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Pathway\u2010based polygenic risk scores (p\u2010PRS) can be used to examine how groups of risk genes with similar biological functions impact disease\u2010related endophenotypes such as cognitive decline. potentially aiding in differentiating pre\u2010clinical dementia from normal age\u2010related cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Data from 1,737 participants (53.5% female) from the Betula study were analyzed. AD\u2010weighted p\u2010PRS were calculated for five AD\u2010related pathways: immune response, tau, cholesterol, protein\u2013lipid, and amyloid. The p\u2010PRS were tested for associations with all\u2010cause dementia risk (\n                      <jats:italic>n<\/jats:italic>\n                      = 315 cases), with follow\u2010up analyses restricted to AD (\n                      <jats:italic>n<\/jats:italic>\n                      = 168) or vascular dementia (VD) (\n                      <jats:italic>n<\/jats:italic>\n                      = 110), in comparison to a genome\u2010wide (gw) PRS. Linear mixed effect models were used to examine the same genetic predictors in relation to cognitive decline in subsequently demented and non\u2010demented.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>All\u2010cause dementia risk was significantly predicted by the gw\u2010 and immune PRS. Hazard ratios for gw\u2010, immune\u2010, tau\u2010, cholesterol\u2010, and amyloid p\u2010PRS were larger for prediction of AD risk and smaller for VD risk relative to all\u2010cause dementia, while the opposite was seen for the protein\u2013lipid p\u2010PRS. Cognitive decline was stronger associated with the immune p\u2010PRS than the gw\u2010PRS, and this effect was driven by participants that remained non\u2010demented (linear age\u2010effects). Amyloid p\u2010PRS showed accelerated age\u2010effect at the oldest age in both non\u2010demented and subsequently demented.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our results show that AD\u2010weighted p\u2010PRS have differential roles on dementia risk and cognitive decline. Specifically, results suggest a broad role of immune p\u2010PRS in both age\u2010related cognitive decline and dementia risk, while amyloid p\u2010PRS influences AD risk and pre\u2010clinical cognitive decline, and protein\u2010lipid p\u2010PRS does not influence AD risk nor cognitive decline but show a potential role in VD. Results are of value for development of precision medicine based on genetic risk profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            All\u2010cause dementia and Alzheimer's disease (AD) risk is strongest predicted by apolipoprotein E (\n                            <jats:italic>APOE)<\/jats:italic>\n                            \u03b54 and global polygenic risk scores (PRS).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Cognitive decline is stronger predicted by immune pathway\u2010based PRS (p\u2010PRS) relative to global PRS.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Effect of\n                            <jats:italic>APOE<\/jats:italic>\n                            \u03b54 on cognitive decline is driven by pre\u2010clinical dementia.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Immune p\u2010PRS predicts cognitive decline unrelated to subsequent dementia.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Protein\u2013lipid p\u2010PRS may have a stronger role in vascular dementia than AD.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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