Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, Harerimana NV, White B, Thambisetty M, Troncoso JC, Kim N, Schneider JA, Hajjar IM, Lah JJ, Bennett DA, Seyfried NT, Levey AI, Wingo TS. Shared proteomic effects of cerebral atherosclerosis and Alzheimer's disease on the human brain. Nat Neurosci. 2020 Jun;23(6):696-700. Epub 2020 May 18 PubMed. Correction.

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  1. Johnson et al. provide fascinating findings on mass spectroscopy proteomics in brain tissue from over 2,000 pathologically defined individuals with AD, other dementias, and controls as part of the multicenter Accelerating Medicine Partnership for AD (AMP-AD) project.

    They clustered 3,334 proteins in a discovery cohort of 453 individuals with AD or controls and identified 13 modules by weighted co-expression network analysis (WCNA). A strong finding was that these clusters were reproduced across cohorts, tissues, and proteomic techniques. The proteomic dataset is a major asset for the research community.

    Module 4 showed the strongest association with amyloid CERAD, tau Braak, and MMSE scores. It included 186 proteins, which were on average increased in AD relative to controls. The model was enriched for microglia and astrocyte proteins, and MAGMA analyses suggest overrepresentation for AD SNPs. Remarkably, the proteins associated with this module were also increased in FTLD-TDP and CBD. This result seems at first glance unexpected, since amyloid pathology is the pathological hallmark for AD and not commonly seen in FTLD-TDP and CBD. Possibly, this overlap could be explained by abnormal tau processing, which is shared between these disorders. 

    Further analyses on module 4 proteins showed that they could be involved in an anti-inflammatory response, which the authors suggested may reflect a protective response. However, higher concentrations of module 4 proteins were also associated with worse cognitive impairment and pathology. 

    In the related study, Wingo et al. tested the association of tissue proteomics with cerebral atherosclerosis (CA). Of the 8,362 proteins investigated in 438 individuals, 114 proteins showed an association with CA, of which 82 proteins showed lower concentrations with the presence of CA. These proteins were enriched for RNA processing. Another 32 proteins showed increased levels, and were enriched for oligodendrocyte development. WCNA was also performed in the total group, producing 31 modules. Five of these modules were related to CA, including a module with synaptic proteins, which were decreased relative to controls. Two of those modules also showed an association with a clinical AD dementia diagnosis, but not with amyloid plaque or tau tangle burden. This could mean that CA could contribute to dementia that shows clinical similarities with AD, independent of AD pathology.

    View all comments by Betty Tijms

  2. This impressive study demonstrates the potential of combining proteomics with detailed pathological phenotyping to yield important mechanistic insights into the causes of dementia. Using this approach, the authors elegantly demonstrate a number of molecular changes specific to atherosclerosis, as well as others shared with AD.

    A particularly intriguing conclusion is that the well-established relationship between AD and neurofilament light (NfL)—increasingly measured as a biomarker of neurodegeneration where it is thought to reflect damage to large-caliber myelinated axons—is mediated via cerebral atherosclerosis. While this is not likely to explain elevation of NfL in all conditions—CSF and blood NfL concentration is elevated in numerous neurodegenerative and non-neurodegenerative diseases, some of which, e.g. Huntington’s, familial Alzheimer’s, head injury, are unlikely to be mediated via conventional vascular risk factors—it reinforces the importance of considering cerebrovascular disease both as a co-pathology and also as a potentially core (and modifiable) feature of late-onset sporadic AD.

    Importantly, however, any temporal associations between these pathologies can only be inferred from autopsy studies: longitudinal in vivo studies incorporating biomarkers are required to determine the exact sequences of changes and their interrelationships.

    View all comments by Dylan Williams

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