In one of the largest study of Alzheimer's disease patients and their relatives, researchers at Mayo Clinic Jacksonville have found genes other than APOE4, a well known susceptibility risk factor, that are also responsible for determining who is at risk for developing the disease later in life.
For the study, led by Nilufer Ertekin-Taner, M.D., Ph.D., individuals of 25 multigenerational families were diagnosed with onset Alzheimer's disease (LOAD), the most common form of the disorder, including hundreds of other participants.
The researchers found that that blood levels of amyloid beta (A▀) proteins associated with AD were significantly elevated in first-degree relatives compared to protein found in non-blood relatives, such as spouses. These first-degree relatives were cognitively normal and age 65 or less, many of them were too young for symptoms of LOAD to show up.
"These results indicate that genetic factors of substantial magnitude lead to significant elevations of A▀ in the blood of asymptomatic, young individuals from extended LOAD families. This fits with our hypothesis that Ab levels rise years before development of the disorder," said Ertekin-Taner.
Three candidate genes on chromosome 10 that is associated with LOA have already been identified. One of these genes, that produces insulin degrading enzyme (IDE), is considered as the prime candidate for contributing to the disease.
IDE degrades both insulin and amyloid protein, and scientists hypothesize that when there is too much insulin in the brain such as due to diabetes or lower expression levels of IDE, this may lead to toxic accumulation of A▀. According to Ertekin-Taner, the impact of these three genes could equivalent to APOE4, a variant of the APOE gene that has been linked to LOAD.
The Mayo researchers have earlier discovered that one form of A▀ known as A▀42 is much more toxic than the other common form of A▀, which is A▀40. Also, with the progression of AD, A▀42 levels that have been rising for years begin to decline, perhaps because a large amount of the protein is being deposited within the brain.
As all known forms of early onset AD caused by genetic mutations are linked to an increase of A▀42, and due to such strong genetic determinants of these rarer forms of AD, the scientists speculated that the common late onset form may also be partly caused by genes that raise A▀ levels.
In the current study the researchers collected data on 25 extended multigenerational LOAD families. 103 first-degree relatives of AD patients as well as a group of 116 participants in the federally-funded Mayo Clinic Study of Aging, who served as their comparison group, were also studied. None of the study participants were diagnosed with AD.
Comparing first-degree relatives with non-relatives, it was found that for Ab42, the average level for the first-degree relatives is about 1.2-1.3 times that of non-relatives, and for Ab40, it was 1.1-1.4 times greater.
Later it was found that this rise in A▀ is not due to the APOE4 gene. In contrast, the plasma A▀ levels of relatives with the APOE4 gene variant were lower, significantly so for A▀42, than the levels of those who lacked the gene.
According to co-author Steven Younkin, M.D., Ph.D., this implies two things, that genetic factors other than the ones already known must lead to plasma Ab elevations in first-degree LOAD relatives, and that there is a strong mechanistic interaction between APOE4 and Ab leading to increased deposition of Ab in the brain and hence lower plasma Ab levels in these subjects.
"These findings indicate that there are genetic elevations in A▀ levels in LOAD that cannot be explained by shared family environment," said Dr. Younkin.
"it is conceivable that plasma Ab, along with other information such as genetic variants, neuroimaging and cognitive test results, may be used in the future to identify individuals at risk for developing AD, before the onset of disease symptoms," said Dr. Ertekin-Taner.
The results of the study will be published in the forthcoming issue of Neurology.