Combination Therapy in Alzheimer's Disease: Is It Time?

Alzheimer's disease (AD) is the most common cause of dementia globally. There is increasing evidence showing AD has no single pathogenic mechanism, and thus treatment approaches focusing only on one mechanism are unlikely to be meaningfully effective. With only one potentially disease modifying treatment approved, targeting amyloid-ß (Aß), AD is underserved regarding effective drug treatments. Combining multiple drugs or designing treatments that target multiple pathways could be an effective therapeutic approach. Considering the distinction between added and combination therapies, one can conclude that most trials fall under the category of added therapies. For combination therapy to have an actual impact on the course of AD, it is likely necessary to target multiple mechanisms including but not limited to Aß and tau pathology. Several challenges have to be addressed regarding combination therapy, including choosing the correct agents, the best time and stage of AD to intervene, designing and providing proper protocols for clinical trials. This can be achieved by a cooperation between the pharmaceutical industry, academia, private research centers, philanthropic institutions, and the regulatory bodies. Based on all the available information, the success of combination therapy to tackle complicated disorders such as cancer, and the blueprint already laid out on how to implement combination therapy and overcome its challenges, an argument can be made that the field has to move cautiously but quickly toward designing new clinical trials, further exploring the pathological mechanisms of AD, and re-examining the previous studies with combination therapies so that effective treatments for AD may be finally found.

Risk factors, time to onset and recurrence of delirium in a mixed medical-surgical ICU population: A secondary analysis using Cox and CHAID decision tree modeling.

A retrospective secondary analysis of 4,200 patients was collected from two academic medical centers. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in all patients. Univariate and multivariate Cox models, logistic regression analysis, and Chi-square Automatic Interaction Detector (CHAID) decision tree modeling were used to explore delirium risk factors. Increased delirium risk was associated with exposed only to artificial light (AL) hazard ratio (HR) 1.84 (95 % CI: 1.66-2.044, P<0.001), physical restraint application 1.11 (95 % CI: 1.001-1.226, P=0.049), and high nursing care requirements (>8 hours per 8-hour shift) 1.18 (95 % CI: 1.048-1.338, P=0.007). Delirium incidence was inversely associated with greater family engagement 0.092 (95 % CI: 0.014-0.596, P=0.012), low staff burnout and anticipated turnover scores 0.093 (95 % CI: 0.014-0.600, P=0.013), non-ICU length-of-stay (LOS)<15 days 0.725 (95 % CI: 0.655-0.804, P<0.001), and ICU LOS ≤15 days 0.509 (95 % CI: 0.456-0.567, P<0.001). CHAID modeling indicated that AL exposure and age <65 years were associated with a high risk of delirium incidence, whereas SOFA score ≤11, APACHE IV score >15 and natural light (NL) exposure were associated with moderate risk, and female sex was associated with low risk. More rapid time to delirium onset correlated with baseline sleep disturbance (P=0.049), high nursing care requirements (P=0.019), and prolonged ICU and non-ICU hospital LOS (P<0.001). Delirium recurrence correlated with age >65 years (HR 2.198; 95 % CI: 1.101-4.388, P=0.026) and high nursing care requirements (HR 1.978, 95 % CI: 1.096-3.569), with CHAID modeling identifying AL exposure (P<0.001) and age >65 years (P=0.032) as predictive variables. Development of ICU delirium correlated with application of physical restraints, high nursing care requirements, prolonged ICU and non-ICU LOS, exposure exclusively to AL (rather than natural), less family engagement, and greater staff burnout and anticipated turnover scores. ICU delirium occurred more rapidly in patients with baseline sleep disturbance, and recurrence correlated with the presence of delirium on ICU admission, exclusive AL exposure, and high nursing care requirements.