Understanding the genetic link between dementia and Down's Syndrome

Read about a research project we funded into Functional genetic analysis: mechanisms of dementia in people with Down's Syndrome.

Lead Investigator: Dr Emma Jones
Institution: Wolfson Centre for Age-Related Diseases, King's College London
Grant type: Research Fellowship
Grant amount: £196,680
Start date: August 2009
Completion date: January 2013

What was the project, and what did the researchers do?

Down's syndrome is the most common cause of learning difficulties and occurs in approximately one in 800 births. The majority of people with Down's syndrome develop Alzheimer's disease in their 40s and 50s, and most will have Alzheimer's disease pathology (amyloid-beta plaques and tau tangles) in their brains from their 40s. 

People with Down's syndrome have an extra copy of chromosome 21 and as a consequence there will be three copies of the genes on this chromosome, including key genes related to amyloid-beta, tau and the development of Alzheimer's disease. The amyloid precursor protein (APP) gene is located upon chromosome 21. APP is processed into amyloid-beta, which forms the plaques seen in the brains of people with Alzheimer's disease. It is thought that the extra copy of APP is responsible for the early onset of Alzheimer's disease in people with Down's syndrome.

The gene DYRK1A is also present on chromosome 21, and this gene can provide a link between amyloid-beta and the protein tau, which forms the tangles also seen in the brains of people with Alzheimer's. DYRK1A adds phosphate groups to tau, and this is an important stage in producing these tangles. DYRK1A becomes more active when higher levels of amyloid-beta are present. As people with Down's syndrome produce more amyloid-beta, DYRK1A will become even more active.

What were the key results, and how will this help in the fight against dementia?

Dr Jones found that genetic changes in both APP and DYRK1A affect the age of onset of Alzheimer's disease in people with Down's syndrome. People with a particular form of APP developed dementia seven years before people with different APP genetics. This is an important difference in people who are already developing Alzheimer's disease at an early age.

The levels of amyloid and tau in the brains of people with Down's syndrome are associated with age. Three brain regions affected by Alzheimer's disease were studied – entorhinal, frontal and temporal cortices. Before the age of 40, people with Down's syndrome had levels of these proteins similar to those found in people without Down's syndrome, but after this age the levels increased dramatically. This is a similar result to that found previously.

Dr Jones performed a large genetic study of the DNA samples, called a genome-wide association study, which found that similar genes (PICALM and ApoE) increase the risk of developing Alzheimer's in people with Down’s syndrome, as they do in the general population. This shows that genetic information obtained from studies in people with Down's syndrome will also be able to provide information that will help people in the general population and vice versa.

What happened next? Future work and additional grants:

Dr Jones has now taken up a position as a lecturer in translational stem cell biology at King's College London. She will also be continuing the work from this project.

How were people told about the results? Conferences and publications:


  • Presentation, Alzheimer's Society Roadshow, London, April 2011.
  • Departmental seminar, May 2011.
  • Poster – Alzheimer's Association International Conference (AAIC) 2010.
  • Poster – Alzheimer's Association International Conference (AAIC) 2011.
  • Poster – Society for Neuroscience Conference 2012.

Papers: Emma L. Jones, Kin Mok, Marisa Hanney, Denise Harold, Rebecca Sims, Julie Williams, John Hardy, Clive Ballard. A pilot genome-wide association study of Alzheimer's disease in individuals with Down syndrome.  Neurobiol Aging.  (Provisionally accepted, minor revisions required).

  • B Creese, C Ballard, E Jones (2013). Cognitive Impairment in Studies of 5HTTLPR and Psychosis in Alzheimer's Disease: A Systematic Review.  Dement Geriatr Cogn Disord 2013.  35:155-164. 
  • B Creese, C Ballard, D Aarsland, E London, S Sharp, E Jones (2012). Determining the Association of the 5HTTLPR Polymorphism with Delusions and Hallucinations in Lewy Body Dementias. J Geriatr Psychiat. 2012.  Accepted.
  • Emma L Jones, Nathan Gauge, Odd Bjarte Nilsen, David Lowery, Keith Wesnes, Eirini Katsaiti, James Arden, Derek Amoako, Nicholas Prophet, Balaji Purushothaman, David Green, Clive Ballard (2012). Analysis of NSE and S100B as Biomarkers of Cognitive Decline following Surgery in Older People. Dement Geriatr Cogn Disord.  2012. 34:307-311.
  • B Creese, C Ballard, D Aarsland, E Londos, S Sharp, E Jones (2012). No association of COMT val158met polymorphism and psychotic symptoms in Lewy body dementias. Neurosci Lett.  2012. 531:1-4.  
  • Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB, Edison P, Hagan JJ, Holmes C, Jones E, Katona C, Kearns I, Kehoe P, Mudher A, Passmore A, Shepherd N, Walsh F, Ballard C (2012). Drug repositioning for Alzheimer's disease. Nat Rev Drug Discov. 2012;11:833-846.
  • Clive Ballard, Emma Jones, Nathan Gauge, Dag Aarsland, Odd Bjarte Nilsen, Brian K Saxby, David Lowery, Anne Corbett, Keith Wesnes, Eirini Katsaiti, James Arden, Derek Amaoko, Nicholas Prophet, Balaji Purushothaman, David Green (2012). Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial.  PLoS One.  2012;7:e37410.  Erratum in: PLoS One. 2012;7.
  • Jones EL, Aarsland D, Londos E, Ballard C (2012). A pilot study examining associations between DYRK1A and alpha-synuclein dementias. Neurodegener Dis. 2012; 10:229-231.             
  • Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu LM, Tyrer S, Francis PT, Johnson T, Bullock R, Ballard C; on behalf of the MEADOWS trial researchers (2012). Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;379:528-536.
  • Jones EL, Kalaria RN, Sharp SI, O'Brien JT, Francis PT, Ballard CG (2011). Genetic Associations of Autopsy-Confirmed Vascular Dementia Subtypes. Dement Geriatr Cogn Disord. 2011; 31:247-253.
  • Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011). Alzheimer's disease.  Lancet. 2011;377:1019-1031.
  • Ballard C, Corbett A, Jones EL (2011). Dementia: challenges and promising developments.  Lancet Neurol. 2011 Jan;10:7-9.  
  • Jones EL, Ballard CG, Prasher VP, Arno M, Tyrer S, Moore B, Hanney ML (2010). An Intron 7 Polymorphism in APP Affects the Age of Onset of Dementia in Down Syndrome. Int J Alzheimers Dis. 2010 Dec 20;2011:929102.
  • Ballard CG, Jones EL (2010). CSF α-synuclein as a diagnostic biomarker for Parkinson disease and related dementias. Neurology. 2010 ; 75: 1760-1761.
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