Comparisons of AD subtypes on MRI and clinical findings. a, Median hippocampal volume as a percentage of total intracranial volume (TIV) relative to dementia stage subtypes. b, Choroid plexus volume as a percentage of VTI versus subtypes at dementia stage. c, Cortical atrophy associated with AD subtypes in dementia stage compared to controls. d, Clinical progression from MCI to dementia by subtype and time from dementia to death by subtype (right). Credit: Natural aging (2024). DOI: 10.1038/s43587-023-00550-7
A large team of neuroscientists and neurodegenerative disease specialists affiliated with several entities in the Netherlands, working with colleagues from the United States, Belgium, the United Kingdom and Sweden, have discovered five categories of fluids surrounding the brains of patients with Alzheimer’s disease. Their study is published in the journal Natural aging.
Previous research has shown that people who develop Alzheimer’s disease have differences in protein levels in their spinal fluid compared to people without the disease, differences associated with certain molecular processes in the brain. In this new effort, the research team discovered differences in protein levels among patients with the disease.
The work involved studying 1,058 proteins in cerebrospinal fluid from 419 patients and 187 control volunteers, known to be different in Alzheimer’s patients when they noticed certain patterns appearing. The patterns, they found, could be divided into five distinct subtypes, suggesting that there could be five distinct types of Alzheimer’s disease. They named subtypes 1 through 5.
Specifically, researchers found that patients with subtype 1 had altered levels of proteins associated with hyperplasticity in addition to increased levels of amyloid production. People with subtype 2 had proteins associated with innate immune activation associated with excessive pruning of synapses and microglial proteins. Subtype 3 patients showed signs of RNA dysregulation, while subtype 4 patients showed signs of dysfunction of the choroid plexus (where cerebrospinal fluid is made). And subtype 5 patients had deficiencies in the blood-brain barrier as well as reduced levels of amyloid production.
The research team noted that each of the subtypes also had a unique associated genetic profile. They also suggest that if Alzheimer’s disease has five main types, this could explain why the search for therapies to treat it has met with so little success, highlighting that a different therapy may be needed for each subtype. They further suggest that treatment of future Alzheimer’s patients could begin by first testing their spinal fluid and identifying their subtype.
More information:
Betty M. Tijms et al, Cerebrospinal fluid proteomics in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles, Natural aging (2024). DOI: 10.1038/s43587-023-00550-7
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