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influence longitudinal heterogeneous changes in Alzheimer's disease (AD) may provide insight into disease mechanisms and potential therapeutic targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Longitudinal endophenotypes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) representing amyloid, tau, neurodegeneration (A\/T\/N), and cognition were selected. Genome\u2010wide association analysis was performed using a linear mixed model (LMM) approach, followed by gene and pathway enrichment with significant and functionally relevant SNPs.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>A total of 33 and 19 statistically significant pathways were identified associating with the intercept and longitudinal trajectory, respectively. The longitudinal intercept pathways represent eight groups: immune, metabolic, cell growth and survival, DNA maintenance, neuronal signaling, <jats:italic>R<\/jats:italic><jats:italic>AS<\/jats:italic>\/<jats:italic>MAPK<\/jats:italic>\/<jats:italic>ERK\u00a0signaling\u00a0pathways<\/jats:italic>, vesicle and lysosomal transport, and transcription modification. Longitudinal trajectory pathways represented six groups: Immune, metabolic, cell signaling, cytoskeleton, and glycosylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Longitudinal enrichment identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition, providing new insight into AD course\u2010related mechanisms and potential new therapeutic targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A systematic genome\u2010wide analysis with longitudinal AD biomarker endophenotypes was performed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Enriched pathways were identified with functionally derived SNP to gene analysis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Fifty\u2010two pathways were associated with longitudinal trajectory and intercept.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Many of the identified pathways are specific steps in larger pathways implicated in AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The identified pathways may provide therapeutic targets and areas for further study.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.14308","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T07:43:36Z","timestamp":1729669416000},"page":"8639-8650","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathway enrichment in genome\u2010wide analysis of longitudinal Alzheimer's disease biomarker endophenotypes"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7025-0222","authenticated-orcid":false,"given":"Thea J.","family":"Rosewood","sequence":"first","affiliation":[{"name":"Indiana Alzheimer's Disease Research Center  Indianapolis Indiana USA"},{"name":"Department of Medical and 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