Scientists are gaining new insight into how Alzheimer’s disease affects the brain long before memory loss and dementia become apparent. This preclinical phase can span a decade or more and represents a critical window when the disease might be slowed or halted, potentially preventing later cognitive decline.
New findings published in Lancet Neurology report progress in validating a proposed system for identifying and classifying people with preclinical Alzheimer’s disease. Researchers at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St. Louis, in collaboration with investigators at the University of Maastricht in the Netherlands, applied the classification scheme to a longitudinal cohort and found that preclinical Alzheimer’s can be detected during life, is common among cognitively normal older adults, and predicts future cognitive decline and higher mortality.
A panel convened by the National Institute on Aging together with the Alzheimer’s Association proposed the classification system based on biomarker changes tracked during the preclinical period. The system divides preclinical Alzheimer’s disease into three sequential stages defined by changes in cerebrospinal fluid biomarkers and subtle cognitive measures. Validating such a system is essential for designing preventive clinical trials and for improving how clinicians and researchers identify individuals at highest risk for symptomatic disease.
Anne Fagan, PhD, research professor of neurology and senior author on the study, emphasized the potential clinical and research value of knowing where individuals fall on the path to Alzheimer’s dementia. Standardizing how biomarkers and cognitive data are collected and determining which indicators best predict outcome remain important next steps before routine clinical use. Still, she and colleagues describe the research results as compelling and encouraging.
The three stages of preclinical Alzheimer’s disease used in the analysis are:
- Stage 1: Cerebrospinal fluid (CSF) levels of amyloid beta begin to decline, reflecting accumulation of amyloid plaques in the brain.
- Stage 2: CSF levels of tau protein rise, indicating neuronal injury and cell death; amyloid beta remains abnormal.
- Stage 3: With abnormal amyloid and tau biomarkers present, subtle cognitive changes become detectable on sensitive neuropsychological testing, though these changes alone do not establish a clinical diagnosis of dementia.
The investigators applied these criteria to 311 research participants aged 65 or older who were cognitively normal at their first evaluation at the Knight Alzheimer Disease Research Center between 1998 and 2011. Participants underwent annual assessments including cognitive testing and biomarker sampling; the longest follow-up spanned 15 years. At baseline, 41 percent of participants showed no indicators of Alzheimer’s disease (stage 0), 15 percent met criteria for stage 1, 12 percent for stage 2, and 4 percent for stage 3. Another 23 percent had cognitive impairment attributed to non‑Alzheimer’s causes, while 5 percent did not meet the proposed criteria.
Overall, 31 percent of the cognitively normal participants met criteria for preclinical Alzheimer’s disease. This proportion corresponds closely with autopsy studies that have identified Alzheimer’s pathology in roughly 30 percent of older adults who were clinically normal before death.
The study also supports the view that risk of symptomatic decline increases as individuals progress through preclinical stages. Five years after initial evaluation, 11 percent of individuals in stage 1, 26 percent in stage 2, and 52 percent in stage 3 had developed symptomatic Alzheimer’s disease. In addition, those with preclinical Alzheimer’s were approximately six times more likely to die over the following decade than cognitively normal older adults without preclinical biomarkers, although the mechanisms behind the increased mortality risk are not yet clear.
Researchers note several possible explanations for the higher mortality, including shared risk factors that raise vulnerability to other life‑threatening conditions or the possibility that undetected Alzheimer’s pathology complicates diagnosis and treatment of other diseases. Additional study is required to clarify these links.
Notes about this Alzheimer’s disease research
This research received support from the National Institute on Aging of the National Institutes of Health (NIH) and from several collaborative research initiatives and foundations, including the Internationale Stichting Alzheimer Onderzoek, the Center for Translational Molecular Medicine, Project Learn, the EU/EFPIA Innovative Medicines Initiative, and the Charles F. and Joanne Knight Alzheimer’s Disease Research Initiative.
Written by Michael C. Purdy
Contact: Michael C. Purdy – Washington University in St. Louis
Source: Washington University in St. Louis press release
Original Research: Abstract for “Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study” published in Lancet Neurology.