New study links genetic mosaicism to lower Alzheimer’s risk in adults with Down syndrome

By Hugo Francisco de SouzaReviewed by Danielle Ellis, B.Sc.Nov 8 2024

Researchers identified mosaicism as a possible factor influencing Alzheimer’s risk in adults with Down syndrome, offering new insights into amyloid biomarkers and their broader implications for the general population.

In a recent study published in the journal eBioMedicine, researchers leveraged biomarker and neuropsychological data from two large-scale DS studies to elucidate the association between mosaicism and Alzheimer's disease onset.

Study findings revealed that mosaicism, a rare genetic condition recorded in between 1.3-5% of DS patients, alters normal DS endophenotypes, substantially reducing AD risk. Mosaicism was further associated with reduced congenital heart disease severity and delayed cognitive decline.

These findings provide biological explanations for previous unconfirmed genetic hypotheses and may provide clues for AD prevention and management across both DS and non-DS cohorts.

Background

Down syndrome (DS), also known as trisomy 21, is a genetic condition characterized by the duplication of chromosome 21, resulting in patients carrying three copies of the APP gene instead of the regular two. DS is a relatively common genetic condition responsible for most gene-associated cognitive declines. The condition is further associated with several comorbidities, including congenital heart disease (CHD) and greatly elevated Alzheimer's disease (AD) risk.

A rare subset (1.3-5%) of individuals born with AD exhibit 'mosaicism,' wherein some of their cells retain the biologically normal two APP gene copies instead of three. While this introduces a symptomatic spectrum between typical human cognitive decline and DS-mediated phenotypes, a growing body of observational evidence suggests that DS patients exhibiting mosaicism live longer, AD-free lives than their non-mosaicism-demonstrating counterparts.

About the study

The present study aims to address existing knowledge gaps and progress our understanding of the role of mosaicism in DS-AD associations across neurophysiological- and biomarker-centric lines of evidence. Study data was obtained from two independent adult DS cohorts - the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS; n = 357) cohort, and the 'legacy' cohort (long-term New York-based aging and dementia study; n = 468). Notably, the ABC-DS cohort included neuroimaging data (3T magnetic resonance imagining [MRI] and functional MRI [fMRI]), which was absent from the legacy set.

All participants were subjected to blood draws at study initiation, both for screening (participants exhibiting translocations were excluded) and for experimental genetic and biomarker analyses. Biomarkers of interest included Aβ₄₀, Aβ₄₂, tau, and NfL (plasma AD biomarkers). Additionally, a subset of included participants were analyzed for their cerebrospinal fluid biomarkers (plasma markers + ptau181).

Mosaicism status was identified via participant karyotyping, either during the screening process or from previous medical records. Cognitive assessments were carried out every 16-18 months using the Down Syndrome Mental Status Examination (DSMSE) and included DSMSE-memory (memory items), DSMSE-nonmemory (non-memory items), and a total score (maximum = 103). Cronbach's α metric was used to evaluate DSMSE reliability.

Study findings

Due to the lack of karyotyping-at-birth data for most participants, the present study could not verify if mosaicism as a trait is present from conception/birth or develops later during routine aging. However, the study could not identify any mosaicism participants <30 years and observed an increasing trend of mosaicism prevalence in participants>30, suggesting that mosaicism may be acquired through aging. Overall, ~10% of the study sample group exhibited mosaicism.

"The frequency of participants with mosaicism increased from 40 years old in the ABC-DS cohort (<40 vs. 41–50: p = 0.019, Fisher's Exact test) and from 50 years in the legacy cohort (41–50 vs. 51–60: p = 0.014, Fisher's Exact test)"

Plasma biomarker analyses revealed that mosaicism participants demonstrated lower plasma amyloid peptide concentrations (Aβ₄₀ [-11.5%] and Aβ₄₂ -[9.4%]) than their non-mosaicism counterparts. This can be biologically explained due to the lower APP gene count and associated expression reductions. Surprisingly, these trends were absent in cerebrospinal (CSF) biomarkers. Mosaicism was similarly not observed to alter amyloid or tau deposition rates in participants' brains or their baseline cognitive performance.  

The study highlights that mosaicism resulted in slower cognitive decline and significantly reduced clinical dementia risk in DS participants. While the underlying mechanisms remain hypothesis and require future investigation, this study emphasizes the contributions of APP gene products in AD risk and progression, calling for research that may help identify pharmacological interventions extendable to individuals without DS.

Conclusions

The present study sheds light on the effects of mosaicism on AD and dementia risk and progression in DS individuals. Despite their high genetic AD disposition, DS patients exhibiting mosaicism demonstrated substantially attenuated age-associated cognitive decline and reduced dementia risk.

These findings could form the basis for future pharmacological and metabolomic investigations that might unravel anti-AD therapeutics both for DS patients and non-DS individuals.