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Study Finds Hints of Trouble in Brain Decades Before Alzheimer's Develops

While most Alzheimer’s researchers focus their attention on the classic pathological signs of the mind-robbing disease – the so-called plaques and tangles - scientists at the Feinstein Institute for Medical Research have new evidence of molecular hints of trouble in the brain decades before the disease takes hold.

Concepcion Conejero-Goldberg, M.D., Ph.D., and her colleagues are interested in prevention, so headed back in time to study younger adults who carry an Alzheimer's-risk gene called APOE4. The researchers were hoping to find molecular differences in the brains of people with one or two copies of the APOE4 gene, and those of people who don't carry a copy of the risk gene. Having one copy increases the odds of developing Alzheimer’s three to four times those for people without the genetic variant.

The researchers were able to obtain brain tissue from young to middle-age adults who died from a variety of causes. The researchers chose tissue from two different brain areas, one that is hard-hit by Alzheimer’s (middle temporal gyrus) and one that isn't (primary somatosensory cortex). Then the team sampled brain tissue from the cerebellum to find out whether the person had been born with an APOE4 gene. The team had tissue from 41 people who had died on average around the age of 42, and no one in the group had any pathological signs of Alzheimer’s – at least no plaques and tangles.

“We wanted to know whether young people can give us a lead on the development of the disease,” Dr. Conejero-Goldberg said. Once the researchers had the human brain tissue and the genotype of the people whose lives were cut short for a variety of reasons, the team set out to conduct microarray gene-expression studies of the tissue itself. Did the presence of an apoE4 genotype have an impact on the genetic expression of the specific tissue and was the tissue that gets destroyed by the illness molecularly different than the tissue that remains healthy until the very end of the illness?

The researchers found 70 gene transcripts that differed significantly between the two groups, those with APOE4 and those without. And there were regional differences in the expression of APOE4 itself. Some of the genes are known to be involved with pathways that regulate mitochondrial function, calcium regulation and cell-cycle re-entry. The differences in the regulation of the genes between the APOE4 carriers and non-APOE4 carriers and the fact that the changes were observed in the tissue hard-hit by Alzheimer’s suggests to these scientists that these molecular hits could be working for a lifetime to set in motion a disease in old age that wipes away memories and so much more. On the contrary, changes in the spared brain area may be neuroprotective.

“Our findings tell us that something is going on in the brains of at-risk people very early on, decades before the plaques and tangles begin to appear,” said Dr. Conejero-Goldberg, part of the Litwin-Zucker Research Center for the Study of Alzheimer's Disease. Her collaborators outside of the Feinstein include researchers from the National Institute of Mental Health and Albert Einstein College of Medicine.

None of the genes that they identified were involved with the classical Alzheimer’s pathway that leads to amyloid plaques and tau tangles. “These findings may give us clues why some brains are more susceptible to
Alzheimer’s than others,” the Feinstein scientist said. Also, the identification of genes that damage pathways also opened the door to genes that may protect the brain against Alzheimer’s.

The findings of the study were published in Molecular Psychiatry.


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