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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, offering new insights into amyloid biomarkers and their broader implications for the general population.
Study: The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome. Image Credit: vitstudio/Shutterstock.ComIn 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.
BackgroundDown 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 studyThe 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 findingsDue 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.
ConclusionsThe 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.
Journal reference:
Iron Age Infant With Down's Syndrome Identified Using New DNA Testing
An infant with Down's syndrome dating from the Iron Age has been discovered with a new method of DNA testing.
The technique measures the amount of chromosomes in ancient human cells "more precisely", said researchers.
They have also identified the first prehistoric person with mosaic Turner syndrome, from about 2,500 years ago.
The research was carried out by the University of York, the Francis Crick Institute, the University of Oxford and Oxford Archaeology.
Down's syndrome, mosaic Turner syndrome and other conditions the researchers identified all stem from chromosomal abnormalities.
Most cells in the human body have 23 pairs of chromosomes and the conditions occur when a person's cells have an extra or missing chromosome.
Professor Ian Armit, from the University of York's Department of Archaeology, said: "Ancient DNA samples decay over time and can often become contaminated.
"A new technique was needed to help researchers overcome these challenges so that we could see just how far back we can trace these conditions, and we now know that they have been part of human history for a considerable period of time - more than 2,000 years in some cases."
The individuals tested with the new technology lived across a range of time periods, from the Iron Age 2,500 years ago up to the Post-Medieval period, about 250 years ago.
Klinefelter, Jacob's and mosaic Turner syndromes all involve abnormalities with sex chromosomes and the researchers found that the individuals with these conditions had delayed puberty.
All were buried according to their society's customs although no possessions were found with them, the experts said.
Pontus Skoglund, group leader of the Ancient Genomics Laboratory at the Crick, said: "Our method is able to classify DNA contamination in many cases, and can help to analyse incomplete ancient DNA, so it could be applied to archaeological remains which have been difficult to analyse.
"Combining this data with burial context and possessions can allow for a historical perspective of how sex, gender and diversity were perceived in past societies."
DelveInsight Business Research, LLP: Down's Syndrome Market To Exhibit Growth At A CAGR Of 3.81% By 2034DelveInsight
According to DelveInsight's analysis, the market for Down syndrome is anticipated to increase during the forecast period (2024-2034), owing to the launch of emerging therapies such as AEF0217, ACI-24.060, LEUCETTINIB-21, BUNTANETAP, and others and healthcare spending globally.
LAS VEGAS, Nov. 26, 2024 /PRNewswire/ -- DelveInsight's Down's Syndrome Market Insights report includes a comprehensive understanding of current treatment practices, Down's syndrome emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan].
Key Takeaways from the Down's Syndrome Market Report
Discover which therapies are expected to grab the major Down's syndrome market share @ Down's Syndrome Market Report
Down's Syndrome Overview
Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of an extra copy of chromosome 21. This chromosomal anomaly disrupts normal development, resulting in a range of physical and cognitive differences. The condition is primarily caused by random genetic mutations during the formation of reproductive cells or early embryonic development, though advanced maternal age increases the likelihood of having a child with Down's syndrome.
People with Down's syndrome typically exhibit distinct facial features, such as a flattened face, almond-shaped eyes that slant upward, and a small nose. Other common symptoms include developmental delays, intellectual disabilities, and a variety of health issues like heart defects, respiratory and hearing problems, and a higher susceptibility to infections. Despite these challenges, many individuals with Down's syndrome lead fulfilling lives with appropriate support.
Diagnosis of Down's syndrome can occur prenatally through screening and diagnostic tests, such as blood tests and ultrasounds in the first and second trimesters, or through more definitive tests like chorionic villus sampling (CVS) and amniocentesis. Postnatal diagnosis is typically confirmed by a physical examination and a karyotype analysis to identify the extra chromosome. Early diagnosis and intervention can help address developmental needs and improve the quality of life for individuals with Down's syndrome.
Down's Syndrome Epidemiology Segmentation
The Down's syndrome epidemiology section provides insights into the historical and current Down's syndrome patient pool and forecasted trends for the 7MM. It helps recognize the causes of current and forecasted patient trends by exploring numerous studies and views of key opinion leaders.
The Down's syndrome market report proffers epidemiological analysis for the study period 2020-2034 in the 7MM segmented into:
Down's Syndrome Treatment Market
There is no single treatment for Down's syndrome; instead, care plans are customized to address each person's unique physical and intellectual needs, emphasizing their strengths and accommodating their limitations. For some individuals, immediate surgery may be needed after birth to correct heart defects or long-term dietary modifications may be required for digestive concerns. Common interventions include assistive devices such as hearing aids, mobility aids, and adaptive technology to support learning and daily tasks.
People with Down's syndrome often face an earlier and more pronounced cognitive decline than the general population. Treatments for Down syndrome-associated dementia (DSAD) may include medications like rivastigmine, galantamine, memantine, and donepezil, which inhibit acetylcholine breakdown, providing notable benefits.
Seizure management for those with Down syndrome may involve anticonvulsants like carbamazepine and phenytoin, although these can exacerbate other Down syndrome-related issues. Respiratory problems are also common due to immune deficiencies and respiratory tract abnormalities, often requiring antibiotics or inhaled bronchodilators for effective management.
Along with pharmacological treatments, non-pharmacological therapies such as physical, speech, occupational, and behavioral therapies play a vital role in the early development of children with Down syndrome, promoting independence and productivity. Physical therapy aims to improve motor skills, build muscle strength, and enhance posture and balance, laying the groundwork for key abilities. Speech-language therapy focuses on boosting communication skills and addressing physical challenges like low muscle tone to avoid long-term complications.
Occupational therapy adapts daily tasks to suit the individual's abilities, teaching crucial skills such as eating, dressing, writing, and using a computer. Emotional and behavioral therapies tackle challenges like frustration from communication barriers, compulsive behaviors, and ADHD by identifying triggers and creating strategies to foster positive behaviors and reduce undesirable ones.
To know more about Down's syndrome treatment guidelines, visit @ Down's Syndrome Management
Down's Syndrome Pipeline Therapies and Key Companies
Discover more about Down's syndrome drugs in development @ Down's Syndrome Clinical Trials
Down's Syndrome Market Dynamics
The Down's syndrome market dynamics are expected to change in the coming years. The prevalence of Down syndrome has increased with the rise in lifespan over the past three decades. This, along with the combination of several neurological features in Down syndrome patients-such as language impairment, cognition, learning, and memory-has sparked intense neurodevelopmental research.
Studies in this area hold promise for improving clinical care and quality of life for individuals with Down syndrome and their families, as well as for assessing ways to enhance communication between parents and children. A thorough understanding of the factors affecting pharmacotherapy in Down syndrome could significantly contribute to better clinical outcomes for these individuals.
Furthermore, potential therapies are being investigated for the treatment of Down's syndrome, and it is safe to predict that the treatment space will significantly impact the Down's syndrome market during the forecast period. Moreover, the anticipated introduction of emerging therapies with improved efficacy and a further improvement in the diagnosis rate are expected to drive the growth of the Down's syndrome market in the 7MM.
However, several factors may impede the growth of the Down's syndrome market. Down syndrome presents unique challenges in clinical treatment, as there is currently no medical cure or approved products available in the market, complicating the treatment process. This complexity is compounded by the lack of appropriate, validated scales to measure progress or side effects in participants with learning disabilities, making it difficult to gauge treatment impact effectively.
Furthermore, recruiting participants and their families is challenging, adding to the difficulties in conducting research. Down syndrome is also associated with numerous health problems and high healthcare costs, and individuals may require more intensive monitoring for adverse effects, adherence, and treatment efficacy when managing medications. Conducting clinical studies on the efficacy of psychotropic medications in individuals with Down syndrome is particularly challenging due to the unique language and communication characteristics of this population.
Moreover, Down's syndrome treatment poses a significant economic burden and disrupts patients' overall well-being and QOL. Furthermore, Down's syndrome market growth may be offset by failures and discontinuation of emerging therapies, unaffordable pricing, market access and reimbursement issues, and a shortage of healthcare specialists. In addition, the undiagnosed, unreported cases and the unawareness about the disease may also impact Down's syndrome market growth.
Down's Syndrome Market Report Metrics
Details
Study Period
2020-2034
Coverage
7MM [the United States, the EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan].
Down's Syndrome Market CAGR
3.81 %
Down's Syndrome Market Size in the US in 2023
USD 241 Million
Key Down's Syndrome Companies
AELIS FARMA, AC IMMUNE, PERHA PHARMACEUTICALS, ANNOVIS BIO, APHIOS THERAPEUTICS, and others
Key Pipeline Down's Syndrome Therapies
AEF0217, ACI-24.060, LEUCETTINIB-21, BUNTANETAP, APH-1104, and others
Scope of the Down's Syndrome Market Report
Download the report to understand which factors are driving Down's syndrome market trends @ Down's Syndrome Market Trends
Table of Contents
1
KEY INSIGHTS
2
REPORT INTRODUCTION
3
EXECUTIVE SUMMARY OF DOWN'S SYNDROME
4
DOWN'S SYNDROME MARKET OVERVIEW AT A GLANCE
4.1
MARKET SHARE BY THERAPIES (%) DISTRIBUTION OF DOWN'S SYNDROME IN 2020 IN THE 7MM
4.2
MARKET SHARE BY THERAPIES (%) DISTRIBUTION OF DOWN'S SYNDROME IN 2034 IN THE 7MM
5
KEY EVENTS
6
EPIDEMIOLOGY AND MARKET FORECAST METHODOLOGY
7
DOWN'S SYNDROME: DISEASE BACKGROUND AND OVERVIEW
7.1
INTRODUCTION
7.2
ETIOLOGY
7.3
TYPES OF DOWN'S SYNDROME
7.3.1
Trisomy 21
7.3.2
Translocation Down's syndrome
7.3.3
Mosaic Down's syndrome
7.4
CAUSES AND RISK FACTORS
7.5
COMPLICATIONS
7.6
OTHER HEALTH PROBLEMS
7.7
DIAGNOSIS
7.7.1
Screening Tests
7.7.2
Diagnostic Tests
7.8
TREATMENTS
7.8.1
Early Intervention and Educational Therapy
7.8.2
Treatment Therapies
7.8.3
Drugs and Supplements
7.8.4
Assistive Devices
8
CASE REPORTS
8.1
CASE STUDY: AN IPP TEAM HELPS 6-YEAR WITH DOWN'S SYNDROME IMPROVE COMMUNICATION SKILLS
9
EPIDEMIOLOGY AND PATIENT POPULATION
9.1
KEY FINDINGS
9.2
ASSUMPTIONS AND RATIONALE
9.3
TOTAL PREVALENT CASES OF DOWN'S SYNDROME IN THE 7MM
9.4
TYPE-SPECIFIC CASES OF DOWN'S SYNDROME IN THE 7MM
9.5
GENDER-SPECIFIC CASES OF DOWN'S SYNDROME IN THE 7MM
9.6
PREVALENT CASES OF DOWN'S SYNDROME BY CLINICAL MANIFESTATIONS IN THE 7MM
9.7
PREVALENT CASES OF DOWN'S SYNDROME BY AGE IN THE 7MM
9.8
THE UNITED STATES
9.8.1
Total Prevalent Cases of Down's Syndrome in the US
9.8.2
Type-specific Cases of Down's Syndrome in the US
9.8.3
Gender-specific Cases of Down's Syndrome in the US
9.8.4
Prevalent cases of Down's Syndrome by clinical manifestations in the US
9.8.5
Prevalent cases of Down's Syndrome by Age in the US
9.9
EU4 AND THE UK
9.9.1
Total Prevalent Cases of Down's syndrome in EU4 and the UK
9.9.2
Type-specific Cases of Down's syndrome in EU4 and the UK
9.9.3
Gender-specific Cases of Down's syndrome in EU4 and the UK
9.9.4
Prevalent cases of Down's syndrome by clinical manifestations in EU4 and the UK
9.9.5
Prevalent cases of Down's syndrome by Age in EU4 and the UK
9.10
JAPAN
9.10.1
Total Prevalent Cases of Down's syndrome in Japan
9.10.2
Type-specific Cases of Down's syndrome in Japan
9.10.3
Gender-specific Cases of Down's syndrome in Japan
9.10.4
Prevalent cases of Down's syndrome by clinical manifestations in Japan
9.10.5
Prevalent cases of Down's syndrome by Age in Japan
10
PATIENT JOURNEY
11
EMERGING DRUGS
11.1
KEY COMPETITORS
11.2
AEF0217: AELIS FARMA
11.2.1
Product Description
11.2.2
Other Developmental Activities
11.2.3
Clinical Development
11.2.3.1
Clinical Trials Information
11.2.4
Safety and Efficacy
11.3
ACI-24.060: AC IMMUNE
11.3.1
Product Description
11.3.2
Clinical Development
11.3.2.1
Clinical Trials Information
11.3.3
Safety and Efficacy
11.4
LEUCETTINIB-21: PERHA PHARMACEUTICALS
11.4.1
Product Description
11.4.2
Clinical Development
11.4.2.1
Clinical Trials Information
11.4.3
Other Developmental Activities
11.4.4
Safety and Efficacy
11.5
BUNTANETAP: ANNOVIS BIO
11.5.1
Product Description
11.5.2
Other Developmental Activities
11.5.3
Safety and Efficacy
11.6
APH-1104: APHIOS THERAPEUTICS
11.6.1
Product Description
11.6.2
Other Developmental Activities
12
DOWN'S SYNDROME: MARKET ANALYSIS
12.1
KEY FINDINGS
12.2
MARKET OUTLOOK
12.3
CONJOINT ANALYSIS
12.4
KEY MARKET FORECAST ASSUMPTIONS
12.5
TOTAL MARKET SIZE OF DOWN'S SYNDROME IN THE 7MM
12.6
UNITED STATES MARKET SIZE
12.6.1
Total Market Size of Down's Syndrome in the United States
12.6.2
Market Size of Down's Syndrome by Therapies in the United States
12.7
EU4 AND THE UK MARKET SIZE
12.7.1
Total Market Size of Down's Syndrome in EU4 and the UK
12.7.2
Market Size of Down's Syndrome by Therapies in EU4 and the UK
12.8
JAPAN MARKET SIZE
12.8.1
Total Market Size of Down's Syndrome in Japan
12.8.2
Market Size of Down's Syndrome by Therapies in Japan
13
UNMET NEEDS
14
SWOT ANALYSIS
15
MARKET ACCESS AND REIMBURSEMENT
15.1
UNITED STATES
15.1.1
Centre for Medicare & Medicaid Services (CMS)
15.2
EU4 AND THE UK
15.2.1
Germany
15.2.2
France
15.2.3
Italy
15.2.4
Spain
15.2.5
United Kingdom
15.3
JAPAN
15.3.1
MHLW
16
APPENDIX
16.1
BIBLIOGRAPHY
16.2
REPORT METHODOLOGY
17
DELVEINSIGHT CAPABILITIES
18
DISCLAIMER
19
ABOUT DELVEINSIGHT
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