A Mendelian randomization study investigated the causal relationships between 18 neurodegenerative and neuropsychiatric disorders and Alzheimer's disease (AD). The study found that four disorders—bipolar disorder (BD), migraine, schizophrenia, and Parkinson's disease (PD)—were causally associated with an increased risk of AD, with odds ratios (ORs) of 1.09, 1.09, 1.05, and 1.07, respectively. Attention-deficit/hyperactivity disorder (ADHD) was associated with a decreased risk of AD (OR: 0.80). Suggestive evidence of causal effects was found for amyotrophic lateral sclerosis (ALS) and Tourette's syndrome. The study suggests that genetic factors predisposing to BD, migraine, schizophrenia, and PD may contribute to the development of AD. Conversely, ADHD may be associated with a reduced risk of AD. Treatments targeting early-onset neuropsychiatric diseases may influence the risk of AD-related cognitive decline. Neurodegenerative and neuropsychiatric diseases represent different parts of the brain disorder spectrum. Neurodegenerative disorders are typically late-onset and have a progressive clinical course, while neuropsychiatric conditions are more "soft," with early or middle adulthood onset and a remitting course. These conditions share genetic relationships, forming a hierarchical classification system. Previous studies have shown that polygenic risk scores (PRS) for one neurodegenerative disease may predict the risk of another. Recent studies suggest that genetic relationships among neurodegenerative and neuropsychiatric diseases may form a complex, entangled pattern, involving pleiotropic genes and multiple co-regulated or cross-talking pathways. The study used genome-wide association study (GWAS) summary datasets for 19 neuropsychiatric disorders and performed Mendelian randomization (MR) analysis to assess causal relationships. The MR analysis revealed that BD, migraine, schizophrenia, and PD were causally associated with an increased risk of AD, while ADHD was associated with a decreased risk. The study also found suggestive evidence of causal effects for ALS and Tourette's syndrome. The results suggest that genetic components of BD, schizophrenia, migraine, and PD may contribute to the risk of AD. The findings highlight the potential for shared genetic pathways between neurodegenerative and neuropsychiatric diseases, with implications for understanding the molecular pathobiology of brain illnesses. The study also notes that environmental factors, such as physical activity, may mediate the associations between these conditions. The study has limitations, including the focus on genetic liability and the potential for overlapping samples in some datasets. The results suggest that future research should consider the role of physical activity and voluntary exercise in the ADHD-AD relationship. The study provides new insights into the shared genetics of AD and neuropsychiatric conditions, emphasizing the importance of understanding the complex interactions between these diseases.A Mendelian randomization study investigated the causal relationships between 18 neurodegenerative and neuropsychiatric disorders and Alzheimer's disease (AD). The study found that four disorders—bipolar disorder (BD), migraine, schizophrenia, and Parkinson's disease (PD)—were causally associated with an increased risk of AD, with odds ratios (ORs) of 1.09, 1.09, 1.05, and 1.07, respectively. Attention-deficit/hyperactivity disorder (ADHD) was associated with a decreased risk of AD (OR: 0.80). Suggestive evidence of causal effects was found for amyotrophic lateral sclerosis (ALS) and Tourette's syndrome. The study suggests that genetic factors predisposing to BD, migraine, schizophrenia, and PD may contribute to the development of AD. Conversely, ADHD may be associated with a reduced risk of AD. Treatments targeting early-onset neuropsychiatric diseases may influence the risk of AD-related cognitive decline. Neurodegenerative and neuropsychiatric diseases represent different parts of the brain disorder spectrum. Neurodegenerative disorders are typically late-onset and have a progressive clinical course, while neuropsychiatric conditions are more "soft," with early or middle adulthood onset and a remitting course. These conditions share genetic relationships, forming a hierarchical classification system. Previous studies have shown that polygenic risk scores (PRS) for one neurodegenerative disease may predict the risk of another. Recent studies suggest that genetic relationships among neurodegenerative and neuropsychiatric diseases may form a complex, entangled pattern, involving pleiotropic genes and multiple co-regulated or cross-talking pathways. The study used genome-wide association study (GWAS) summary datasets for 19 neuropsychiatric disorders and performed Mendelian randomization (MR) analysis to assess causal relationships. The MR analysis revealed that BD, migraine, schizophrenia, and PD were causally associated with an increased risk of AD, while ADHD was associated with a decreased risk. The study also found suggestive evidence of causal effects for ALS and Tourette's syndrome. The results suggest that genetic components of BD, schizophrenia, migraine, and PD may contribute to the risk of AD. The findings highlight the potential for shared genetic pathways between neurodegenerative and neuropsychiatric diseases, with implications for understanding the molecular pathobiology of brain illnesses. The study also notes that environmental factors, such as physical activity, may mediate the associations between these conditions. The study has limitations, including the focus on genetic liability and the potential for overlapping samples in some datasets. The results suggest that future research should consider the role of physical activity and voluntary exercise in the ADHD-AD relationship. The study provides new insights into the shared genetics of AD and neuropsychiatric conditions, emphasizing the importance of understanding the complex interactions between these diseases.