Study reveals timeline of Alzheimer’s brain changes

Science and Translational Medicine: Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury

A study led by researchers in Germany has shed more light on the sequence of biological changes that precedes the symptoms of Alzheimer’s disease. The team found that signs of inflammation can be detected in spinal fluid around five years before people develop Alzheimer’s symptoms but after other key brain changes associated with the disease. The research is published today (Wednesday 14 December) in the journal Science and Translational Medicine.

Scientists know that certain biological changes associated with Alzheimer’s disease, such as the build-up of the amyloid and tau proteins in the brain, can occur many years before people experience symptoms. Recent research has implicated the brain’s immune response in contributing to damage in Alzheimer’s but it is not clear when exactly this process might begin. The authors of this study set out to investigate the point at which unusual immune system activity begins and place this in the timeline of Alzheimer’s brain changes.

Indicators of key Alzheimer’s brain changes, such as the build-up of amyloid and tau proteins, can be detected by analysing levels of these proteins in spinal fluid. TREM2 is a protein that regulates the brain’s immune response to damage in Alzheimer’s, and levels of this protein in the spinal fluid reflect immune system activity. TREM2 was first linked to the disease when researchers funded by Alzheimer’s Research UK identified changes in the gene associated with a higher risk of Alzheimer’s.

This study involved 127 people with a rare genetic mutation that causes Alzheimer’s who had not yet developed symptoms of the disease. While this form of the Alzheimer’s shares many important features with the more common non-genetic form, one key difference is that researchers know who will go on to develop the disease in advance. This allows them to identify and monitor biological changes that precede the symptoms of the disease. The researchers in this study compared levels of TREM2 in the spinal fluid of people with and without the genetic mutation.

They also looked at indicators of several other brain changes linked to Alzheimer’s, including:

• The build-up of the amyloid and tau proteins.
• changes in glucose metabolism – an indicator of how much energy the brain is using.
• shrinkage of a brain area involved in memory.
• changes in memory and thinking ability.

The researchers found that people with the genetic mutation had detectably higher levels of TREM2 in their spinal fluid five years before they were expected to develop symptoms, in comparison to those without the mutation. The study indicates that this rise in inflammation is years later than detectable changes of amyloid and tau but around the same point as the other Alzheimer’s indicators, such as brain shrinkage and changes in metabolism.

Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:

“Alzheimer’s is a complex disease involving changes in a number of different biological processes, that scientists are still working hard to unravel. A growing body of evidence points to a role for inflammation in the development of Alzheimer’s, but this study has helped to establish how this fits into the biological chain of events that plays out as the disease develops. The discovery linking TREM2 to Alzheimer’s, made by UK scientists and funded by Alzheimer’s Research UK, has been hugely influential in shaping Alzheimer’s research and it’s promising to see further progress being made in this important area.

“While the TREM2 test used in this study isn’t being proposed as a way of diagnosing Alzheimer’s, understanding how the underlying processes fit together is crucial in the search for new ways to fight the disease. It is likely that the best future treatment approaches will involve tackling the disease on multiple fronts, so knowing which processes take hold and when is essential groundwork. We’re already seeing new treatments being developed to target the immune system as a potential approach to treat Alzheimer’s. Continued investment in research is vital to ensure findings such as these are translated into new treatments that are desperately needed to help the 500,000 people living with Alzheimer’s in the UK.”