Thanks to active dementia research, some progress has been made in preventing dementia and slowing its progression. However, research aimed at complete recovery, that is, returning to a state before the disease, has not moved beyond a standstill.
A breakthrough that could change this situation has emerged. In animal experiments, a successful first step toward curing dementia has been taken.
According to a recent study published in the journal 《Cell Reports Medicine》, researchers at Case Western Reserve University in the United States found that Alzheimer's disease can be reversed through treatments that restore metabolic balance in the brain using animal models. The study showed that restoring the levels of specific energy molecules allows the brain to repair damage and recover cognitive function even in advanced stages of the disease.
The researchers used two types of rat models. The first model was made to accumulate amyloid plaques severely and exhibit tau protein changes similar to those in humans. The second model had human mutations of tau protein that cause toxic neurofibrillary tangles and neuronal cell death.
As the disease progressed, the brain energy balance of the rat models deteriorated. At 2 months old, before symptoms appeared, the 'Nicotinamide Adenine Dinucleotide (NAD+)' levels in the rats were normal. However, by the 6th month, when clear signs of cognitive impairment appeared, this level had decreased by 30%. By the 12th month, when the disease was very advanced, it had dropped by 45%.
NAD+ is essential for cellular energy production and damage repair throughout the body, and it naturally decreases with age, with a more pronounced decline in patients with neurodegenerative diseases. A study published in 2018 showed that supplementing NAD+ precursors in rats could normalize neuroinflammation and DNA damage. Another study published in 2021 revealed that restoring this energy balance could reduce cellular aging, which is related to chronic inflammation that occurs in aging brains when cells stop dividing but do not die.
The researchers began treatment when the rats were 6 months old. At this point, brain lesions had already progressed, and cognitive decline was clearly evident. The rats received daily injections of a treatment called P7C3-A20 until they were 1 year old. This compound acts as a neuroprotective agent, helping cells maintain an appropriate balance of NAD+ even under extreme stress and preventing NAD+ levels from becoming abnormally high.
The results showed that the brain functions of the treated rats were generally restored. In memory tests like the Morris water maze, where they had to remember the location of a submerged platform, the treated rats performed at the same level as healthy controls. Despite genetic mutations, spatial learning and memory were restored to normal levels.
There was also an improvement in physical coordination. In the rotarod test, which measures motor learning, rats in advanced stages of the disease regained their ability to balance and stay on the rod. By the end of the treatment period, the performance of the rats was indistinguishable from that of healthy rats.
The blood-brain barrier, a protective shield surrounding the brain's blood vessels, was also restored. In Alzheimer's disease, this barrier often develops gaps that allow harmful substances to infiltrate brain tissue. Analysis of electron microscope images confirmed that this treatment closed the gaps and restored the health of supporting cells known as pericytes.
Currently, the levels of a marker called p-tau217, a form of tau protein used as a standard clinical biomarker in human patients, have also decreased. This is an objective way to confirm that the disease is improving.
Notably, 46 specific proteins that changed in the same way in both human patients and diseased rats were identified, and their levels were restored to normal through treatment.
The researchers stated, "By restoring the brain's energy balance, both types of rats with progressive Alzheimer's disease showed pathological and functional recovery," and added, "Confirming these effects in animal models with different genetic causes gives hope that recovery may also be possible in patients with progressive Alzheimer's disease if the brain's NAD+ balance is restored."
