A recent study published in eBioMedicine has uncovered a potential connection between genetic mosaicism and a lower risk of Alzheimer’s disease (AD) in adults with Down syndrome (DS). This research offers new insights into amyloid biomarkers and their implications for both DS patients and the general population.
Researchers utilized biomarker and neuropsychological data from two extensive studies focused on Down syndrome to explore the relationship between mosaicism and the onset of Alzheimer’s disease. The findings indicate that mosaicism, a rare genetic phenomenon occurring in approximately 1.3-5% of individuals with Down syndrome, modifies typical DS characteristics and significantly reduces the risk of developing Alzheimer’s. Additionally, mosaicism was linked to less severe congenital heart disease and a slower decline in cognitive function.
Down syndrome, also known as trisomy 21, results from the presence of an extra copy of chromosome 21, leading to three copies of the amyloid precursor protein (APP) gene rather than the usual two. This genetic condition is associated with various comorbidities, including congenital heart disease and a markedly increased risk of Alzheimer’s disease.
A small subset of individuals with Down syndrome exhibit mosaicism, where some cells possess the normal two copies of the APP gene. This genetic variation appears to create a spectrum of cognitive outcomes, with observational evidence suggesting that individuals with mosaicism tend to live longer and remain free of Alzheimer’s disease compared to those without this genetic trait.
The study aimed to bridge existing gaps in knowledge regarding the role of mosaicism in the relationship between Down syndrome and Alzheimer’s disease. Data were drawn 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, which included 468 participants. Notably, the ABC-DS cohort featured neuroimaging data, including advanced MRI techniques.
Participants underwent blood tests to assess various biomarkers, including amyloid beta (Aβ40 and Aβ42), tau, and neurofilament light chain (NfL). Additionally, some participants had their cerebrospinal fluid analyzed for biomarkers, including phosphorylated tau (ptau181). The mosaicism status of participants was determined through karyotyping, while cognitive assessments were conducted every 16-18 months using the Down Syndrome Mental Status Examination (DSMSE).
The study found that approximately 10% of participants exhibited mosaicism. Although the research could not confirm whether mosaicism is present from birth or develops later, it noted a rising prevalence of mosaicism with age, particularly in individuals over 30.
Participants with mosaicism demonstrated lower plasma levels of amyloid peptides (Aβ40 and Aβ42) compared to their non-mosaic counterparts, likely due to the reduced expression of the APP gene. Interestingly, these differences were not observed in cerebrospinal fluid biomarkers, and mosaicism did not appear to affect amyloid or tau deposition rates in the brain or baseline cognitive performance.
Significantly, individuals with mosaicism experienced slower cognitive decline and a markedly reduced risk of clinical dementia. While the mechanisms behind these findings remain speculative and warrant further investigation, the study underscores the potential influence of APP gene products on Alzheimer’s disease risk and progression.
Conclusions
This research highlights the impact of genetic mosaicism on Alzheimer’s disease risk and cognitive decline in individuals with Down syndrome. Despite their genetic predisposition to Alzheimer’s, those with mosaicism exhibited significantly less cognitive deterioration and lower dementia risk as they aged.
The findings 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 broader population.
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