PRODROMAL ALZHEIMER’S DISEASE (AD)
Prodromal Alzheimer’s Disease (figure above) is the second stage of the presymptomatic period, and the beginning of neurodegeneration. Braak and Braak 1991 autopsy statement “disease must have occurred many years before symptoms appeared” established the term presymptomatic period. Bruce’s opinion is that the presymptomatic period is an uncertain timeframe, that is currently being assumed as about 20 years. Bruce’s separates the presymptomatic period into 2 stages. An asymptomatic stage recognizes amyloid aggregation accumulation without neuron loss or symptoms. The Prodromal stage is where the amyloid aggregation accumulation has triggered Tau protein fibrils and tangles along with neurodegeneration (neuron loss). The significance event in these stage is an unknown mechanism that triggers neurodegeneration. Since neurons are not known to be regenerated after birth, once the disease starts claiming neurons, intervening with Tau pathology and neurodegeneration becomes increasing more complicated. The complications include a) insufficient knowledge of the brain’s immune system involvement; b) determining which of the Tau protein multiple functions or which isoform of the Tau protein is correct to target for stopping fibrils and tangles; c) tau pathology; and d) hyperphosphorylation of the Tau protein.
It seems logical to target amyloid in the asymptomatic stage for prevention. In parallel pursue research knowledge of the Tau protein’s complexity, whereby delay might be achieved during the Prodromal AD stage. The following discusses the Prodromal AD stage.
Assume the Prodromal stage a ten-year period where neurodegeneration (neuron loss) increases unknowingly and without adequate detectable diagnostic tools. In addition, the brain’s immune system becomes involved with Tau fibrils and tangles as well as pathology and neurodegeneration. Knowledge about the immune system’s and its involvement is currently being aggressively pursued. The targets appear to be the Tau protein’s hyperphosphorylation, fibrils and tangles, tauopathy, and isoforms (different functions directed by the DNA structure through instruction carried by a designated enzyme.
The Tau Protein
The Tau protein linkage to neurofibrillary tangles was first made in 1986. The tau protein is produced (synthesized) from the Microtubule-Associated Protein Tau (MAPT) gene on Chromosome 17.
Prodromal Alzheimer’s Disease research is trying to quantify the amyloid aggregate accunulation through analysing PET Scans with various ligands (tracers). Differnet ligands and methods have produced different accumulations for triggering fibrils and tangles.
Italics are extracts from Bruce’s book
A main function of the tau protein is to modulate the stability of axonal microtubules within the axon where communication is processed through the axon to the synapse terminal. Hyperphosphorylation is assumed to cause abnormal inclusions that form paired helical fibers, which aggregate into insoluble tangles and disrupt communication. Eventually, affected neurons die, and the neurofibrilary tangles remain in extra-cellular space as tombstones of the cells destroyed by the disease (Principles of Neural Science, Fifth Edition Eric Kandel et. al.).
What causes phosphorylation to become hyperphosphorylation is unknown.
- Tauopathy is name for the many pathways that AD spreads throughout the brain and cause functional decline as observed by symptoms. Pathways are an ongoing research activity as to how and what causes this spread. Is it the immune system? Is it Hyperphosphorylation? Is it a function in the Isoforms of Tau?
There are multiple isoforms of the tau protein for different functions. What this means is that he protein structures contains many amino acids with different sequences which are repeated 2, 3, or 4 times to convey instructions. To achieve the specific instruction, up to half of the enzyme messengers are involved. It is this complex structural arrangement that researchers are trying to find causes and answer whereby an AD intervention could delay the tauopathy process.
With biological biomarkers to identify people with Prodromal AD and gaining more knowledge on Tau isoforms, phosphorylation, and tauopathy, an intervention during this stage of Presymptomatic AD becomes a possibility. A time frame is unknown. You be the judge. Bruce won’t be around.