BY SIMON FROST | 10 APRIL 2024
As concerns abound over side-effects of monoclonal antibodies, a new method for early detection of Alzheimer's disease shows promise.
Scientists at the University of Florida, US, have identified a potential link between abnormal blood levels of the protein amyloid-β and subtle changes in brain structure, detectable through diffusion MRI – a technique that measures the movement of water molecules in the brain.
Their findings, published in Alzheimer’s & Dementia (doi: 10.1002/alz.13693), could pave the way for a blood test to identify pre-symptomatic signs of Alzheimer’s disease (AD).
The researchers found that even when a PET scan didn’t detect amyloid build-up, participants with abnormal blood levels of amyloid showed structural changes in the brain on diffusion MRI.
‘Our findings suggest there seem to be events occurring both in the blood and in the brain before you detect amyloid positivity in the brain,’ explained David Vaillancourt, senior study author. While UK medicines regulator, the MHRA, is evaluating this test, the researchers note that more work is needed to confirm its effectiveness.
The next step, according to Vaillancourt, is to monitor participants to see if those with positive blood tests eventually show positive PET scans. This will help researchers understand how blood and brain changes correlate with the progression of AD.
Speaking at the AAAS Annual Meeting in Denver, Colorado in February 2024, Madhav Thambisetty, a practising neurologist and senior clinical investigator at the National Institute on Aging, US, asserted that improved early detection will be the key to developing the most effective treatments.
‘I think there’s going to be a very clear push towards redefining AD by biomarkers based on the presence or absence of abnormal levels of proteins, either in the blood, in the spinal fluid, or on brain imaging,’ he said.
His talk focused on concerns around monoclonal antibodies in development to treat AD. Last year, lecanemab became the first such drug to receive approval as an AD treatment by the US Food and Drug Administration (FDA), offering a glimmer of hope for patients.
Sold under the brand name Leqembi, lecanemab has been shown to effectively clear the accumulation of amyloid plaques. But, as the MHRA investigates whether the UK should follow suit, experts are grappling with concerns about the drug’s safety.
Researchers are debating whether the relatively modest clinical benefits demonstrated so far outweigh the potential side effects of brain bleeding, swelling, and shrinkage. Lecanemab carries a black box warning – the strongest precaution that the FDA imposes on medicines that risk serious side effects.
‘I don’t think you should require a board-certified neurologist to say that brain volume loss, bleeding in the brain or swelling in the brain is bad for somebody with Alzheimer’s disease,’ Thambisetty said.
A spokesperson for Japan-headquartered Eisai, which jointly developed lecanemab with US firm Biogen Inc, noted: ‘Changes in brain volume have been noted and reported in trials of amyloid-targeting treatments for AD, including lecanemab. There is no evidence to support that a reduction in brain volume, following treatment with an amyloid-targeting therapy, is linked to an increase in neurodegeneration.
‘Some experts believe that the loss of volume in other parts of the brain, such as the cortex, which was observed in the Phase 3 Clarity AD trial, may be linked to the removal of amyloid plaques and the reduction of abnormalities and inflammation caused by the plaques. This is sometimes referred to as pseudo-atrophy. However, the clinical relevance of these observed changes in brain volumes is unclear.’
Meanwhile, Thambisetty is not convinced that amyloid plaques are the target that will deliver an effective cure. ‘There really is no statistically significant association between brain amyloid lowering and primary clinical outcomes [...] the very premise that these drugs, by lowering brain amyloid, are likely to result in clinical benefit is somewhat questionable,’ he says.
Eisai points out that the safety profile and efficacy data of lecanemab has been reviewed by three independent regulatory authorities – in the US, Japan and China.
‘All available data from the clinical trials, including information on brain volume, has been provided to regulatory authorities. They assess this information alongside the safety profile and efficacy to determine whether to grant a licence,’ the company noted.
‘By the end of January 2024, over 2000 people living with early AD had received the medicine outside of the clinical trial setting.’
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