Age 60 seems to be the defining year for many homozygous carriers of the apolipoprotein ϵ4 gene –the time when age-related changes in cognition focus more on memory and begin a steeper decline into mild cognitive impairment and, eventually Alzheimer's disease, according to new unpublished observations from a longitudinal study of apo ϵ4 carriers and normal controls.
“We saw normal age-related patterns of memory loss that occurred before age 60, but during this period, we didn't see any significant cognitive differences between the apo ϵ4 homozygotes, heterozygotes, and noncarriers,” said Dr. Richard Caselli, a lead investigator for the Arizona Apoϵ4 Cohort Longitudinal Study of Cognitively Normal Individuals. “But our latest information shows that at around age 60, a separation begins and continues for as long as we have been able to follow our subjects. There is a particular pattern of decline in apo ϵ4 homozygotes that tends to precede any diagnosis of mild cognitive impairment [MCI] or anything that can be seen with routine clinical brain imaging,” he said in an interview.
This pattern suggests that pathologic changes could be occurring earlier in homozygous ϵ4 carriers, although the exact nature of these changes, and their triggers, remain speculative, said Dr. Caselli, chairman of the department of neurology at the Mayo Clinic, Scottsdale, Ariz., and a member of the Arizona Alzheimer's Disease Consortium.
The Arizona cohort was initiated in 1994, and now includes more than 600 people, enrolled at ages 20–90 years, who have at least one first-degree relative with Alzheimer's disease. The subjects are all genotyped for the apo ϵ4 allele, and undergo extensive neuropsychological testing every 2 years.
Dr. Caselli's recent substudy focuses on 214 of these subjects aged 50–69 years. Almost half are apo ϵ4 carriers–43 homozygous and 59 heterozygous.
The study set out to characterize the effect of apo ϵ4 status on the development of presymptomatic cognitive changes. It's well known that the gene has a dose-response effect on the age at AD diagnosis: 80%–90% of homozygotes will develop the disease, at a mean age of 68 years. About 30% of heterozygotes will develop AD and will do so at a mean age of 73, while 9% of noncarriers will develop the disease and are usually diagnosed around age 80.
As in the larger cohort, subjects in the substudy took the battery of neuropsychological tests every 2 years. The battery consists of four tests in each of five domains: executive, memory, language, spatial, and behavioral. Significant decline was defined as a drop of two standard deviations beyond that of the entire cohort in one or more domain test scores. Subjects were judged to have cognitive domain decline if their scores were lower on at least two tests in any single domain.
“We found that there was really no difference between the genetic subgroups in patterns of decline in the younger group of patients, aged 50–59 years,” Dr. Caselli said. “Some had no decline, some showed improvement, and some had domain decline, but there were no statistically significant differences.”
Significant differences did emerge in the group of 60- to 69-year-olds, however. Homozygotes had the highest proportion of cognitive decline, with 40% showing domain decline, compared with 8% of heterozygotes and noncarriers. None of the older noncarriers or heterozygotes experienced a decline in two or more domains, while this occurred in 20% of the homozygous subjects.
Dr. Caselli has additional data on 97 subjects who have been tested again in the years following their initial decline. “We saw that it was those who initially declined on memory who tended to continue to decline significantly in other areas, and if that subsequent decline was in the memory domain, it was even more pronounced.”
Seven subjects developed MCI or AD during the study; five of these were apo ϵ4 homozygotes, one was an apo ϵ4 heterozygote, and one was a noncarrier. “Typically, it took about 2 years following the epoch of domain decline for the diagnosis to occur.”
By looking at the larger cohort and including subjects aged 30–90 years, Dr. Caselli also found a striking age-related separation of memory domain performance between apo ϵ4 carriers and noncarriers. From age 30 to 60, memory performance on the Auditory Verbal Learning Test, which requires subjects to recall 15 words from a list, declined slowly and consistently, from a mean of 11 words at age 30 to about 9.5 words at age 60. Immediately thereafter, however, the groups separated. Noncarriers continued a slow, almost linear decline, and by age 90, their predicted mean word recall was about 8.5 of 15. But carriers entered a phase of sharper decline; by the time they reached 90 years, their predicted mean word recall was about 5.5.