New era for AD

Early detection of Alzheimer’s could lead to speedier interventions and treatments – years before symptoms appear, Maria Burke reports

In 2022, a drug made by Eisai called lecanemab demonstrated a small but clear effect on memory decline. The US FDA approved its use through its Accelerated Approval pathway in January 2023, the second drug it has licensed to slow progression of Alzheimer’s. What’s more, there are now over 140 experimental drugs in clinical testing today, offering hope to the millions afflicted by the disease.

However, as well as the lack of effective treatments of Alzheimer’s, there are few ways to diagnose it. A definitive diagnosis requires examining the brain directly after the patient has died. Alternatively, Aβ accumulation in the brain can be measured by cerebrospinal fluid testing, but this is very invasive, or by expensive positron emission tomography.

Most people are diagnosed only after they’ve shown well-known signs of the disease, such as memory loss. By that point, the best treatment options can only slow further progression of symptoms. But research has shown that the seeds of Alzheimer’s are planted years – even decades – earlier, long before symptoms appear.

‘What clinicians and researchers have wanted is a reliable diagnostic test for Alzheimer’s disease – and not just an assay that confirms a diagnosis, but one that can also detect signs of the disease before cognitive impairment happens,’ says Valerie Daggett of the University of Washington, US.

Her team is working on a blood test to detect the small, misfolded clumps of Aβ. The formation of these toxic oligomers is one of the earliest events in the molecular pathology of the disease. They lead to a variety of effects, including impaired neuronal signalling, neuroinflammation, phosphorylation of the brain protein tau and neurodegeneration. These events can begin an estimated ten to twenty years before symptoms appear.

Their test called SOBA (soluble oligomer binding assay) exploits a unique property of the oligomers. When misfolded Aβ proteins start to congregate into oligomers, they form a structure called an alpha sheet, which tends to bind to other alpha sheets. Daggett’s team designed a synthetic alpha sheet, which could capture oligomers. They then used standard methods to confirm that the oligomers attached to the test surface were made up of Aβ proteins.

The team tested SOBA on blood samples taken from over 300 people who had previously made their samples and medical records available for Alzheimer’s research.[1] They found it successfully detected oligomers in the blood of individuals who went on to develop mild cognitive impairment and moderate to severe Alzheimer’s. In 53 cases, the subject’s diagnosis of Alzheimer’s was verified by autopsy after death.

SOBA didn’t detect protein in most members of a control group who showed no signs of cognitive impairment at the time the blood samples were taken. However, it did detect oligomers in the blood of 11 individuals from the control group. Follow-up examination records were available for ten of these individuals, and all were diagnosed years later with mild cognitive impairment or brain pathology consistent with Alzheimer’s.

What clinicians and researchers have wanted is a reliable diagnostic test for Alzheimer’s disease – and not just an assay that confirms a diagnosis, but one that can also detect signs of the disease before cognitive impairment happens.
Valerie Daggett University of Washington, US

‘We believe that SOBA could aid in identifying individuals at risk or incubating the disease, as well as serve as a readout of therapeutic efficacy to aid in development of early treatments for Alzheimer’s,’ says Daggett. ‘SOBA could also be adapted to diagnose other diseases characterised by protein misfolding. We are finding that many human diseases are associated with the accumulation of toxic oligomers that form these alpha sheet structures. Not just Alzheimer’s, but also Parkinson’s, Type 2 diabetes and more.’

Researchers from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, UK, are also working on a blood test, which they say could predict the risk of Alzheimer’s disease almost four years before diagnosis. They have taken a different approach, choosing instead to study how new brain cells form (neurogenesis) in the hippocampus – part of the brain involved in learning and memory. Autopsies have shown this process is affected by Alzheimer’s.

The researchers modelled the process of neurogenesis in a dish by treating human brain cells with blood samples. These samples were taken over several years from 56 people with mild cognitive impairment; of these, 36 were diagnosed with Alzheimer’s. The team observed how the brain cells changed in response to blood as the disease progressed.

They discovered that changes in neurogenesis occurred 3.5 years before a clinical diagnosis.[2] The blood collected from participants who went on to develop Alzheimer’s reduced cell growth and division in human brain cells and increased apoptotic (programmed) cell death. However, it also boosted the conversion of immature brain cells to hippocampal neurons. The researchers suggest this could be an early compensating mechanism for the loss of brain cells experienced by those developing Alzheimer’s.

‘We found the first evidence in humans that the body’s circulatory system can have an effect on the brain’s ability to form new cells,’ says lead author Sandrine Thuret. She thinks their results could potentially be used to predict Alzheimer’s early and help select people with memory problems for clinical trials of promising drugs. Such tests would complement other blood-based biomarkers that reflect the classical signs of the disease, such as the accumulation of amyloid proteins.

A new study that confirms the link between gut disorders and Alzheimer’s may also lead to earlier detection as well as new potential treatments. Observational studies have previously suggested a relationship, but the mechanism has remained unclear. Now genetic data indicate both conditions are associated with unusually high levels of cholesterol.

Researchers at Edith Cowan University in Western Australia analysed large sets of genetic data from studies on people with Alzheimer’s and people with gastrointestinal tract diseases, each of about 400,000 people. They found the two groups have genes in common, and abnormal levels of cholesterol were shown to be a risk for both.[3]

‘Looking at the genetic and biological characteristics common to Alzheimer’s and these gut disorders suggests a strong role for lipids metabolism, the immune system and cholesterol-lowering medications,’ says team leader Emmanuel Adewuyi. ‘Whilst further study is needed into the shared mechanisms between the conditions, there is evidence high cholesterol can transfer into the central nervous system, resulting in abnormal cholesterol metabolism in the brain. There is also evidence suggesting abnormal blood lipids may be caused or made worse by gut bacteria (H. pylori), all of which support the potential roles of abnormal lipids in Alzheimer’s and gut disorders. For example, elevated cholesterol in the brain has been linked to brain degeneration and subsequent cognitive impairment.’

The research suggests that cholesterol lowering medications such as statins could help treat Alzheimer’s and gut disorders, and that diet could have a role in treating and preventing both. ‘Evidence indicates statins have properties that help reduce inflammation, modulate immunity and protect the gut,’ says Adewuyi. However, more research is needed, and patients should be assessed individually to gauge if statins would help them.

‘Looking at the genetic and biological characteristics common to Alzheimer’s and these gut disorders suggests a strong role for lipids metabolism, the immune system and cholesterol-lowering medications.
Emmanuel Adewuyi Edith Cowan University, Western Australia

Novel targets

Meanwhile, the search is still on for new drug targets. One area of research centres on microglia, the immune cells of the central nervous system that are key to keeping neurons healthy. Their job is to clear away dead neurons and unwanted proteins, including the Aβ plaques. But sometimes microglia can get over-stimulated and end up damaging neurons and the networks they form.

These cells are understudied, despite the fact that changes in them are known to play a significant role in Alzheimer’s and other brain diseases, says Martin Kampmann of the University of California, San Francisco, US. Most of the genes known to increase the risk for Alzheimer’s disease act through microglial cells.

Kampmann’s team wanted to pinpoint which genes are involved in specific states of microglial activity, and how each of those states are regulated. This would mean that they could turn genes on and off, resetting over-stimulated microglia.

To do this, the team adapted a gene editing platform to screen specially generated microglia derived from human stem cells (iPSCs). The platform is based on a form of Crispr – the technique used in biomedical research to turn off or enhance gene expression – together with data read-outs giving information on functions and states of individual microglia cells.

This approach allowed them to identify genes that influence the cell’s ability to survive and proliferate, to actively produce inflammatory substances, and how aggressively it prunes synapses.[4] They were then able to reset the genes and ‘repair’ the cell. Kampmann believes that the repaired microglia should return to their usual immune duties, removing plaques associated with neurodegenerative disease and protecting synapses rather than taking them apart.

‘Now, using the new Crispr method we developed, we can uncover how to actually control these microglia, to get them to stop doing toxic things and go back to carrying out their vitally important cleaning jobs,’ says Kampmann. ‘This capability presents the opportunity for an entirely new type of therapeutic approach.’

Next, he wants to study how to control specific microglia states by targeting the cells with existing pharmaceutical molecules. With preclinical models, he hopes to identify any molecules that act on the genes necessary to nudge diseased cells back to a healthy state.

Nutraceuticals

Meanwhile, yet another approach is to focus on prevention rather than treatment. One strategy involves diet and researchers are looking to identify food-derived compounds that can protect nerve cells. For example, Cristina Airoldi and Alessandro Palmioli of the University of Milano-Bicocca, Italy, have shown that chemicals extracted from hop flowers can inhibit Aβ aggregation.[5] Their team created and characterised extracts of four common varieties of hops. The most potent extract was from the Tettnang hop, found in many types of lagers and lighter ales. The team tested this in worms and found that it gave some protection from paralysis related to Alzheimer’s. Analysis of the extracts revealed a pool of molecular components involved in protecting nerve cells, namely feruloyl and p-coumaroylquinic acids, flavan-3-ol glycosides, and procyanidins. These molecules bind to Aβ oligomers, hindering the proteins from aggregating into fibres and clumps, and also appear to prevent cell death by reducing oxidative stresses.

Recent research brings the promise of novel targets. However, new treatments for AD and dementias are urgently needed. The FDA approved lecanemab because it showed a large reduction in Aβ plaque in the brain, says Gill Livingston, a professor in psychiatry of older people at University College London (UCL). ‘Lecanemab was tested as a disease modifying medication rather than to help symptoms. The benefit is small and is less than the cholinesterase drugs which are available.’ Three cholinesterase inhibitors are often prescribed in the UK. They reduce the breakdown of acetylcholine – involved in passing messages between brain cells involved in memory – and increase its levels in the brain; it is significantly reduced in Alzheimer’s.

‘In practice, lecanemab’s benefits are likely to be measured in extra months rather than years,’ acknowledges Hilary Evans, Chief Executive at Alzheimer’s Research UK. ‘However, it gives the research community great confidence that we will, one day, be able to deliver a range of treatments that tackle different aspects of Alzheimer’s, as well as other diseases that cause dementia.’

References
1 D. Shea et al, Proc. Nat. Acad. of Sci., doi: 10.1073/pnas.2213157119.
2 A. Maruszak et al, Brain, doi: 10.1093/brain/awac472.
3 E. O. Adewuyi et al, Commun. Biol., 2022, 5, 691.
4 N. M. Dräger et al, Nat. Neurosci., 2022, 25, 1149.
5 A. Palmioli et al, ACS Chem. Neurosci., 2022, 13, 3152.