Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles

Abstract

Alzheimer's disease (AD) is heterogenous on the molecular level. Understanding this heterogeneity is critical for AD drug development. We aimed to define AD molecular subtypes by mass spectrometry proteomics in cerebrospinal fluid (CSF). Of the 3863 proteins detected in CSF, 1058 proteins had different levels in individuals with AD (n=419) compared with controls (n=187). Cluster analyses of AD individuals on these 1058 proteins revealed five subtypes: subtype 1 was characterized by neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier dysfunction. Distinct genetic profiles were associated with subtypes, e.g., subtype 1 was enriched with TREM2 R47H. Subtypes also differed in brain atrophy and clinical outcomes. For example, survival was shorter in subtype 3 compared to subtype 1 (5.6 versus 8.9 years). These novel insights into AD molecular heterogeneity highlight the need for personalized medicine.

CSF proteomic analysis of semorinemab Ph2 trials in prodromal-to-mild (Tauriel) and mild-to-moderate (Lauriet) Alzheimer’s disease identifies distinct trial cell-type specific proteomic signatures

“…To this end, a mass-spectrometry-based CSF proteomics dataset on a subset of Tauriel and Lauriet participants was generated, which, to our knowledge, is the first CSF proteomics study that provides insight into the pharmacodynamic response of an anti-tau antibody. More than 3500 proteins were measurable in the CSF, which is a comparable or greater number of proteins than detected in recently published AD CSF proteome datasets ( 8 , 9 , 20 ). By integrating the CSF proteomics dataset with tissue-specific bulk RNA-seq data from GTEx as well as single-nucleus RNA-seq data from post-mortem brains, we were able to show that although, predictably, a portion of the CSF proteome is likely derived from the periphery, a substantial proportion of detected proteins likely originate from the brain based on their gene expression in brain-resident cell types.…”

“…Cerebrospinal fluid (CSF) is a clear liquid surrounding the brain and spinal cord, and it has been broadly utilized as an accessible biofluid for biomarker discovery in AD ( 8 , 9 ). To this end, amidst the differences in clinical findings between the Tauriel and Lauriet studies, we utilized deep CSF proteomic profiling approaches to unravel the molecular intricacies underlying semorinemab’s differential impact.…”

CoVAMPnet: Comparative Markov State Analysis for Studying Effects of Drug Candidates on Disordered Biomolecules

“…70 The observation of significant effects of TMP and SPA on ApoE4, but weaker ones on Aβ, is also important in the context of a recently published paper reporting the existence of five subtypes of AD. 96 All subtypes showed a higher prevalence of the APOE e4 genotype, while only selected ones are characterized by modified levels of Aβ. In the future, it will be interesting to relate this information to the data collected within phase 3 of clinical trials, which will reveal the efficacy of TMP on the different subtypes.…”

Alzheimer’s disease as a women’s health challenge: a call for action on integrative precision medicine approaches

“…These sex-specific immune and inflammatory responses are likely contributors to disease heterogeneity in AD 35,36 . Multiomic studies, using transcriptomics or proteomics, can facilitate a better understanding of the differences in AD pathogenesis and clinical manifestations to help identify and stratify patients at risk 37 for clinical trials and precise treatments.…”

“…The current and ever-growing availability of public omics data of normal and AD brains, including Gene Expression Omnibus, Array Express, and the new National Institute on Aging Accelerating Medicines Partnership for AD portal (AMP-AD), along with computational tools to dissect molecular drivers of disease at a network level, present a unique new opportunity to explore sex differences in AD pathogenesis from a molecular multiomic perspective. Using proteomics 37 , metabolomics 26 , or transcriptomics 19,34 , new biological insights will enable greater precision in patient identification and stratification to improve treatment effectiveness. In addition, real-world datasets such as EHR provide an abundance of longitudinal clinical data, yet these datasets have yet to be optimally utilized to investigate sex-specific AD complexity.…”