A Multiomics Approach to Heterogeneity in Alzheimer's Disease

Focused Review and Roadmap

AmanPreet Badhwar; G. Peggy McFall; Shraddha Sapkota; Sandra E. Black; Howard Chertkow; Simon Duchesne; Mario Masellis; Liang Li; Roger A. Dixon; Pierre Bellec

Disclosures

Brain. 2020;143(5):1315-1331. 

In This Article

Materials and Methods

We conducted parallel focused reviews of PubMed articles published between January 2011 to June 2018 in three omics domains: brain connectomics (and morphometry), metabolomics, and genomics. It should be noted that for brain connectomics (and morphometry), we only focused on MRI-based studies, and did not include studies using PET imaging methods, as data-driven subtype literature is sparse in the latter. We included studies investigating Alzheimer's disease in humans and published in English (termed 'common' inclusion criteria). Additional articles (that met criteria) were identified by scanning the reference lists of selected PubMed articles. Described in the following three sections are search characteristics specific to each omics domain. Characteristics of the 40 domain-specific omics studies included are provided in Supplementary Table 1, Supplementary Table 2 and Supplementary Table 5.

Brain Morphology and Connectomics

Search term combinations used for brain morphology and connectomics in neuroimaging were: (i) Alzheimer's disease OR Alzheimer pathology AND subtype; (ii) mild cognitive impairment OR amnestic mild cognitive impairment OR MCI OR amnestic MCI AND hierarchical clustering; resting-state AND functional MRI AND Alzheimer AND clustering; (iii) Alzheimer's disease OR Alzheimer pathology AND structural subtype; (iv) Alzheimer's disease OR Alzheimer pathology AND structural MRI AND clustering; (v) resting-state AND functional MRI AND Alzheimer AND hierarchical clustering; (vi) diffusion MRI AND Alzheimer AND clustering; and (vii) diffusion MRI AND Alzheimer AND hierarchical clustering; diffusion MRI AND hierarchical clustering. To these we applied the 'common' inclusion criteria. Thereafter, only studies reporting Alzheimer's disease spectrum subgroups identified using data-driven methods were included. It should be noted that neuroimaging-based subtyping is an emergent field and there is still a lack of consistent terminology. Therefore, to avoid missing relevant studies due to stringent use of terminology, search combinations (i) and (ii), using relaxed and inclusive keywords, captured all of the morphometry-based literature. In total, 12 papers met our criteria, and were reviewed.

Metabolomics

Search term combinations for metabolomics were: (i) Alzheimer's disease AND metabolomics panels; (ii) Alzheimer's disease AND metabolomics profiles; (iii) Alzheimer's disease AND metabolomics networks; (iv) Alzheimer's disease AND metabolomics pathways; and (v) Alzheimer's disease AND metabolomics biomarkers. To these we applied the common inclusion criteria. We further excluded: reviews and technical reports; articles not relevant to Alzheimer's disease metabolomic panels, pathways, or networks; and studies using a targeted metabolomics approach. Five papers were identified from reference list scans. In total, 11 studies were reviewed. Details on key metabolites highlighted in the 11 studies were compiled from three different databases: Human Metabolome Database (HMDB, http://www.hmdb.ca/), Kyoto Encyclopedia of Genes and Genomes (KEGG, https://www.genome.jp/kegg/pathway.html) Pathway Database, and PubMed. These details were used to generate Figure 2B and are provided in Supplementary Table 3.

Genomics

Search term combinations used for the genomics were: (Polygenic Risk Scale OR Polygenic Risk Index OR Genetic Risk Score OR Genetic Risk Scale OR Genetic Risk Index) AND (Alzheimer Disease OR Alzheimers Disease OR Alzheimer's Disease), which identified 264 potential papers. To these we applied the 'common' inclusion criteria, followed by exclusion of single-gene studies. In total, 17 studies were reviewed. References used for the compilation of the genes in Supplementary Table 4 are provided in the Supplementary material.

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