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Therapeutic strategies that alter the course of cognitive deterioration have the potential to sustain activities of daily living, promote quality of life, and delay transition to nursing\u2010home care.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We performed longitudinal linear regression analysis of National Alzheimer's Coordinating Center (NACC) cognitive data from 7653 mild dementia AD participants at baseline with at least one medication for diabetes (DBMD), lipid\u2010lowering (LIPL), anti\u2010hypertensive (AHTN), and non\u2010steroidal anti\u2010inflammatory (NSD) medications or any combination in 5684 (74%) participants and in 1969 (26%) participants with no study\u2010relevant prescriptions over 10 years. Change in cognitive function was determined by Mini\u2010Mental State Examination (MMSE) and\n                      <jats:italic>CDR\u00ae Dementia Staging Instrument<\/jats:italic>\n                      Sum of Boxes (CDR\u2010SB) scores relative to non\u2010treated participants stratified by sex and apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      ) genotype. Validation analysis was performed using Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Combination of DBMD+LIPL+AHTN+NSD (QuadRx) resulted in a significant 46% MMSE and 32% CDR\u2010SB delay in cognitive decline at 5 years, which was sustained at 10 years with a delay in decline of 47% MMSE and 33% CDR\u2010SB. QuadRx was equally effective for the delay of cognitive decline in both females and males at 5 and 10 years. QuadRx mitigated the impact of the\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 genotype. Findings were validated in ADNI AD participants in which QuadRx was associated with a significant 60% MMSE delay in cognitive decline at 1 and 2 years.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Combination therapy was associated with a significant delay in cognitive decline in NACC AD participants at a magnitude comparable to or greater than amyloid beta immunomodulators. Further, the delay in decline was sustained for 10 years. The impact of QuadRx to delay cognitive decline was validated in deeply characterized ADNI participants. These data support combination therapy in persons with AD risk factors to alter the course of AD that persists for a decade, enabling cognitive function at a magnitude associated with independent living.<\/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>QuadRx slowed Alzheimer's disease (AD) cognitive decline by 47% in the National Alzheimer's Coordinating Center NACC and 60% in Alzheimer's Disease Neuroimaging Initiative ADNI participants.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Combination therapy exhibited additive and synergistic slowing of cognitive decline.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>QuadRx was equally effective in females and males at 5 and 10 years.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>QuadRx mitigated the impact of the apolipoprotein E \u03b54 genotype.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>QuadRx was effective in AD participants reporting drug use for their AD risk factor.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70074","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T01:11:26Z","timestamp":1743297086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Combination therapy targeting Alzheimer's disease risk factors is associated with a significant delay in Alzheimer's disease\u2013related cognitive decline"],"prefix":"10.1002","volume":"11","author":[{"given":"Yuan","family":"Shang","sequence":"first","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona Health Sciences  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina","family":"Torrandell\u2010Haro","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona Health Sciences  Tucson Arizona USA"},{"name":"Department of Pharmacology College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Vitali","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona Health Sciences  Tucson Arizona USA"},{"name":"Department of Neurology College of Medicine University of Arizona  Tucson Arizona USA"},{"name":"Center for Biomedical Informatics and Biostatistics University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Diaz","family":"Brinton","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona Health Sciences  Tucson Arizona USA"},{"name":"Department of Pharmacology College of Medicine University of Arizona  Tucson Arizona USA"},{"name":"Department of Neurology College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Alzheimer's Disease Neuroimaging Initiative 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