Genetic risk for Alzheimer’s disease linked to highly active brains

A growing body of evidence supports the theory that neural hyperactivity and hyperconnectivity precede the pathological changes that lead to neurodegeneration.

There are approximately 5.6 million people over the age of sixty five living with Alzheimer’s disease in the US. With an ageing population, this number is projected to rise to 7.1 million by 2025.

Researchers know that age, a family history of Alzheimer’s disease, and carrying a genetic variant known as APOE4 are all associated with a higher chance of developing the condition.

But the biological mechanisms leading to Alzheimer’s are still largely a mystery.

Over the last decade, scientists have amassed evidence for a hypothesis that, prior to developing full blown Alzheimer’s disease, people experience a period of hyperactivity and hyperconnectivity in the brain.

Several functional magnetic resonance imaging studies have reported that people with mild cognitive impairment (MCI), a condition that often precedes Alzheimer’s, appear to have higher brain activity levels than their age matched counterparts.

Researchers have also found signs of such changes in healthy people carrying the APOE4 allele, as well as in presymptomatic stages of Alzheimer’s in rodent models of the disease.

In rodents, researchers have found that hyperactivity can increase the production and spread of amyloid-ß.

Krishna Singh, a physicist and imaging neuroscientist at the Cardiff University Brain Research Imaging Center (CUBRIC) and his colleagues wanted to investigate this theory further.

He said previous studies of brain activity in young APOE4 carriers were mostly conducted using small sample sizes. But by the mid 2010s his team had access to neuroimaging data from nearly two hundred participants studied at CUBRIC as part of an effort to build a massive dataset of healthy brains.

So the researchers decided to use the data to search for signs of unusual brain activity and connectivity in people with the APOE4 allele.

Using magnetoencephalography (MEG), a neuroimaging technique that records the magnetic fields generated by electrical activity in the brain, the team had measured resting state brain activity in a group of one hundred and eighty three healthy adults, which included fifty one people who carried at least one copy of APOE4. The average age of the participants was twenty four years old, although ages ranged from eighteen to sixty five.

The researchers found young carriers of the APOE4 allele have brains that are more connected and active than the brains of those without the allele.

Analysis of the imaging data revealed that, compared with controls, young APOE4 carriers displayed greater activity in several regions in the right side of the brain, including parts of what’s known as the default mode network, which is active when a person is not focused on a specific task. A similar set of brain regions also showed an overall increase in connectivity.

The researchers next compared the results to brain activity and connectivity data from a previous neuro­imaging study they had conducted, which found that elderly people with early stage Alzheimer’s disease had decreased neuronal activity and connectivity compared with that of age matched controls.

The team found the network of brain areas that displayed increased connectivity in young APOE4 carriers partially overlapped with the brain regions that exhibited a decrease in connectivity in people with early stage Alzheimer’s.

Krishna Singh said these findings are intriguing because they suggest brain areas that end up getting impaired in Alzheimer’s may be highly active and connected early in life, long before symptoms of the disease appear.

Tal Nuriel, a professor of pathology and cell biology at the Columbia University Medical Center who wasn’t involved in the work, said “This study adds further evidence that hyperactivity and hyperconnectivity may play an influential role in Alzheimer’s disease.”

He said because this was an observational study, the findings can only establish a correlation between brain activity and Alzheimer’s, so it’s still unclear whether the hyperactivity and hyperconnectivity observed during the early stages of the disease are a cause or a consequence of pathological changes that lead to neurodegeneration.

Willem de Haan, a neurologist at the Amsterdam University Medical Center, who was not involved in the latest study, said scientists used to think that increased activity was simply a compensatory effect, the brain trying to make up for a loss of neurons and synapses.

He said “But I think there’s overwhelming evidence that this may actually be pathological hyperactivity.”

Much of that evidence comes from animal experiments conducted over the last decade or so. In rodents, researchers have found that hyperactivity can increase the production and spread of amyloid-ß, the peptide that accumulates into plaques found in the brains of people with Alzheimer’s, and that amyloid-ß can in turn induce neuronal hyperactivity. These findings have led some scientists to speculate that there might be a self-amplifying loop, where a progressive hyperactivity and build up of amyloid-ß drives pathological changes associated with the neurodegenerative disease.

Research in humans also supports the idea that hyperactivity could play a causal role in Alzheimer’s disease. In 2012, researchers at Johns Hopkins University treated individuals with MCI with the anti-epileptic drug levetiracetam and found that the therapy suppressed activity in the hippocampus and led to improved memory performance.

The team is currently testing levetiracetam for MCI in clinical trials.

Willem de Haan said “I think this is one of the most interesting results. It seems to show that by correcting hyperactivity we can actually find some improvements in patients that might point to a completely new type of therapy for [Alzheimer’s disease].”

For the current study, Krishna Singh’s team also trained a machine learning algorithm to distinguish APOE4 carriers from non-carriers based on their MEG data and tested whether it would be able to predict cases of Alzheimer’s.

They found that while the programme was able to perform above chance, the effect was not significant.

Krishna Singh said “In a way, that was kind of encouraging. Because I don’t think anybody would predict that we could find a signature [for Alzheimer’s] in 20- and 30-year-olds.”

For now, Krishna Singh said his team’s findings simply shed light on what might be going on in the brains of people with the APOE4 allele. There are still a number of unanswered questions, such as when the transition from hyper to hypoconnectivity and activity happens, what changes occur in the largely understudied middle aged cohort, and whether there are differences between APOE4 carriers who go on to develop Alzheimer’s and those who don’t.

Krishna Singh said ultimately, to understand how disruptions in neuronal activity lead to behavioural and cognitive deficits, scientists need to decipher what’s going on inside a healthy brain.

He said “[We] require a model of how the brain works—and those are still in their infancy.”

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