The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.

So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. “Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers].”

Dr. Richard J. Caselli
The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. “One gets the sense that there are newer, better tests … that might have picked up cross-sectionally the differences,” said Dr. Howard Chertkow of McGill University in Montreal.

Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.

“The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. … Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease,” said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.

Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.

Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. “Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years,” he said.

“Extrapolating from these group analyses,” Dr. Caselli said, “neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like … the lorazepam challenge,” for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).

A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.

The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).

Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.

“Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills,” Dr. Caselli commented.

In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.

Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.

Dr. Caselli disclosed no relevant conflicts of interest.