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The cell\u2010type specific and, separately, peptide specific associations of VGF with pathologic and cognitive outcomes remain largely unknown. We leveraged gene expression and protein data from the human neocortex and investigated the VGF associations with common neuropathologies and late\u2010life cognitive decline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Community\u2010dwelling older adults were followed every year, died, and underwent brain autopsy. Cognitive decline was captured via annual cognitive testing. Common neurodegenerative and cerebrovascular conditions were assessed during neuropathologic evaluations. Bulk brain RNASeq and targeted proteomics analyses were conducted using frozen tissues from dorsolateral prefrontal cortex of 1,020 individuals. Cell\u2010type specific gene expressions were quantified in a subsample (N\u2009=\u2009424) following single nuclei RNASeq analysis from the same cortex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The bulk brain <jats:italic>VGF<\/jats:italic> gene expression was primarily associated with AD and Lewy bodies. The <jats:italic>VGF<\/jats:italic> gene association with cognitive decline was in part accounted for by neuropathologies. Similar associations were observed for the VGF protein. Cell\u2010type specific analyses revealed that, while <jats:italic>VGF<\/jats:italic> was differentially expressed in most major cell types in the cortex, its association with neuropathologies and cognitive decline was restricted to the neuronal cells. Further, the peptide fragments across the VGF polypeptide resembled each other in relation to neuropathologies and cognitive decline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Multiple pathways link VGF to cognitive health in older age, including neurodegeneration. The <jats:italic>VGF<\/jats:italic> gene functions primarily in neuronal cells and its protein associations with pathologic and cognitive outcomes do not map to a specific peptide. 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