If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. 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, may 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 2 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 Alzheimer’s disease.
"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.
"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."
DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.