-DS cohort included advanced neuroimaging data, which was not available in the legacy cohort.
Participants underwent blood tests for screening and biomarker analysis, focusing on key biomarkers such as Aβ40, Aβ42, tau, and neurofilament light chain (NfL). Some participants also had cerebrospinal fluid (CSF) biomarker assessments.
Mosaicism status was determined through karyotyping during screening or from prior medical records. Cognitive assessments were conducted every 16 to 18 months using the Down Syndrome Mental Status Examination (DSMSE), which evaluates memory and non-memory functions.
The study found that while it could not confirm whether mosaicism is present from birth or develops later, it did observe a rising prevalence of mosaicism in participants over 30 years old, with about 10% of the study sample exhibiting this condition. Notably, the frequency of mosaicism increased significantly after age 40 in the ABC-DS cohort and after age 50 in the legacy cohort.
Plasma biomarker analysis indicated that participants with mosaicism had lower concentrations of amyloid peptides Aβ40 and Aβ42 compared to those without mosaicism, likely due to a reduced expression of the APP gene. However, these differences were not observed in CSF biomarkers, nor did mosaicism appear to affect amyloid or tau deposition in the brain or baseline cognitive performance.
Importantly, the study highlighted that individuals with mosaicism experienced a slower rate of cognitive decline and a significantly lower risk of clinical dementia. While the mechanisms underlying these findings require further investigation, the study underscores the role of APP gene products in the risk and progression of Alzheimer’s disease.
Conclusion
This research provides valuable insights into how genetic mosaicism may influence Alzheimer’s disease risk and cognitive decline in individuals with Down syndrome. Despite their genetic predisposition to Alzheimer’s, those with mosaicism showed markedly reduced cognitive decline and dementia risk.
These findings could pave the way for future pharmacological and metabolomic studies aimed at developing anti-Alzheimer’s therapeutics that could benefit both individuals with Down syndrome and the general population.
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