Behaviour change interventions to reduce opioids in chronic non-cancer pain in primary care: A systematic review and mapping of behavior change techniques.

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide, accounting for 60 to 80% of dementia cases. While non-modifiable risk factors like age and the APOE ε4 allele are well established, a significant portion of AD risk is attributed to modifiable factors, offering crucial opportunities for prevention. Among these, psychiatric disorders have emerged as prominent yet mechanistically ambiguous risk factors. Conditions such as depression, anxiety, and post-traumatic stress disorder (PTSD) are frequently associated with cognitive decline, but whether this link is causal or merely correlational remains a critical unanswered question. Clarifying this relationship is essential for developing effective strategies that target mental health to mitigate dementia risk. A substantial body of observational evidence consistently links psychiatric conditions to an elevated risk of AD. For instance, evidence from longitudinal studies reports that depression is associated with a nearly twofold increase in dementia risk. However, the interpretation of this association is complex and subject to debate. Some evidence, including neuropathological studies, suggests that late-life depression may be a prodromal manifestation of underlying AD pathology rather than an independent risk factor. Conversely, other long-term longitudinal studies indicate that depressive symptoms can precede the clinical onset of dementia by decades, supporting a causal role. This ongoing controversy underscores the inherent limitations of observational designs in disentangling cause from effect. Similar associations have been reported for PTSD and anxiety disorders, but these findings are inherently limited by susceptibility to residual confounding and the intractable problem of reverse causality, where preclinical AD pathology may manifest as psychiatric symptoms. This fundamental uncertainty hinders the translation of epidemiological findings into clinical practice and underscores the need for analytical methods that can overcome these biases. Mendelian randomization (MR) offers a powerful approach to dissect causality by leveraging randomly allocated genetic variants as IVs for an exposure. This design mimics a randomized controlled trial, thereby minimizing confounding and being robust to reverse causality. By utilizing summary statistics from large-scale genome-wide association studies (GWAS), two-sample MR can efficiently estimate the causal effect of a genetically predicted exposure on an outcome. A limited number of MR studies have directly investigated the depression-AD link, yielding mixed results. One study found genetic evidence supporting a causal role of depression on AD, while others, particularly those focusing on Major Depressive Disorder (MDD), have reported null findings. A recent systematic review of MR studies highlighted this inconsistency and called for further investigation. These conflicting findings may stem from differences in the definition of the depression phenotype, the selection of genetic instruments, or the presence of horizontal pleiotropy.