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Curated Papers > Recent high-impact research on "Alzheimer's Disease" (IF≥30, last 5 years)

Alzheimer's disease associated with Down syndrome: a genetic form of dementia. ​

Literature Information ​

DOI10.1016/S1474-4422(21)00245-3
PMID34687637
JournalThe Lancet. Neurology
Impact Factor45.5
JCR QuartileQ1
Publication Year2021
Times Cited189
KeywordsDown syndrome, Alzheimer's disease, early-onset dementia, biomarkers, treatment strategies
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1474-4422
Pages930-942
Issue20(11)
AuthorsJuan Fortea, Shahid H Zaman, Sigan Hartley, Michael S Rafii, Elizabeth Head, Maria Carmona-Iragui

TL;DR ​

Adults with Down syndrome are at a significantly increased risk of early-onset dementia, a leading cause of death in this group, yet diagnosing dementia is challenging due to overlapping symptoms with intellectual disabilities. This research highlights the potential of fluid and imaging biomarkers for accurate diagnosis and emphasizes the need for preventive trials in this population, which could pave the way for disease-modifying therapies that may also benefit other Alzheimer's disease populations.

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Down syndrome · Alzheimer's disease · early-onset dementia · biomarkers · treatment strategies

Abstract ​

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

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Primary Questions Addressed ​

  1. What specific genetic factors contribute to the development of Alzheimer's disease in individuals with Down syndrome?
  2. How do the neuropathological changes in Down syndrome differ from those in typical Alzheimer's disease patients?
  3. What are the current advancements in diagnostic criteria for detecting dementia in individuals with Down syndrome?
  4. How might future therapies for Alzheimer's disease in Down syndrome populations inform treatment approaches for other forms of dementia?
  5. What role do fluid and imaging biomarkers play in the early detection of Alzheimer's disease among adults with Down syndrome?

Key Findings ​

Research Background and Purpose ​

Adults with Down syndrome (DS) are at an increased risk of developing Alzheimer's disease (AD), which is now the leading cause of death in this population. The primary aim of the research is to address the challenges in diagnosing dementia in individuals with DS due to overlapping symptoms of intellectual disability and the absence of validated diagnostic criteria. The study seeks to explore the potential of biomarkers for diagnosis and to highlight the need for preventive treatments for AD in this vulnerable group.

Main Methods/Materials/Experimental Design ​

The research employs a multi-faceted approach to evaluate the neuropathological features of AD in adults with DS, focusing on the use of fluid and imaging biomarkers.

Mermaid diagram
  • Participants: Adults with Down syndrome.
  • Biomarkers: Fluid and imaging biomarkers are assessed for their diagnostic performance.
  • Comparison: The results are compared with those from sporadic and autosomal dominant Alzheimer's disease to understand the temporality of changes.

Key Results and Findings ​

  • Adults with DS exhibit neuropathological changes similar to those seen in Alzheimer's disease.
  • Fluid and imaging biomarkers demonstrate good diagnostic performance in detecting early signs of dementia.
  • The timing of biomarker changes in DS closely aligns with patterns observed in typical Alzheimer's disease cases.

Main Conclusions/Significance/Innovation ​

The findings underscore the critical need for developing validated diagnostic criteria for dementia in individuals with Down syndrome. The promising performance of biomarkers suggests they could serve as effective tools for early diagnosis. Moreover, the research highlights the potential of adults with DS as a target population for Alzheimer's disease prevention trials, paving the way for disease-modifying therapies that could also benefit broader populations.

Research Limitations and Future Directions ​

  • Limitations: The study may be limited by the small sample size and the challenges in generalizing findings across the diverse DS population.
  • Future Directions: Further research is needed to establish standardized diagnostic criteria and to initiate preventive trials targeting Alzheimer's disease in adults with Down syndrome. Exploring the efficacy of emerging therapies in this population could lead to significant advancements in both AD and DS care.
SectionSummary
Research BackgroundIncreased risk of AD in adults with DS; challenges in diagnosis due to overlapping symptoms.
Main MethodsAssessment of fluid and imaging biomarkers; comparison with sporadic AD.
Key ResultsSimilar neuropathological changes; effective biomarkers for early diagnosis.
Main ConclusionsNeed for validated diagnostic criteria; potential for preventive trials in DS population.
Research LimitationsSmall sample size; generalizability issues.
Future DirectionsStandardization of diagnostic criteria; initiation of preventive trials.

References ​

  1. The pathological association between Down syndrome and Alzheimer disease. - D M Mann - Mechanisms of ageing and development (1988)
  2. A prospective 20-year longitudinal follow-up of dementia in persons with Down syndrome. - M McCarron;P McCallion;E Reilly;P Dunne;R Carroll;N Mulryan - Journal of intellectual disability research : JIDR (2017)
  3. Intracerebral haemorrhage in Down syndrome: protected or predisposed? - Lewis Buss;Elizabeth Fisher;John Hardy;Dean Nizetic;Jurgen Groet;Laura Pulford;André Strydom - F1000Research (2016)
  4. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study. - Yakeel T Quiroz;Henrik Zetterberg;Eric M Reiman;Yinghua Chen;Yi Su;Joshua T Fox-Fuller;Gloria Garcia;Andres Villegas;Diego Sepulveda-Falla;Marina Villada;Joseph F Arboleda-Velasquez;Edmarie Guzmán-Vélez;Clara Vila-Castelar;Brian A Gordon;Stephanie A Schultz;Hillary D Protas;Valentina Ghisays;Margarita Giraldo;Victoria Tirado;Ana Baena;Claudia Munoz;Silvia Rios-Romenets;Pierre N Tariot;Kaj Blennow;Francisco Lopera - The Lancet. Neurology (2020)
  5. Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis. - María Carmona-Iragui;Laura Videla;Alberto Lleó;Juan Fortea - Developmental neurobiology (2019)
  6. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. - C A Lemere;J K Blusztajn;H Yamaguchi;T Wisniewski;T C Saido;D J Selkoe - Neurobiology of disease (1996)
  7. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. - Adam S Fleisher;Kewei Chen;Yakeel T Quiroz;Laura J Jakimovich;Madelyn Gutierrez Gomez;Carolyn M Langois;Jessica B S Langbaum;Auttawut Roontiva;Pradeep Thiyyagura;Wendy Lee;Napatkamon Ayutyanont;Liliana Lopez;Sonia Moreno;Claudia Muñoz;Victoria Tirado;Natalia Acosta-Baena;Anne M Fagan;Margarita Giraldo;Gloria Garcia;Matthew J Huentelman;Pierre N Tariot;Francisco Lopera;Eric M Reiman - JAMA neurology (2015)
  8. Clinical and EEG features of seizures in adults with down syndrome. - Stela Lefter;Daniel J Costello;Brian McNamara;Brian Sweeney - Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society (2011)
  9. Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. - A M Cataldo;C M Peterhoff;J C Troncoso;T Gomez-Isla;B T Hyman;R A Nixon - The American journal of pathology (2000)
  10. The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale and methodology. - Benjamin L Handen;Ira T Lott;Bradley T Christian;Nicole Schupf;Sid OBryant;Mark Mapstone;Anne M Fagan;Joseph H Lee;Dana Tudorascu;Mei-Cheng Wang;Elizabeth Head;William Klunk;Beau Ances;Florence Lai;Shahid Zaman;Sharon Krinsky-McHale;Adam M Brickman;H Diana Rosas;Annie Cohen;Howard Andrews;Sigan Hartley;Wayne Silverman; - Alzheimer's & dementia (Amsterdam, Netherlands) (2020)

Literatures Citing This Work ​

  1. Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity. - Miren Altuna;Sandra Giménez;Juan Fortea - Journal of clinical medicine (2021)
  2. Development of treatments for Down syndrome. - Michael S Rafii - The Lancet. Neurology (2022)
  3. Cortical atrophy and amyloid and tau deposition in Down syndrome: A longitudinal study. - Concepcion Padilla;Victor Montal;Madeleine J Walpert;Young T Hong;Tim D Fryer;Jonathan P Coles;Franklin I Aigbirhio;Sigan L Hartley;Ann D Cohen;Dana L Tudorascu;Bradley T Christian;Benjamin L Handen;William E Klunk;Anthony J Holland;Shahid H Zaman - Alzheimer's & dementia (Amsterdam, Netherlands) (2022)
  4. Dissecting the clinical heterogeneity of early-onset Alzheimer's disease. - Daniel W Sirkis;Luke W Bonham;Taylor P Johnson;Renaud La Joie;Jennifer S Yokoyama - Molecular psychiatry (2022)
  5. Feasibility and Long-Term Compliance to Continuous Positive Airway Pressure Treatment in Adults With Down Syndrome, a Genetic Form of Alzheimer's Disease. - Sandra Giménez;Ariadna Farre;Fátima Morente;Laura Videla;Marta Gutiérrez;Susana Clos;Ana Fernández;Marta Blanco;Miren Altuna;Jordi Pegueroles;Amparo Asensio;Bessy Benejam;Mar Batista;Isabel Barroeta;Ana Fortuna;Juan Fortea;Mercedes Mayos - Frontiers in neuroscience (2022)
  6. The Hole-Board Test in Mutant Mice. - Robert Lalonde;Catherine Strazielle - Behavior genetics (2022)
  7. Commentary on Oeckl et al., "Serum Beta-Synuclein Is Higher in Down Syndrome and Precedes Rise of pTau181". - Elizabeth Head;Henrik Zetterberg - Annals of neurology (2022)
  8. Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome. - Maria Florencia Iulita;Diana Garzón Chavez;Maria Klitgaard Christensen;Natalia Valle Tamayo;Oleguer Plana-Ripoll;Sonja A Rasmussen;Marta Roqué Figuls;Daniel Alcolea;Laura Videla;Isabel Barroeta;Bessy Benejam;Miren Altuna;Concepción Padilla;Jordi Pegueroles;Susana Fernandez;Olivia Belbin;María Carmona-Iragui;Rafael Blesa;Alberto Lleó;Alexandre Bejanin;Juan Fortea - JAMA network open (2022)
  9. Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta. - Jun Sugimoto;Danny J Schust;Tomomi Yamazaki;Yoshiki Kudo - Scientific reports (2022)
  10. Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches. - Clíona Farrell;Paige Mumford;Frances K Wiseman - Frontiers in neuroscience (2022)

... (179 more literatures)

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