Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer's disease

Background: There are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer9s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer9s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer9s. Methods: We estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer9s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization. Results: There was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer9s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer9s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14). Conclusions: In the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer9s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.