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New drugs a boost for Alzheimer's treatment but finding cause must be a priority

While the world finally has a disease-modifying drug for Alzheimer’s – and by the end of this year, likely to have another – and although these treatments can slow the inexorable march of the disease, there is a clear need to treat patients earlier and to find other drugs that have a stronger effect.

Eisai and Biogen’s treatment Leqembi, and a second drug from Eli Lilly & Co called donanemab, both reduce levels of the amyloid plaques long considered a hallmark of the disease. Data suggest these drugs can ease the decline in people with mild forms of Alzheimer’s by about 30%, reports Bloomberg.

Yet while these amyloid-clearing drugs appear to work, they’re only slowing the disease, not halting it, says Keenan Walker, a neuroscientist at the National Institute on Ageing, and lead author of a recent study.

“We need to target other pathways to achieve better outcomes.”

So far, much of the focus of drug development beyond amyloid has been on the other obvious player in Alzheimer’s, tau, another protein that tangles up in the brains of people with the disease. And targeting amyloid and tau made sense: they light up on specialised brain scans and can be detected in the blood tests, diagnostic tools that transformed how Alzheimer’s drugs were tested.

But the many amyloid-targeted drugs preceding Leqembi and donanemab made it clear that plaques are not the only culprits – or even maybe the main culprits – in the disease.

Other processes unquestionably contribute to the memory loss and overall declining function of people with the disease – that probably happen well before amyloid or tau might show up on a brain scan.

Now, as technology makes it easier to single out those players, scientists should hasten the search for alternative approaches to diagnosing and treating Alzheimer’s even earlier.

Midlife

In the latest study, published in Science Translational Medicine, the team found a collection of proteins that appear perturbed in midlife in the people who develop Alzheimer’s disease 15 or even 25 years down the road. Many of those proteins were not directly involved with amyloid and tau, but instead were involved in immune processes, communication between nerve cells, and protein regulation.

The US National Institute on Ageing team was able to find this potential sign of early risk by capitalising on a rich data source: nearly 15 800 people recruited when they were between 45 and 64 for a long-term study of atherosclerosis – plaque build-up in the arteries. Those volunteers were recruited in the mid-1980s and are still being followed today.

As part of that atherosclerosis study, participants agreed to regularly answer questions about their health and have an examination every few years. By 2010, as people in the group started hitting their 70s and 80s, researchers added in a new battery of tests to capture everyone with dementia.

Using health records, they could even track Alzheimer’s development among patients lost to attrition – giving them an overall group of nearly 11 000 people to study.

In the decades since they started following these people, technology has surged. The National Institute on Ageing team could revert to those early samples and take inventory of thousands of proteins contained within each person’s plasma to ask if any were associated with a risk of Alzheimer’s later in life.

They came up with a list of a few dozen proteins that were more prominently expressed in people who went on to develop the disease.

But one, called GDF15, rose above the crowd, Walker says. That protein seems to be involved with regulating certain kinds of inflammation and, though it had been linked to Alzheimer’s and other neurodegenerative diseases, until now, it has never been shown to be a predictor of dementia.

Further digging showed that while it is a predictor, it is not a driver of the disease, Walker says. The researchers hypothesise that it is possibly an anti-inflammatory molecule that is kicking into action in response to some danger – a process happening as early as someone’s 40s.

That adds to growing evidence from genetic studies pointing to the immune system’s role in the disease long before plaques are visible in a brain scan.

These findings are not an early test for Alzheimer’s risk; they do not even clearly identify a target for new drugs. But by flagging these proteins, the study could help scientists better understand the early processes that set some people on the path to dementia. That, in turn, could lead to better ideas for drugs and tests.

For too long, the field has focused on the obvious targets of amyloid and tau. Happily, that work is finally bearing fruit, but getting closer to cures will require a deeper understanding of the early stages of this disease.

Study details

Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life

Keenan Walker, Jingsha Chen, Liu Shi,Yunju Yang, Josef Coresh, et al.

Published in Science Translational Medicine on 19 July 2023

Abstract

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organisation. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterised by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signalling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomisation genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritised a set of candidate markers for AD and dementia risk prediction in midlife.

 

Science Translational Medicine article – Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life (Open access)

 

Bloomberg article – Fight against Alzheimer’s is entering critical phase (Restricted access)

 

See more from MedicalBrief archives:

 

Patients who defied Alzheimer’s gene may help with therapies

 

Promising results for new Alzheimer’s drug

 

Brain atrophy link to anti-Aβ drugs in Alzheimer’s treatment – Australian meta-analysis

 

 

 

 

 

 

 

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