BALTIMORE—The focus of Alzheimer’s disease research should shift from curing patients in the symptomatic stage to intervention in the preclinical stage, suggested John C. Morris, MD, in a presentation at the 134th Annual Meeting of the American Neurological Association. The early detection of several key biomarkers may allow researchers to determine which cognitively healthy adults are most likely to develop dementia.

“New evidence indicates that [the presence of amyloid in the brain is] predictive of which normal individuals will develop symptomatic Alzheimer’s disease in a matter of years,” said Dr. Morris, who is the Harvey A. and Dorismae Hacker Friedman Professor of Neurology at the Washington University School of Medicine in St. Louis.

Dr. Morris and colleagues recently used Pittsburgh Compound B (PIB) to measure potential pathologic hallmarks of Alzheimer’s disease in 241 healthy people (mean age, 67) enrolled in various Washington University research programs. A high level of binding potential indicates the number of amyloid plaques in the brain of a living person. Seventy-eight persons carried at least one copy of apolipoprotein (APOE) ε 4, and approximately 30 carried the protective gene, APOE ε 2. During the four-week baseline phase, patients recorded their headaches and associated symptoms in electronic diaries. The mean baseline patient diary-day compliance rate was 99% and remained high (greater than 93%) in both treatment groups during the 24-week phase.

“Preliminarily, our biomarker conclusions are [that] Aβ-42 in the cerebral cortex is the pathobiologic phenotype of APOE ε 4, and it increases as a function of age,” said Dr. Morris. “In cognitively healthy people, we call this preclinical Alzheimer’s disease. The most promising biomarkers of preclinical Alzheimer’s disease, antecedent to symptomatic stages, include PET of the brain using tracers for amyloid-beta and assays of CSF for amyloid-beta and tau proteins.”

Amyloid Levels

The majority of participants showed no elevation of binding potential; no amyloid plaques were seen, even in the oldest participant (age 88). “However, around age 55, we start to see some individuals with increased binding potential, and the number of individuals and the degree of binding potential both increase as a function of age,” Dr. Morris said.

This increase is related to APOE ε 4 status. About 13% of APOE ε 4–positive people ages 50 to 55 showed elevated binding potential with PIB, which increased with age. An age-related increase was also seen in a much smaller group of APOE ε 4–negative individuals, indicating that factors besides APOE play a role in cerebral deposition of amyloid-beta.

“We don’t think that the presence of cerebral amyloid, even in cognitively normal individuals, necessarily is benign,” Dr. Morris commented. Other studies at Washington University have shown that cognitively healthy people with elevated PIB binding potential are declining in their cognitive performance over time.

Another indicator of cerebral deposits of amyloid beta that appears to be reduced is CSF Aβ-42 levels. In cognitively healthy people, reduced Aβ-42 levels are associated with lower whole brain volume, but once dementia is manifest there is no relation. The opposite is true for elevated levels of CSF tau, which is an indicator of the symptomatic stages of Alzheimer’s disease; in cognitively normal people, there is no relation of CSF tau and whole brain volume, but there is a strong correlation once dementia is expressed.

“We think that the effects of amyloid-beta may be most deleterious in the preclinical state, but when sufficient neuronal degeneration occurs such that the dementia appears, then the stronger effect is with tau,” Dr. Morris commented.

Identifying At-Risk Individuals

In 159 cognitively normal people followed for up to four years, those with elevated cortical binding potential for PIB at baseline showed a significant hazard ratio of about 5 for development of symptomatic Alzheimer’s disease. “Although this is a very small sample, we think that it provides preliminary evidence that PIB can identify cognitively healthy people who, in a matter of years, [will be at] high risk for converting to the symptomatic stage,” noted Dr. Morris.

Evidence supports that the formation of oligomers and other amyloid-beta species are pathologically relevant, although there currently is no in vivo biomarker to detect upstream events. “Eventually these oligomers aggregate, and they get deposited as diffuse plaques in the cerebral cortex,” Dr. Morris explained, noting that the earliest biomarker detection is probably reduced CSF Aβ-42. Subsequently, the plaques become fibrillar, and then are detected by PIB.

The Future of Alzheimer's Disease Research

Dr. Morris noted that this research does not take into account other pathologic processes that likely operate in Alzheimer’s disease, such as inflammation, oxidative stress, and vascular insufficiency. However, an “organizing scheme” is emerging for future research, wherein amyloid dysregulation begins in cognitively normal persons but ultimately exerts pathological effects on the brain to transition from a presymptomatic to a symptomatic stage of Alzheimer’s disease. “We need to change the focus in Alzheimer’s disease, from only attempting to cure symptomatic people, to ultimately being able to intervene before symptoms appear, and thus move to preventing Alzheimer dementia,” Dr. Morris said. “Confirmation of these early findings in larger studies will perhaps change the therapeutic paradigm in Alzheimer’s disease from cure to prevention.”

—Laura Sassano

Predicting Alzheimer's Disease in Healthy Older Adults