Scientists have uncovered some of the strongest evidence yet
that epigenetic changes in the brain play a role in Alzheimer's
disease.
The work was done by a team of researchers at the Institute of
Psychiatry, King's College London, and the University of
Exeter.
Epigenetic changes affect the expression or activity of genes
without changing the underlying DNA sequence and are believed to be
one mechanism by which the environment can interact with the
genome. Importantly, epigenetic changes are potentially reversible
and may therefore provide targets for the development of new
therapies.
Globally, more than 26 million people are currently affected by
Alzheimer's disease. As this number grows in line with an
increasingly aging population, the need to identify new disease
mechanisms is more important than ever. Post-mortem examinations
have revealed much about how Alzheimer's damages the brain, with
some regions, such as the entorhinal cortex, being particularly
susceptible, while others, such as the cerebellum, remain virtually
unscathed. However, little is yet known about how and why the
disease develops in specific brain regions.
The current study found that chemical modifications to DNA
within the ANK1 gene are strongly associated with measures of
neuropathology in the brain. The study found that people with more
Alzheimer's disease-related neuropathology in their brains had
higher levels of DNA modifications within the ANK1 gene. The
finding was particularly strong in the entorhinal cortex, and also
detected in other cortical regions affected by the disease. In
contrast, no significant changes were observed in less affected
brain regions or blood.
Professor Jonathan Mill, from the MRC Social, Genetic and
Developmental Psychiatry Centre at King's College London and the
University of Exeter Medical School, said: "This is the strongest
evidence yet to suggest that epigenetic changes in the brain occur
in Alzheimer's disease, and offers potential hope for understanding
the mechanisms involved in the onset of dementia. We don't yet know
why these changes occur - it's possible that they are involved in
disease onset, but they may also reflect changes induced by the
disease itself."
Dr Katie Lunnon from the University of Exeter Medical School
added: "It's intriguing that we find changes specifically in the
regions of the brain involved in Alzheimer's disease. Future
studies will focus on isolating different cell-types from the brain
to see whether these changes are neuron-specific."
Dr Simon Ridley, Head of Research at Alzheimer's Research UK,
the UK's leading dementia research charity, who also provided
funding for the study said: "We know that changes to the DNA code
of certain genes are associated with an increased risk of
developing Alzheimer's disease. Investigating how epigenetic
changes influence genes in Alzheimer's is still a relatively new
area of study. The importance of understanding this area of
research is highlighted by the fact that epigenetic changes have
been associated with development of other diseases, including
cancer.
"This innovative research has discovered a potential new
mechanism involved in Alzheimer's by linking the ANK1 gene to the
disease. We will be interested to see further research into the
role of ANK1 in Alzheimer's and whether other epigenetic changes
may be involved in the disease."
The international research team used cutting-edge technology to
examine brain tissue from different areas of the brain across three
cohorts - the MRC London Brain Bank for Neurodegenerative Disease
at King's, the Oxford Thomas Willis Brain Bank, and the Mount Sinai
Alzheimer's Disease and Schizophrenia Brain Bank. They analysed
three cortical regions, cerebellum, and blood obtained from several
hundred individuals representing the spectrum of disease; from
those with no evidence of dementia and neurodegeneration, through
to patients with very advanced disease.
The paper, Methylomic profiling implicates cortical deregulation of ANK1 in
Alzheimer's disease, is published in Nature
Neuroscience.