{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:12:18Z","timestamp":1777392738251,"version":"3.51.4"},"reference-count":41,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T00:00:00Z","timestamp":1691366400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer's Disease Reports"],"published-print":{"date-parts":[[2023,11,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The AT[N] research framework focuses on three major biomarkers in Alzheimer\u2019s disease (AD): amyloid-\u03b2 deposition (A), pathologic tau (T), and neurodegeneration [N].<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>We hypothesize that the diverse mechanisms such as A\u27f6T and A\u27f6[N] pathways from one brain region to others, may underlie the wide variation in clinical symptoms. We aim to uncover the causal-like effect of regional AT[N] biomarkers on cognitive decline as well as the interaction with non-modifiable risk factors such as age and APOE4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We apply multi-variate statistical inference to uncover all possible mechanistic spreading pathways through which the aggregation of an upstream biomarker (e.g., increased amyloid level) in a particular brain region indirectly impacts cognitive decline, via the cascade build-up of a downstream biomarker (e.g., reduced metabolism level) in another brain region. Furthermore, we investigate the survival time for each identified region-to-region pathological pathway toward the AD onset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>We have identified a collection of critical brain regions on which the amyloid burdens exert an indirect effect on the decline in memory and executive function (EF) domain, being mediated by the reduction of metabolism level at other brain regions. APOE4 status has been found not only involved in many A\u27f6N mechanistic pathways but also significantly contributes to the risk of developing AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>Our major findings include 1) the region-to-region A\u27f6N\u27f6MEM and A\u27f6N\u27f6MEM pathways exhibit distinct spatial patterns; 2) APOE4 is significantly associated with both direct and indirect effects on the cognitive decline while sex difference has not been identified in the mediation analysis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3233\/adr-230081","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T11:08:02Z","timestamp":1691492882000},"page":"855-872","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering Diverse Mechanistic Spreading 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