Melatonin receptor type 1A gene linked to Alzheimer's disease in old age

Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer's disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer's disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer's disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer's disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer's disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer's disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism. Statement of Significance The previous systematic search for molecular genetic risk factors for intolerance to shift work identified a risk variant close to melatonin receptor 1a (MTNR1A). Here, we showed association of the same risk variant with clinical and pathological Alzheimer's disease in the very elderly. In line, modulation of the MTNR1A expression level in cell culture regulated amyloid beta production. Thus, we revealed a novel molecular genetic connection between circadian phenotype in the working age and neurodegeneration in old age, which supports the view that circadian regulation, possibly through weaker physiological melatonin signaling, contributes to the pathological cascade of Alzheimer's disease. Future studies are needed to clarify whether the poor tolerance to shift work per se indicates increased risk of Alzheimer's disease.