Studies Take Aim at Groups at High Risk for Alzheimer's

Imaging in the precuneus and caudate with Pittsburgh compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop AD. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, might be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at two standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then AD.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target, so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.

Jeff Evans contributed to this report.