Alzheimer’s Disease (AD) is possibly more diverse than our conventional models.
Postmortem, RNA sequencing has divulged three major molecular subtypes of the disease, each of which is different in the brain and which holds a distinct genetic risk.
Such knowledge may help us anticipate which one is most vulnerable to each subtype, how their disease might intensify and what treatments might be suitable for them leading to better results.
Presently, the mouse models we have for pharmaceutical research match a particular subset of AD, but not all subtypes.
This may partially elaborate why a vast majority of drugs successful in particular mouse models do not align with generalised human trials across all AD subtypes.
Therefore, subtyping patients with AD is a crucial step toward accurate medicine for this devastating disease.
AD is assumed to be marked by clumps of amyloid-beta plaques (Aβ), as well as tangles of tau proteins (NFTs) found in postmortem biopsies of the brain.
Both of these markers have become synonymous with the disease, but over the recent past, what they actually do to our brains have come under question.
Generally, accumulations of Aβ and NFT are considered to drive neuronal and synaptic loss, mostly within the cerebral cortex and hippocampus. More degeneration then follows, including inflammation and degeneration of nerve cells’ protective coating, which slows down signals in our brains.
But, the latest findings have proved that for one-third of patients, the clinical diagnosis has no Aβ plaques in postmortem biopsies. Surprisingly, many of those found with plaques at death did not show cognitive impairment in life.
Instead of being an initial trigger of AD, setting off neurodegeneration and driving memory loss and confusion, in some people, Aβ plaques seem to be latecomers.
Few latest findings suggest tau proteins are there from the very earliest stages.
It’s most likely that there are certain subtypes of AD that we haven’t teased apart yet. The new research has helped unbraid three major strands.
Researchers analysed 1,543 transcriptomes. The genetic processes being express in the cell across five brain regions were collected during post mortem from two AD cohorts.
Applying RNA sequencing to profile these transcriptomes, three major molecular subtypes of AD were identified, which correspond to different dysregulated pathways.
These include susceptibility to tau-mediated neurodegeneration; amyloid-β neuroinflammation; synaptic signalling; immune activity; mitochondria organisation; and myelination.
All these subtypes were both independents of age and disease severity. Their molecular signatures were also evident in all brain regions, more in the hippocampus, which is largely associated with forming new memories.
Aβ and tau proteins could not fully elaborate the different subtypes, which suggests cognitive impairment is neither dependent on nor fully assured by their accumulation in the brain.
The mere presence of Aβ and tau clumps may not be as significant as the way they communicate with each other and other cell processes.
Comparing the results to contemporary mouse models, a serious mismatch was discovered. Most mouse models employed in clinical research are based on ‘typical’ presentations of AD, that covers one-third of the cases in this study.
This implies treatments tested on mice may be fruitful for all patients. To develop a more personalised approach to treatment, scientists are trying to find out and verify molecular biomarkers just like these.