Linking Neurodevelopmental and Neurodegenerative Diseases: Genetic Analysis of ADHD to Markers Modifying Cognition and Neurodegeneration as an Example

Abstract

As development and ageing are, to some extent, two intertwined processes in the healthy brain, the question of whether neurodevelopmental disorders and neurodegenerative diseases could also be related arises. Thus my thesis aims to study the possible relationship between a neurodevelopmental disorder, ADHD, and 79 genetic variants involved in neurodegenerative traits like dementia, Alzheimer's disease (AD), vascular dysfunction, and cognitive decline. To this end, I performed genetic association analyses on three cohorts representing different ADHD-related traits. The first cohort is a multigenerational family from a genetic isolate presenting familial ADHD (30% prevalence). The second cohort is 60+ years elderly who were surveyed for ADHD symptoms. The third cohort is a cohort of toddlers aged from 24 to 36 months surveyed for temperamental traits, as ADHD cannot be determined at such a young age. Specifically to ADHD, four SNPs were found related. For rs163030 in WDR41 and rs700518 in CYP19A1, it was unattainable to determine the effect direction. rs17125944 in FERMT2 and rs1800629 in TNF-a exhibit an opposite effect direction to what is reported for neurodegenerative traits. Related to ADHD symptoms in the elderly population, rs8093731 within the gene DSG2 was detected as a low-penetrance statistically significant associated variant showing an opposite effect direction in ADHD compared with AD. Regarding temperamental traits early in life, rs4938933 and rs670139, both harboured in MS4A4A, were significantly associated with shyness without concluding the effect direction. The highlighted genes are implied in brain amyloidosis, tau dysregulation, APP processing, inflammation response, and the immune system. The results, overall, support the alternative hypothesis that ADHD might protect against neurodegeneration. This is the first genetic evidence pointing out a protective effect of ADHD against unhealthy brain ageing worthy of further exploration. Until now, ADHD is considered a disorder that mainly represents disadvantages. However, if the conception change and ADHD denotes an advantage over unhealthy brain aging, it might prompt to rethink of ADHD therapies and ADHD itself.