Major Discovery May Alter Thinking on Alzheimer’s Disease

Investigators at the Blancette Rockefeller Neurosciences Institute (BRNI) recently discovered that the most significant genetic risk factor associated with Alzheimer’s disease, the Apolipoprotein E4 (ApoE4) gene, leads to a decrease in brain synapses, which occurs frequently prior to the onset of amyloid plaques or tangles developing in Alzheimer’s patients. This discovery may alter the paradigm, treatment and prevention of the disease.

In the study entitled “ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation,” which was recently published at the Journal of Neuroscience, the investigators revealed that ApoE4 is able to reduce synapses through its interaction with the DNA that is responsible for synapse formation and maintenance. The gene raises the nuclear translocation and activity of histone deacetylases (HDACs) in human neurons.

This means that by interfering with the HDACs enzymes, which work as an on/off switch for genes, the levels of DNA-programmed brain-derived neurotrophic factor (BDNF) are reduced. Consequently, it influences the formation, repairing and plasticity capacities of brain cell synapses. The loss of mature, functional synapses is a critical component of early Alzheimer’s disease and is related to cognitive deficits.

“We know that people with the complete ApoE4 genes are 10 times more likely to suffer from the most common form of late, age-dependent Alzheimer’s disease. We also know from previous autopsy studies that Alzheimer’s patients have deficits of BDNF, Protein Kinase C (PKC) epsilon and synapses,” stated the scientific director of BRNI, Daniel Alkon.

“Now, in the present study, the brains of Alzheimer’s patients were found to have increased levels of HDACs. These findings, taken together, suggest that substituting the abnormal ApoE4 gene for the ApoE3 gene is one of the earliest causes of synaptic loss in Alzheimer’s disease,” he explained.

All late-phase clinical trials that evaluated drugs to cure Alzheimer’s disease to this point have failed — even the ones with promising preclinical studies. The BRNI believe that, while most of the research is focused on brain hallmarks and its pathology, such as extracellular clumps of proteins; the cellular debris called “amyloid plaques;” and twisted intracellular tau fibers known as “tangles,” the new findings may revolutionize these studies.

“Our study provides evidence for a major shift in current thinking around Alzheimer’s disease and research,” said Alkon. “Synaptic loss often occurs before the onset of amyloid plaques or tangles in Alzheimer’s patients, so our latest findings suggest that many of today’s trials that only focus on plaques and tangles aren’t targeting a critical pathway responsible for early synaptic loss and, therefore, Alzheimer’s disease.”

The promising outcomes from the findings may particularly benefit the field of Alzheimer’s prevention. The new research found potent activators that may prevent ApoE4. One of them is Bryostatin, which has been demonstrated in previous pre-clinical studies to lower soluble A Beta oligomers that work like ApoE4 and lead to plaque formation.

The findings suggest that these kinds of activators may be further studied to improve Alzheimer’s treatment and possibly provide a new hope to healthy people with the ApoE4 gene, even prior to the onset of the disease. “We are excited and encouraged by these results. In essence, our findings suggest that Bryostatin could be used in some patients to prevent Alzheimer’s disease before it ever begins,” concluded Alkon.