Further Consideration of Subtypes of Alzheimer's Disease

There has been some thought given to whether Alzheimer's disease is a collection of fairly distinct subtypes, with different origins and different dominant processes of pathology. The evidence for subtypes of Alzheimer's disease is suggestive, as noted in this article. It remains to be seen as to what the research community will do with all of this data, but it is possible that some therapies are not as bad as originally thought, if analysis were restricted to only one subtype of Alzheimer's disease.

Proteins floating in the cerebrospinal fluid (CSF) might do more than diagnose Alzheimer's disease (AD) - they may identify different subtypes. Of the 3,863 proteins measured, 1,058 were either more or less abundant in people with AD. Researches clustered these by whether they were upregulated or downregulated in sync, then used gene ontology to identify biological pathways associated with each cluster. Proteomic profiles suggested five subtypes based on cellular processes predicted to be dysfunctional: the three previously identified - neuronal hyperplasticity, innate immune activation, and blood-brain barrier (BBB) dysregulation - and two new ones, dubbed choroid plexus dysfunction and RNA dysregulation.

Among the 419 people with AD, 137 fell into the neuronal hyperplasticity subtype. Upregulation of proteins involved in synapse assembly, axon guidance, and neurogenesis and gliogenesis suggested overactive neuron signaling and possibly an overabundance of neurons. Indeed, MRI scans showed the least atrophy in this subtype. Only the hippocampus and temporal and parietal lobes shrank. Prevalence of the TREM2 R47H variant was highest in this group. This hypofunctional TREM2 hobbles microglial pruning of synapses in mouse models of amyloidosis and was recently linked to cortical synapse growth. This subtype represented the mildest disease, with people living nine years, on average, after being clinically diagnosed with dementia.

Fifty-six people fit the BBB dysfunction criteria, having blood proteins, such as albumin, fibrinogens, and plasminogen, show up in the CSF. In contrast, there was a dearth of proteins made by brain vascular cells that typically leach into the CSF, such as platelet-derived growth factor receptor β and the cell adhesion proteins cadherin and laminin, suggesting disrupted brain tissue around blood vessels. Along these lines, people with the BBB dysfunction subtype had more microbleeds on MRI than people in other subtypes. In contrast, microglia may be overactive in the second of the three previously identified subtypes, innate immune activation. Among the 124 people in this group, complement components, regulators of cytokine production, and microglial proteins were overrepresented. Researchers saw severe and widespread cortical atrophy in this group, perhaps because microglia prune synapses too vigorously, she speculated. People with this subtype progressed the quickest from mild cognitive impairment to dementia.

As for the two new subtypes, molecules from the extracellular matrix and the choroid plexus (CP), including transthyretin, wound up in the CSF of 78 people with the CP subtype. MRI scans showed that the CP, a network of extracellular matrix and blood vessels, was enlarged. Large CPs associate with inflammation and cortical atrophy in multiple sclerosis, and in this fourth AD subtype, researchers detected elevated cytokines and severe, widespread cortical thinning. The other new subtype, RNA dysregulation, comprised just 24 people. They had high levels of chaperones and RNA-binding proteins in their CSF. Intriguingly, they had little of the microtubule-binding protein stathmin-2 (STMN2). Correct splicing and translation of STMN2 requires the RNA-binding protein TDP-43, best known for its role in frontotemporal dementia. This RNA dysregulation subtype seems the most aggressive. People had the most total tau and neurofilament light in their CSF, both signs of neuron damage, and they died soonest, about 5.5 years on average, after a clinical dementia diagnosis.

Link: https://www.alzforum.org/news/research-news/and-then-there-were-five-csf-proteomics-defines-alzheimers-subtypes