An update on advances in understanding, diagnosing and treating Alzheimer’s Disease - Fellows' seminar by Carlos Ibanez

It’s been said that nothing much has happened in Alzheimer’s Disease in the last 40 years. Carlos Ibáñez of the Department of Neuroscience at the Karolinska Institute, Stockholm, Sweden, the School of Life Sciences at Peking University and the Chinese Institute for Brain Research, Beijing, China, disagrees. “I believe there’s been great progress in the understanding, diagnosis and treatment of Alzheimer’s Disease, he said. “Clinical work is showing that passive immunisation with Lecanemab and Donanemab can slow down cognitive decline by about 30% in early symptomatic Alzheimer’s Disease; recent phase II clinical trials targeting p75^NTR have shown improved MRI, PET and CSF markers; and, our results in mouse models show that disruption of p75 neurotrophin receptor (p75^NTR) activity reduces both amyloid β plaques and Tau neurofibrillary tangles, and restores learning and memory even during symptomatic stages of the disease.” Alzheimer’s Disease (AD) is a progressive, irreversible brain disorder and the most common form of dementia, currently affecting over 55 million people worldwide. AD gradually destroys memory and ability to learn, reason, communicate, make judgments and carry out daily activities. It’s fatal, with death usually within eight to 10 years of diagnosis. Familial AD is inherited but rare, with 95% occurring without a clear family link. “It’s a progressive disorder that destroys personhood not just memory,” said Ibáñez. AD is characterised by shrinkage of the brain caused by neurons dying. It’s specifically characterised by the presence of amyloid β plaques and Tau neurofibrillary tangles. Together these lead to synapse and neurite loss which is the hallmark of AD. “The dominant hypothesis is that the Aβ peptide first accumulates causing plaque formation and the Tau tangles come later,” said Ibáñez. “Then synaptic and neuronal function and density declines. The plaques accumulate for years and are well established by the time of diagnosis.” “During this the brain is compensating all the time so there is no cognitive manifestation until at some point it can’t compensate anymore and then there is catastrophic decline in cognition.” Familial AD is linked to mutations in the Amyloid Precursor Protein (APP) from which the Aβ peptide that forms amyloid plaques originates as well as mutations in presenilin. Familial AD is highly penetrant and early onset, but comprises less than 5% of all AD cases. Other genetic risk factors include carriers of Apolipoprotein E (ApoE) who are four to 12 times more likely to develop AD, and mutations in TREM2 which is involved in amyloid plaque neuroinflammation. But genes are not the only culprits, risk factors include age, education, head injury, diabetes, vascular and environmental factors (including air pollution and micro plastics). Very recent research in mice models has also shown the role of lithium deficiency. Diagnosis of AD is initially done by cognitive tests, followed by Magnetic Resonance Imaging (MRI) which looks for enlarged ventricles and reduced size of structures like the hippocampus. However, MRI alone is not definitive and is usually followed by PET – Positron Emission Tomography – which shows the active regions of the brain allowing more clarity on the type of dementia. Ibáñez highlighted revolutions in diagnostic methods including Amyloid PET and Tau PET as well as testing of blood and cerebrospinal fluid to measure amyloid and Tau biomarkers. “These biomarkers can appear in sequence up to 20 years before clinical symptoms. By the time you have symptoms presence of these biomarkers is very high,” he said. “Soon it will be possible to screen people many years before onset – there are two clinical trials underway now of people without symptoms.” All these tests are more sensitive and conclusive, however, also expensive and not available everywhere. “Artificial Intelligence is also being developed to analyse large datasets of digital biomarkers, imaging and even voice and motion data for early detection,” added Ibáñez.

But what’s the point if there are no therapies?

Most available AD drugs only address the symptoms and don’t slow the disease mechanisms or progression. Research is therefore looking at trying to block the enzymes leading to amyloid formation. “But inhibitors of enzymes that generate amyloid from APP have failed due to high toxicity as these enzymes affect multiple targets. So now they are trying some that don’t totally inhibit but tweak.” There are currently 182 clinical trials underway of which one-third target amyloids. This includes two trailblazer trials in patients without cognitive impairment but positive amyloid markers – TRAILBLAZER-ALZ3 and AHEAD 3-45. Ibáñez also noted that so far there is no Tau or Aβ vaccine that has proven clinically effective in preventing or halting cognitive decline in humans. However, passive vaccination using anti-amyloid monoclonal antibodies like Lecanemab and Donanemab are showing promise. Recent trials are showing a decline in plaques by approximately 27% with Lecanomab and an average reduction of plaques of 84% at 18 months with Donanemab tested in adults with early symptomatic disease. “But there’s lots of controversy about these kinds of vaccines, because they are very expensive – about $26 000 to $32 000 per year per patient −and there have been some side-effects,” said Ibáñez.

Targeting receptors

Ibáñez and his colleagues are working with protein receptors – specifically manipulating the gene encoding the p75 neurotrophin receptor, a transmembrane protein present in different classes of brain cells, including neurons. Signalling of p75^NTR is linked with loss of synapses, neurites and neuron death. There is a lot of evidence of a link between this receptor and Aβ and a recent phase IIA trial has highlighted this receptor as a valid target for AD. Their work in mouse models looks at manipulating the genes controlling the receptor to see the effect at different time periods and to determine if this can alleviate the neuropathological and behavioural manifestations of AD in these models. Thus far they have shown that amyloid plaques can be reduced by half after intervention. “We are showing that disruption of p75^NTR activity reduces both Aβ and Tau pathologies and restores learning and memory even during symptomatic stages of the disease,” he explained. “We therefore believe that targeting p75^NTR may offer a therapeutic approach in AD that may be alternative or complementary to passive vaccination.” Ibáñez concluded by addressing the challenges of unequal access to cutting-edge treatments and diagnostics. However, he remains optimistic. “There will be an explosion of new information from the nearly 200 trials underway,” he said. “I’m optimistic that we will see something substantial in this century. It will be a shame if we don’t.” Michelle Galloway: Part-time media officer at STIAS Photograph: SCPS Photograph