Inside Neuroscience: Scientists Work to Detect Alzheimer's Disease Earlier
Long before a person shows signs of Alzheimer’s disease (AD), the disease has begun changing the brain. By the time most therapies are offered the disease has quietly run rampant for years.
“Right now, we don’t know how early before symptoms begin we need to intervene in order to have a meaningful impact on the trajectory of the disease,” explained Sam Gandy of Icahn School of Medicine at Mount Sinai during a press conference about early detection of AD at Neuroscience 2012. At the event, presenters discussed tools capable of measuring biomarkers for AD and studies pointing to early treatments for the disease.
Changes in Brain Activity Precede Cognitive Decline
Studies show that abnormal accumulation of beta-amyloid and tau proteins — the main pathological partners in the disease — occur 10 to 20 years before the onset of AD symptoms. Lori Beason-Held and colleagues at the National Institute on Aging wanted to know whether they could use positron emission tomography (PET) to identify changes in brain function before cognitive symptoms of the disease emerged.
As part of an ongoing, 18-year study, Beason-Held’s group collected yearly PET brain scans and performed a battery of cognitive tests on older adults, some of whom began to show cognitive decline several years into the study. When analyzing the results of the PET scans from previous years, the researchers found that those who developed cognitive impairment had increased brain activity in the frontal lobe and decreased activity in temporal and parietal lobe areas, regions vulnerable to early beta-amyloid and tau accumulation in AD.
“These findings are important because we’re seeing changes in brain activity in areas critical for specific aspects of cognition long before people start showing symptoms of cognitive decline,” Beason-Held said.
Probe Enables View of Toxins That Initiate AD
Scientists are now better able to see the beta-amyloid plaques associated with AD with recent advances in imaging technology. But, as William Klein of Northwestern University pointed out, “What we really need to do is try to find ways to image the toxins that actually initiate the disease.”
Klein described how he and colleagues developed a probe that uses antibodies that bind specifically to beta-amyloid fragments in the brain. The antibody is fused with magnetic nanoparticles so the toxins appear during magnetic resonance imaging (MRI). The new technique has enabled Klein’s group to accurately distinguish between the autopsied brains of people diagnosed with AD and controls.
Epigenetic Signatures Discriminate Between Neurodegenerative Diseases
Scientists want to not only be able to detect AD early, but also discriminate between the types of dementia affecting patients. Could epigenetic signatures serve as biomarkers to distinguish AD from Parkinson’s disease (PD) and Lewy body dementia (DLB), which share some overlapping pathology and symptoms?
To answer this question, Paula Desplats and colleagues at the University of California, San Diego measured the expression of 84 genes encoding enzymes known or predicted to modify chromatin in post-mortem frontal cortex tissue from patients with confirmed diagnoses of AD, PD, and DLB. The team identified differences in expression of the chromatin modifiers in tissue from disease patients compared with controls, suggesting that chromatin modifiers may have a role in these diseases.
Further analysis revealed that the gene expression patterns appear to be unique to each disease. The findings suggest that the development of blood tests capable of measuring such epigenetic signatures could allow scientists to differentiate between the three diseases, Desplats said.
A Closer Look at Tau
Animal models that mimic AD pathology in humans provide researchers with the opportunity to further explore the mechanisms of the disease. Fred Van Leuven of the University of Leuven in Belgium described his group’s work with two transgenic strains of mice bred to develop a defective human version of tau. Previous studies show that the accumulation of beta-amyloid protein alters the phosphorylation of tau in AD. Van Leuven’s group wondered if other modifications to tau, such as the sugar modification glucose N-acetylation (O-GlcNAc-ylation), also affect the pathology of the disease.
Previous studies show O-GlcNAc-ylation levels are lower in the brains of people with AD. When the researchers treated the Alzheimer’s model mice with a compound that increased O-GlcNAc-ylation, the team saw improvements in the pathology, behavior, and survival of the mice. Surprisingly, the researchers were unable to detect evidence that the increase in O-GlcNAc-ylation led to an increase of sugars on tau. The findings suggest the compound is not working directly on tau, but downstream of the protein, Van Leuven said.
Building a Better AD Model
The closer the animal models of AD mimic the changes that take place in the brains of people with the disease, the more accurately scientists can evaluate preclinical treatments. While high levels of amyloid precursor protein (APP) often fail to appear in humans until later in life, many AD animal models express high levels of APP early on.
Alena Savonenko of Johns Hopkins University described an AD mouse with temporally controlled production of APP. Through a drug-inducible transgenic strategy, the researchers delayed production of the protein in mice until late in life. The researchers then compared the mice that produced
APP throughout life (early expressers) to mice that did not produce the protein until later (late expressers). When the mice were tested at the age of 13 months, researchers discovered both groups had spatial memory deficits compared to controls. However, when the researchers stopped APP production in both groups of aged mice for seven days, they found the spatial memory in late, but not early, expressers improved. The findings suggest mice that express high levels of APP throughout life may be less sensitive to anti-amyloid treatments later in life. Savonenko said it’s possible this is why some drugs have worked success- fully in animal studies but have failed in clinical trials.
The panelists agreed scientists have made notable gains in identifying biomarkers that could help detect AD earlier in patient populations, but they acknowledged there is still work to be done before they are able to use biomarkers to determine with certainty whether a person will go on to develop the disease. The presenters also discussed efforts to develop and test disease-modifying therapies.
“One challenge for so-called preventative or pre-symptomatic interventions is finding an effective drug that is also sufficiently safe. You will be exposing people for perhaps 20 years of their lives, during which they would have been cognitively intact anyway,” Gandy said. “On the other hand, Alzheimer’s disease is not a troublesome little memory disorder. This is a universally fatal malignant neurodegeneration that destroys the cerebral cortex of everyone who gets it.”