Summary: Researchers report a variation of the MTNR1A gene is linked to an increased risk of developing Alzheimer’s disease in older people. The same gene has previously been implicated in reduced tolerance to shift work in the aging population.
Source: University of Helsinki.
A Finnish study published in the respected SLEEP journal shows that a variation in the melatonin receptor 1A (MTNR1A) gene is linked to the risk of Alzheimer’s disease in the elderly. The same research team has previously demonstrated that the same genetic variation reduces tolerance to shift work among the working age population.
Alzheimer’s disease is a memory disorder that causes the brain to deteriorate. One of its risk factors is disruption of sleep and the circadian rhythm. Lack of sleep and disruption of the circadian rhythm are common among shift workers. Tolerance to the negative effects of shift work varies between individuals and is partially linked to intrinsic genetic factors.
The study lead by Professor Tiina Paunio, University of Helsinki and National Institute for Health and Welfare (THL), Finland, showed that in addition to Alzheimer’s diagnosis, the MTNR1A gene variation is linked to brain lesions visible in post-mortem brain tissues. In addition, when the expression of the MTNR1A gene was reduced in the cell culture, beta-amyloid protein characteristic of Alzheimer’s disease started to accumulate.
The previous study observed that the same gene variation that predisposes to shift work fatigue is associated with lower levels of the MTNR1A gene expression in the brain. This means that the previous findings are compatible with the new findings made in the epidemiological cohorts and cell cultures.
A genetic predisposition combined with a lifestyle that disrupts the circadian rhythm can increase the risk of Alzheimer’s disease
The circadian rhythm regulates the release of melatonin, which in turn supports the circadian rhythm through its receptors. The link between a weaker signalling of endogenous melatonin and Alzheimer’s disease supports the view that regulation of the circadian rhythm plays a role in the development of Alzheimer’s disease.
“The finding of a common risk gene for both job-related exhaustion in shift workers and Alzheimer’s disease doesn’t directly mean that shift work would predispose to Alzheimer’s disease. However, the combination of genetic predisposition and a lifestyle that disrupts the circadian rhythm can increase the risk of Alzheimer’s disease,” says Lic. Med Sonja Sulkava from the National Institute for Health and Welfare (THL). “Another possible interpretation is that the brain dysfunctions related to Alzheimer’s disease impair the tolerance to shift work decades before the onset of the clinical disease.”
“Even though our results demonstrate a new molecule-level connection between the tolerance to shift work and incipient Alzheimer’s disease, the now discovered genetic variation has a minimal effect on the individual level and it can’t be used to risk assessment or prediction,” reminds professor Paunio.
The research cohorts consisted of over 85-year-olds living in Vantaa and over 75-year-olds living in Kuopio and of Alzheimer patients and healthy controls living in Eastern Finland. The link could be seen in elderly cohorts but not in the younger patient and control cohorts.
In addition to THL, the research participants included the universities of Helsinki, Eastern Finland, Newcastle and Stanford, Merck research laboratory, Icahn School of Medicine and National Institutes of Health from the United States.
Source: Tiina Paunio – University of Helsinki
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Original Research: Open access research for “Melatonin receptor type 1A gene linked to Alzheimer’s disease in old age” by Sonja Sulkava, Pranuthi Muggalla, Raimo Sulkava, Hanna M Ollila, Terhi Peuralinna, Liisa Myllykangas, Karri Kaivola, David J Stone, Bryan J Traynor, Alan E Renton, Alberto M Rivera, Seppo Helisalmi, Hilkka Soininen, Tuomo Polvikoski, Mikko Hiltunen, Pentti J Tienari, Henri J Huttunen, and Tiina Paunio in Sleep. Published July 6 2018.
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.