Have researchers found the cause of Alzheimer’s disease?

Research suggests activation of astrocytes, along with the build-up of amyloid proteins, is necessary for the condition to progress

Research suggests activation of astrocytes, along with the build-up of amyloid proteins, is necessary for Alzheimer's disease to progress. JustStock

Research has shed light on what could cause some people to develop Alzheimer’s disease while others remain unaffected.

Scientists at the University of Pittsburgh School of Medicine found that the build-up of amyloid protein in the brain, long associated with the disease, may in itself not be enough to cause symptoms.

Patients who went on to develop Alzheimer’s were found to be those who also had indicators in the blood that immune cells called astrocytes were activated.

Researchers tested the blood of 1,000 elderly people without Alzheimer’s symptoms, some of whom had amyloid build-up, and followed them over time to find out who developed the condition.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” Dr Tharick Pascoal, an associate professor of psychiatry and neurology at the university and the senior author of the study, said in a statement.

“This puts astrocytes at the centre as key regulators of disease progression, challenging the notion that amyloid is enough to trigger Alzheimer’s disease.”

About two-thirds of dementia cases are due to Alzheimer’s disease, which involves a loss of connection between the nerve cells or neurons that make up the brain.

Alzheimer’s causes memory loss, speech problems and behavioural changes, among other things, and most patients die within a decade of being diagnosed. There is a long period before symptoms develop, so the whole course of the disease lasts around 25 years.

Along with the accumulation of amyloid plaques, clumps of disordered protein fibres called tau tangles inside the neurons are linked to Alzheimer’s.

Although it is uncertain whether amyloid plaque build-up is a cause of the disease, many treatments have focused on targeting these plaques and tau tangles in the hope that this would treat the disease.

Researchers in the new study looked in the blood for glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, and found that this, along with the presence of amyloid proteins, was linked to progressively more serious tau pathology.

This finding ties in with previous research by Dr Pascoal’s group suggesting that brain inflammation is important to the development of Alzheimer’s.

Like other glial cells, which are immune cells in the brain, astrocytes supply neurons with nutrients and oxygen and are said by Dr Bruna Bellaver, a postdoctoral associate at the University of Pittsburgh who is the study’s first author, to “co-ordinate” the relationship between brain amyloid and tau.

“This [research] can be a game-changer to the field since glial biomarkers in general are not considered in any main disease model,” she added.

The University of Pittsburgh said that the new study would be useful for selecting patients for clinical trials of Alzheimer’s drugs, as looking for GFAP can indicate who is likely to develop the condition.

This is especially useful, the university said, because drug trials are taking place at progressively earlier stages of pre-symptomatic disease, so finding out early who is most at risk is important.

As well as the latest research, other studies, some dating back a number of years, have indicated that the build-up of amyloid proteins in the brain is not sufficient to cause Alzheimer’s.

In a 2018 paper in the International Journal of Geriatric Psychiatry, Dr Jeffrey Fessel of Kaiser Permanente, a US healthcare consortium, wrote that accepting amyloid as the main cause of Alzheimer’s disease was “problematic”. He suggested that the alternative hypothesis, that precursors of amyloid protein were the cause, was also unconvincing.

The reason why amyloid alone did not explain why people developed Alzheimer’s disease was, he wrote, because treatments focusing on amyloid “have provided no clinical benefit” and that about one-third of cognitively normal older people have these plaques.

Dr Fessel wrote that “cofactors” associated with Alzheimer’s disease were also necessary for the condition to develop.

In 2021, the US Food and Drug Administration approved a drug, aducanumab, marketed as Aduhelm, to treat Alzheimer's, citing “substantial evidence” that it reduced beta-amyloid plaques.

This approval – which followed the rejection of numerous other amyloid-based treatments – was controversial, with some researchers saying there was insufficient evidence that the drug slowed disease progression.