Many elderly people function and behave normally despite the fact that a brain scan (or later, an autopsy) will display characteristics of Alzheimer's disease.
So, why do some people become demented while others remain mentally sound even though their brains appear similarly diseased? It’s all a matter of proteins and synapses, say UCLA investigators.
Compared to cognitively sound people with signs of disease, early-stage Alzheimer’s patients show high concentrations of amyloid beta, a type of protein, in their synapses, according to the results of a new study. Meanwhile, in the early stages of disease, Alzheimer’s patients do not show increased levels of hyperphosphorylated tau (p-tau), another Alzheimer's-linked protein. Tau levels rise only after a patient enters the late-stage, says the research team.
The UCLA researchers analyzed a collection of brain autopsy samples taken from different regions of the brain: parietal, superior parietal, entorhinal cortex, and hippocampus. A total of 46 people had contributed these samples. Four had been cognitively normal and so served as controls in the experiment. Fifteen functioned normally, but their brains showed signs of Alzheimer’s-related pathology; these people served as high-pathology controls. Twenty-four people had been diagnosed based on both pathology and clinical signs — both their brains and behavior showed signs of Alzheimer’s. The researchers classified the diagnosed patients as either early-stage or later stage and then included two final cases in their study, two patients who had been diagnosed with an inherited neurological condition that affects movement.
Analyzing the brain samples, the investigators measured concentration levels of amyloid beta and p-tau, hallmarks of Alzheimer’s disease, in the synaptic terminals.
They found little or no evidence of amyloid beta in either of the control groups. However, a rise in concentration levels was linked to later disease stage. Plus, synaptic levels of amyloid beta correlated with the occurrence of plaque, another hallmark of the disease.
Next, the investigators explored how biochemical levels related to demented behavior.
What they observed suggested dementia emerged only after the level of synapse-associated amyloid beta exceeded a certain threshold, a finding which supports the well-known “amyloid cascade hypothesis” for Alzheimer’s disease. This theory suggests amyloid beta oligomers are the primary toxic molecules of Alzheimer’s, yet they eventually initiate downstream tau pathology, which causes the symptoms of disease.
“Our results suggest that effective therapies will need to target synaptic amyloid beta oligomers,” Dr. Karen H. Gylys, lead investigator and researchers at UCLA’s Mary S. Easton Center for Alzheimer's Research, said in a press release.
Source: Bilousova T, Miller CA, Poon WW, et al. Synaptic Amyloid-b Oligomers Precede p-Tau and Differentiate High Pathology Control Cases. The American Journal of Pathology. 2015.