Combination therapy targeting Alzheimer's disease risk factors is associated with a significant delay in Alzheimer's disease-related cognitive decline

BACKGROUND Alzheimer's disease (AD) cognitive decline can be a major contributor to loss of independent living. 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-home care. METHODS 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-lowering (LIPL), anti-hypertensive (AHTN), and non-steroidal anti-inflammatory (NSD) medications or any combination in 5684 (74%) participants and in 1969 (26%) participants with no study-relevant prescriptions over 10 years. Change in cognitive function was determined by Mini-Mental State Examination (MMSE) and CDR (R) Dementia Staging Instrument Sum of Boxes (CDR-SB) scores relative to non-treated participants stratified by sex and apolipoprotein E (APOE) genotype. Validation analysis was performed using Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. RESULTS Combination of DBMD+LIPL+AHTN+NSD (QuadRx) resulted in a significant 46% MMSE and 32% CDR-SB delay in cognitive decline at 5 years, which was sustained at 10 years with a delay in decline of 47% MMSE and 33% CDR-SB. 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 APOE epsilon 4 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. CONCLUSIONS 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.