- Novel research has identified microscopic blood proteins that predict susceptibility to dementia.
- These biomarkers are linked to neural homeostasis — the brain’s ability to remain healthy.
- Changes in these biomarkers herald changes in cognitive status and may be a future target for therapy.
By 2050, 13.5 million people in the United States will live with Alzheimer’s disease unless early diagnosis and treatment can delay the onset of the disease. Current treatment centers around slowing the progression of the disease.
In the journal EMBO Molecular Medicine, scientists revealed this week that circulating microscopic nucleotides — assembled amino acids that bind directly to messenger ribonucleic acids (mRNAs) — can identify cellular imbalance in the brain. These nucleotides, called microRNAs, are easily measured blood proteins that may identify the early risk of Alzheimer’s disease.
The role of these microRNAs in directing mRNAs to protect the brain from inflammation means that targeting them for therapy could inhibit cellular damage in the brain and delay the onset of dementia.
Verna R. Porter, M.D., commented on the pivotal aspects of this research for Medical News Today. Dr. Porter is a neurologist and the director of programs for dementia, Alzheimer’s disease, and neurocognitive disorders at Providence Saint John’s Health Center in Santa Monica, CA.
“Alzheimer’s disease is usually diagnosed at a relatively advanced/symptomatic stage of the disease with relatively advanced biomarker/molecular pathology — for example, the amyloid deposit in the brain is already well-established. The problem has been that by the time the disease is diagnosed, the current treatments have been essentially ineffective in terms of disease modification.”
– Dr. Verna R. Porter
The molecular brain changes linked to Alzheimer’s disease often occur many years before those affected manifest clinical symptoms. Therefore, these researchers designed a model to compare biomarker results in healthy adults with those in people with cognitive decline.
In a multifaceted study, based on the similarities between human and murine neurophysiology, research scientists scored young people aged below 30 years for cognitive function. Then, they identified microRNAs present in the blood that matched their cognitive function. Finally, the scientists linked these microRNAs to larger mRNAs associated with cognitive decline.
Once the researchers had made this connection, they studied microRNAs as possible biomarkers for early cognitive decline.
Aging mice can develop cognitive decline, similar to humans. Therefore, the researchers designed a follow-up experiment measuring these same biomarkers in healthy and aging mice. The scientists could now study the “before and after” of these microRNA biomarkers, looking for their presence in the blood of both mice that were healthy and those that had cognitive decline.
Dr. Islam, Prof. Fischer, and colleagues from the German Center for Neurodegenerative Diseases and the University Medical Center in Göttingen, Germany, found seven microRNAs frequently linked to age-related cognitive decline in mice. They then correlated these microRNAs to their known functions in human genes, which genome-wide association studies (GWAS) had identified.
The scientists compared their mouse microRNA results with the 709 human genes related to cognitive function in healthy individuals. Three microRNAs that regulate genes in cognitively impaired mice were repeatedly linked to crucial genes in human cognitive function.
To further support their results, the researchers imposed the three microRNAs onto cell cultures of the murine
The scientists then directly measured the three microRNAs present in the brains of cognitively impaired mice and found high levels. Finally, they compared their results with those of prior studies, tentatively linking these microRNAs to neuroinflammation and cellular stress. Dr. Porter summarized:
“These researchers noted that circulating microRNAs are linked to cognitive function in young/healthy individuals. Using mouse models, these researchers have identified ‘circulating three-microRNA signatures’ in the blood, which are increased in patients with mild cognitive impairment (MCI) and suggest an enhanced risk of future conversion from MCI to [Alzheimer’s disease].”
In mice, high levels of the three microRNAs correlated with cognitive decline. But is it possible to extrapolate these results to humans? And could the amount of the three microRNAs predict cognitive impairment before clinical signs of dementia appear?
The researchers studied participants from different age groups in cross-sectional settings. First, they analyzed the plasma of individuals with MCI. In comparison with cognitively healthy people, those living with MCI had significantly increased levels of the microRNAs.
The scientists wondered whether the three microRNAs were higher in people with MCI who go on to develop Alzheimer’s disease. By analyzing past blood samples, they learned that people with higher levels of the three microRNAs were more likely to progress from stable MCI to Alzheimer’s disease than those with lower levels.
They also measured the microRNAs in the cerebrospinal fluid of people living with MCI and found significantly elevated levels.
Proposing possible mechanisms in humans, the researchers studied human brain cell cultures, treating them with the three microRNAs. Similar to the previously studied mouse brain cell cultures, they found decreased neuronal synaptic function and increased cellular stress.
So, can we intervene in the function of these elevated three microRNAs and reverse brain cell damage?
The answer is “maybe.” To test this, the scientists developed an inhibitor of each of the three microRNAs. They injected the three microRNA inhibitors (anti-miRs) into mice with Alzheimer’s-like pathology, finding that this improved the animals’ performance in hippocampal-dependent learning strategies, such as escaping from a water maze.
“The therapeutic hope is that by targeting these early biomarkers of disease (i.e., targeting all three microRNAs using anti-miRs), we may be able to ameliorate cognitive decline in humans, as has been shown using mouse models.”
– Dr. Verna R. Porter
The researchers acknowledge that many other complex risk factors likely play a role in Alzheimer’s disease. Due to this, highly effective therapy may require the regulation of several molecular processes.
MNT queried Dr. Porter on why treatments dealing with the onset of Alzheimer’s disease have been so elusive. Dr. Porter described how researchers have rigorously studied a protein deposit in the brain, called beta-amyloid, as a potential cause of Alzheimer’s disease. It seems that
“A great deal of research effort has been focused on the ‘amyloid cascade hypothesis’ of [Alzheimer’s disease] pathology. The numerous clinical trial failures, utilizing various anti-amyloid therapeutic interventions, have been very disappointing […]. It has been suggested that the numerous failed clinical trials that have largely focused on beta-amyloid deposits [indicate] that beta-amyloid may not be the main driver of the disease.”
“Instead, (the) deposition of beta-amyloid in the brain may be a biological response to some other potential trigger. In this view, beta-amyloid deposits would represent residual scars (after-effects) — like the scar that seals a wound, rather than the primary driving process of the disease. It may be that anti-amyloid therapies are simply administered too late in the disease progression.”
“Newer research is looking more broadly at other potential driving factors of the disease, such as tau protein deposition, and the potential preventive role of lifestyle modifications — for example, diet, nutrition, exercise, sleep, and appropriate supplements — as another potential way forward in the prevention of the disease.”
Tau is a protein involved in brain cell stabilization. In some people living with Alzheimer’s disease, it is dysfunctional, causing “
The most promising result of the new study is that the three microRNAs appear to be a suitable, minimally invasive biomarker. They are also easy to measure in routine blood samples — even in a finger prick. Moreover, the data support that this three-microRNA-signature test could be a first step in helping detect individuals at risk of cognitive disease.
For people living with cognitive decline, early detection may increase their chances of successful therapeutic intervention with existing treatment or future novel RNA-based approaches targeting the three-microRNA signature.
In conclusion, Dr. Porter noted to MNT:
“Presently, there is an urgent need for molecular biomarkers that are minimally invasive, able to detect an individual at risk of developing disease, and [able to] detect biomarkers of disease as early as possible — even in the setting of multiple disease pathologies, e.g., “mixed” Alzheimer’s and vascular pathology. The hope is that simple approaches, such as a blood test, could be applicable in the context of routine screening approaches with the [aim] of identifying individuals at risk for developing Alzheimer’s disease, who could then undergo further diagnostic/confirmatory evaluations.”