It may be possible to detect future Alzheimer's in patients before signs such as memory loss and dementia are clinically apparent, scientists have revealed.
Most researchers think this preclinical stage - which can last a decade or more before symptoms appear - is the critical phase when the disease might be controlled or stopped. Therapeutic intervention could prevent the failure of memory and thinking abilities in before they start to decline.
"For new treatments, knowing where individuals are on the path to Alzheimer's dementia will help us improve the design and assessment of clinical trials," said senior author Anne Fagan, PhD, research professor of neurology.
She added: "There are many steps left before we can apply this system in the clinic, including standardising how we gather and assess data in individuals, and determining which of our indicators of preclinical disease are the most accurate. But the research data are compelling and very encouraging."
According to researchers, the new findings offer reason for encouragement. Results show that the system can help predict which cognitively normal individuals will develop symptoms of Alzheimer's and how rapidly their brain function will decline. But they also highlight additional questions that must be answered before the classification system can be adapted for use in clinical care.
The classification system divides preclinical Alzheimer's into three stages:
- Stage 1: Levels of amyloid beta, a protein fragment produced by the brain, begin to fall in the spinal fluid. This indicates that the substance is beginning to form plaques in the brain.
- Stage 2: Levels of tau protein start to rise in the spinal fluid, indicating that brain cells are beginning to die. Amyloid beta levels are still abnormal and may continue to fall.
- Stage 3: In the presence of abnormal amyloid and tau biomarker levels, subtle cognitive changes can be detected by neuropsychological testing. By themselves, these changes cannot establish a clinical diagnosis of dementia.
The researchers applied these criteria to research participants studied from 1998 through 2011 at the Knight Alzheimer Disease Research Center. The center annually collects extensive cognitive, biomarker and other health data on normal and cognitively impaired volunteers for use in Alzheimer's studies.
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Struggling to remember recent events, although they can easily recall things that happened in the past
Repeating themselves or losing the thread of what they are saying
Forgetting the names of friends or everyday objects
Feeling confused even when in a familiar environment
Having problems thinking and reasoning
Feeling anxious, depressed or angry about their memory loss
Finding that other people start to comment on their memory loss
Having difficulty recalling things they have heard, seen or read
Finding it hard to follow conversations or programmes on TV
The scientists analysed information on 311 individuals age 65 or older who were cognitively normal when first evaluated. Each participant was evaluated annually at the center at least twice; the participant in this study with the most data had been followed for 15 years.
At the initial testing, 41% of the participants had no indicators of Alzheimer's disease (stage 0); 15% were in stage 1 of preclinical disease; 12% were in stage 2; and 4%were in stage 3. The remaining participants were classified as having cognitive impairments caused by conditions other than Alzheimer's (23%) or did not meet any of the proposed criteria (5%).
"A total of 31 percent of our participants had preclinical disease," said Fagan. "This percentage matches findings from autopsy studies of the brains of older individuals, which have shown that about 30 percent of people who were cognitively normal had preclinical Alzheimer's pathology in their brain."
Scientists believe the rate of cognitive decline increases as people move through the stages of preclinical Alzheimer's. The new data support this idea. Five years after their initial evaluation, 11% of the stage one group, 26% of the stage two group, and 52% of the stage three group had been diagnosed with symptomatic Alzheimer's.
Individuals with preclinical Alzheimer's disease were six times more likely to die over the next decade than older adults without preclinical Alzheimer's disease, but researchers don't know why.
"Risk factors for Alzheimer's disease might also be associated with other life-threatening illnesses," Fagan said. "It's also possible that the presence of Alzheimer's hampers the diagnosis and treatment of other conditions or contributes to health problems elsewhere in the body. We don't have enough data yet to say, but it's an issue we're continuing to investigate."
The study featured in October's Lancet Neurology. Scientists at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University School of Medicine in St. Louis, working in collaboration with investigators at the University of Maastricht in the Netherlands, helped to validate a proposed new system for identifying and classifying individuals with preclinical Alzheimer's disease.