Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, Wang E, Horgusluoglu-Moloch E, Song WM, Li A, Castranio EL, Tcw J, Ho L, Goate A, Fossati V, Noggle S, Gandy S, Ehrlich ME, Katsel P, Schadt E, Cai D, Brennand KJ, Haroutunian V, Zhang B. Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets. Sci Adv. 2021 Jan;7(2) Print 2021 Jan PubMed.

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  1. Biological heterogeneity of Alzheimer’s disease is a relatively unexplored territory, even though there is ample evidence based on clinical and imaging studies that heterogeneity does exist. Here, Neff and colleagues explored heterogeneity in gene expression profiles in brain tissue of individuals with pathologically confirmed AD.

    Clustering people based on their gene expression profiles revealed at least three molecular subgroups (A, B, C) of which B and C were subdivided (B1, B2, C1, C2). Subtypes A and B1 showed, relative to control brains, increased expression of genes involved in synaptic activity and regulation of tau, as well as lower expression of genes involved in immune function and the blood brain barrier (BBB). Subtype B2 showed increased expression of synaptic proteins and immune/BBB genes. Subtypes C1 and C2 mirrored subtype A and B1 by showing decreased expression of synaptic proteins and increased expression of immune/BBB genes.

    It is striking that some of these subtypes resemble the three subtypes we recently identified in individuals with AD using cerebrospinal fluid (CSF) proteomic analysis of 556 proteins (Tijms et al., 2020). Our subtype 1 showed increased expression of synaptic and plasticity proteins, like subtype A and B1. Our subtype 2 showed increased levels of proteins involved in synaptic activity and immune function, like subtype B2. This subtype had higher AD polygenic risk scores of immune related genes compared to the other subtypes. Our subtype 3 showed decreased concentrations of proteins involved in synaptic function and increased concentrations of proteins associated with BBB dysfunction, like subtype C1 and C2.

    We found that proteins increased in our subtype 1 were enriched for regulation by transcription factors REST and SUZ12, which are important regulators of synaptic plasticity. Using the top 100 genes with highest expression in subtype A from the Neff paper, we found that these genes were also regulated by REST/SUZ12 while the top 100 genes with lowest expression in subtype C were regulated by REST/SUZ12 as well. 

    The convergence between our CSF proteomic subtypes and Neff et al. gene expression subtypes strongly support the presence of AD subtypes with a different underlying molecular pathophysiology. This will have major clinical implications as the different subtypes may need different treatments.

    Also, the current staging system for AD based on amyloid, tau, and neuronal injury markers may need to be reconsidered as this system does not capture these subtypes. Because a wide range of biological processes seems to cluster around specific subtypes, a system may be needed that allows for subtype allocation, rather than scoring individuals on single biological processes. In such a scenario, amyloid pathology could be considered the defining feature of AD with a set of other markers to specify the subtype.

    View all comments by Betty Tijms

  2. In my opinion, this is the clearest indication that Alzheimer's disease is not a single entity, despite the ubiquity of amyloid plaques, and should not be treated as one. Therapies that seek to slow progression of dementia are unlikely to be effective in all subtypes. Biomarkers of all subtypes are less useful than biomarkers of individual subtypes; these signals can be diluted by inclusion of other subtypes.

    View all comments by Peter Lansbury

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