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

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

This is evident from a recent study published in the journal eBioMedicine, researchers used biomarker and neuropsychological data from two large-scale DS studies to elucidate the association between mosaicism and the onset of Alzheimer’s disease.

Study results showed that mosaicism, a rare genetic disorder found in 1.3-5% of DS patients, alters normal DS endophenotypes, significantly reducing the risk of AD. Mosaicism was further associated with reduced severity of congenital heart disease and delayed cognitive decline.

These findings provide biological explanations for previously unconfirmed genetic hypotheses and may provide clues for AD prevention and management in 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 chromosome. APP gene instead of the regular two. DS is a relatively common genetic disorder responsible for most gene-associated cognitive decline. The condition is further associated with several comorbidities, including congenital heart disease (CHD) and a greatly increased risk of Alzheimer’s disease (AD).

A rare subset (1.3-5%) of individuals born with AD exhibit ‘mosaicism’, with some of their cells retaining the biologically normal two properties. APP gene copies instead of three. Although 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-mosaic-demonstrating counterparts.

About the study

The current study aims to address existing gaps in knowledge and advance our understanding of the role of mosaicism in DS-AD associations across neurophysiological and biomarker-centric lines of evidence. Study data were 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 imaging). [MRI] and functional MRI [fMRI]), which was absent from the old set.

All participants had blood drawn at the start of the study, both for screening (participants showing translocations were excluded) and for experimental genetic and biomarker analyses. Biomarkers of interest included Aβ₄₀Aβ₄₂tau and NfL (plasma AD biomarkers). Additionally, a subset of the included participants was analyzed for their cerebrospinal fluid biomarkers (plasma markers + ptau181).

Mosaic status was identified through karyotyping of participants either during the screening process or from previous medical records. Cognitive assessments were performed every 16–18 months using the Down Syndrome Mental Status Examination (DSMSE) and included DSMSE-memory (memory items), DSMSE-non-memory (non-memory items), and a total score (maximum = 103). Cronbach’s α metric was used to evaluate DSMSE reliability.

Findings of the study

Due to the lack of karyotyping data at birth for most participants, the current study could not verify whether mosaicism as a trait is present from conception/birth or develops later during routine aging. However, the study could not mosaicize participants <30 jaar identificeren en constateerde een toenemende trend van mozaïcisme-prevalentie bij deelnemers>30, suggesting that mosaicism can be acquired through aging. In total, approximately 10% of the study group showed mosaicism.

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

Plasma biomarker analyzes revealed that mosaicism participants showed lower plasma amyloid peptide concentrations (Aβ₄₀ [-11.5%] and Aβ₄₂ -[9.4%]) than their non-mosaic counterparts. This can be biologically explained by the lower APP gene number and associated expression reductions. Surprisingly, these trends were absent in cerebrospinal (CSF) biomarkers. Mosaicism was also not observed to change the rate of amyloid or tau deposition in the participants’ brains or their cognitive performance at baseline.

The study highlights that mosaicism resulted in slower cognitive decline and a significantly reduced risk of clinical dementia in DS participants. Although the underlying mechanisms remain hypothetical and require future research, this study highlights the contributions of these mechanisms APP gene products in the risk and progression of AD, calling for research that may help identify pharmacological interventions that can be extended to individuals without Down syndrome.

Conclusions

The current study sheds light on the effects of mosaicism on AD and dementia risk and progression in individuals with Down syndrome. Despite their high genetic predisposition to AD, DS patients exhibiting mosaicism showed significantly attenuated age-related cognitive decline and a reduced risk of dementia.

These findings could provide the basis for future pharmacological and metabolomic studies that could unravel anti-AD therapies for both DS patients and non-DS individuals.