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Early-onset Alzheimer's gene explored in teens

Tuesday 6 November 2012

A "dementia gene" has been found in a third of teenagers, "helping to predict the disease 20 years before devastating symptoms strike", the Daily Mail claims. While, according to the Daily Express, the "dementia gene" is "found in nearly half of teenagers". Both of these claims are inaccurate.

The news is based on the results of a small study exploring the effects of a genetic mutation called PSEN1 E280A. This mutation causes early-onset Alzheimer’s disease, in which the symptoms of Alzheimer’s develop before the age of 65.

Despite the claims in the Mail and the Express this mutation (and other mutations associated with early-onset Alzheimer’s) is rare in European populations. The Alzheimer’s Society estimates that, in the UK, genetic mutations account for fewer than 1 in 1,000 cases.

In this study, the researchers compared the results of brain scans, blood tests and tests of cerebrospinal fluid from young people with the genetic mutation to those from other young people who were not carriers of the mutation.

They found that carriers had functional and structural brain differences, and elevated levels of the protein that forms the deposits characteristic of Alzheimer’s disease in their blood and cerebrospinal fluid. These changes were present when participants were aged between 18 and 26 years old, two decades before symptoms of mild cognitive impairment associated with early-onset Alzheimer’s normally develop.

These findings suggest that brain changes may begin many years before early-onset Alzheimer’s disease becomes symptomatic. However, this was a very small study of a single, rare hereditary form of Alzheimer’s. It is not clear whether the findings will apply to most Alzheimer’s patients who develop the common form of the disease, which develops late in life and with no definite known cause.

While interesting, at the moment the results of this study have no direct implications for the prevention or treatment of Alzheimer’s. 

Where did the story come from?

The study was carried out by researchers from Banner Alzheimer’s Institute, Arizona, and a number of other research institutes in the US and Colombia. It was funded by Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, the US National Institute on Aging, the US National Institute of Neurological Disorders and Stroke, and the State of Arizona.

The study was published in the peer-reviewed journal The Lancet Neurology.

This research was covered reasonably well by BBC News and The Daily Telegraph. Although the reporting by both was mainly accurate, the Telegraph referred to a “test” for Alzheimer’s disease. This study was not designed to develop diagnostic tests for Alzheimer’s disease. Instead it documented the changes that occur in the brain decades before clinical symptoms of the disease develop.

At the other end of the spectrum, the reporting of this study by the Mail and the Express was poor. Claims that a dementia gene is found in nearly half of all teenagers are both unhelpful and untrue.

While the PSEN1 E280A mutation may be relatively widespread in Colombian teenagers with a family history of early-onset Alzheimer’s, there is no evidence that it is widespread in UK teenagers.

Early-onset Alzheimer’s disease remains a relatively rare form of Alzheimer’s both in this country and across the world.

What kind of research was this?

This was a cross-sectional study comparing the brain imaging of ‘cases’ with a particular genetic mutation and ‘controls’ without.

The study included people aged between 18 and 26 with no current cognitive problems who carried or did not carry a mutation that causes a rare, hereditary form of early-onset Alzheimer’s disease. It aimed to determine whether there were differences in brain structure and function and to study the levels of various biological markers in these young people.

Mutations in several genes are known to be associated with early-onset Alzheimer’s disease, such as mutations in:

  • presenilin 1 (PSEN1)
  • presenilin 2 (PSEN2)
  • amyloid precursor protein (APP)

In this study, the researchers were studying carriers of a mutation in PSEN1 (PSEN1 E280A). This mutation is carried by 1,500 people from a related family group of 5,000 residing in the Colombian district of Antioquia. Carriers and non-carriers from this family group were recruited into the study

This mutation causes a single change in the protein, but carriers of this mutation develop mild cognitive impairment at around 44 years of age and dementia at around 49 years of age. 

This study design is ideal for comparing the characteristics of carriers and non-carriers. It would be strengthened if data on the changes in brain structure or function and biomarkers were available over time, to see what really is the first change associated with Alzheimer’s disease.

As it stands, it is unclear whether the differences seen in individuals with the mutation have always been present, or whether they are a specific precursor to Alzheimer’s development.

What did the research involve?

The researchers recruited to their study 20 people aged between 18 and 26 years of age who were carriers of the presenilin 1 (PSEN1) E280A mutation and 24 non-carriers.

The carriers and non-carriers had similar characteristics (gender, age, educational level), clinical ratings relating to Alzheimer’s, such as mini-mental state examination test scores and APOE epsilon 4 status (which predisposes carriers to late-onset Alzheimer’s) and neuropsychological test scores (including tests of verbal fluency and word recall).

The researchers imaged the brains of 16 participants (eight carriers and eight non-carriers).

They used standard magnetic resonance imaging (MRI) to look at brain structure, and also functional MRI, which studies blood flow in the brain.

Changes in blood flow inside the brain can highlight which areas of the brain are functioning while certain tasks are performed, for example, tasks involving memory.

Samples of blood and cerebrospinal fluid (the clear fluid surrounding the brain and spinal cord) were also taken from 20 participants (10 carriers and 10 non-carriers) to look at levels of certain biological markers for Alzheimer’s disease. Specifically these were:

  • amyloid β1-42 (which forms the protein deposits or plaques characteristic of Alzheimer’s disease)
  • tau and phosphorylated tau (which can form the characteristic ‘tangles’ seen in Alzheimer’s disease)

What were the basic results?

The researchers found that, compared with non-carriers, mutation carriers:

  • had significantly higher levels of amyloid β1-42 in their blood
  • had significantly higher levels of amyloid β1-42 in their cerebrospinal fluid
  • had similar levels of tau and phosphorylated tau in their cerebrospinal fluid
  • used different parts of the brain during the memory tasks
  • had less grey matter (the ‘bodies’ of nerve cells) in certain parts of the brain

How did the researchers interpret the results?

The researchers conclude that young adults who are at risk of early-onset Alzheimer’s disease because of their genes have differences in the structure and function of their brain. They also have biological markers in their blood and cerebrospinal fluid that are consistent with overproduction of the protein amyloid β1-42.


This cross-sectional study has found that people carrying a mutation that causes early-onset Alzheimer’s disease have structural and functional differences in their brains and have elevated levels of amyloid β1-42 in their blood and cerebrospinal fluid more than 20 years before the estimated age of onset of mild cognitive impairment. These findings suggest that brain changes may begin many years before Alzheimer’s disease becomes symptomatic.

Although this is an interesting study, it has several limitations:

  • Very few people participated in the trial.
  • The trial was cross-sectional. There were no longitudinal data, and it is unknown whether the changes seen in the brains of those with genetic mutations have always been present or whether they are degenerative changes that have occurred during the person’s lifetime, and if so, how the brain and biological markers have changed over time and at what age they started to develop.
  • As this study only included people with a specific mutation in PSEN1, it is not known whether the results would apply to other people at risk of early-onset Alzheimer’s who have mutations in the APP or PSEN2 genes.
  • Most importantly, this study has looked at people with a rare, hereditary form of early-onset Alzheimer's. It is unclear whether these findings will apply to most people who develop the common form of Alzheimer's disease, which develops late in life and with no definite known cause.

This trial informs scientists and doctors about the development of Alzheimer’s disease – specifically hereditary, early-onset Alzheimer’s.

However, at the moment the results of this study have no direct implications for the prevention or treatment of Alzheimer’s. 

Analysis by Bazian
Edited by NHS Website