Researchers identify new genes that may contribute to Alzheimer's disease

Alzheimer's disease
PET scan of a human brain with Alzheimer's disease. Credit: public domain

Researchers from Boston University School of Medicine, working with scientists across the nation on the Alzheimer's Disease Sequencing Project (ADSP), have discovered new genes that will further current understanding of the genetic risk factors that predispose people to the development of Alzheimer's disease (AD). The ADSP was developed by the National Institutes of Health (NIH) in response to the National Alzheimer's Project Act milestones to fight AD.

The incidence of AD is increasing each year and is the most common cause of dementia. Also, it is the fifth leading cause of death in those 65-years and older, according to the CDC. AD is characterized by the formation of senile plaques (extracellular deposits of β-amyloid protein) and neurofibrillary tangles (aggregates of hyper-phosphorylated tau protein) in the brain, leading to neurodegeneration and decline in memory, and eventually death. Despite the growing prevalence of AD and cost to society, the genetic and environmental factors that make some more susceptible to the development of AD is still not well understood.

"This large and deep gene sequencing study is an important part of identifying which variations may play a part in risk of getting Alzheimer's or protection against it," said Eliezer Masliah, MD, director of the Division of Neuroscience at the National Institute on Aging, part of NIH. "Big data efforts like the ADSP are really helping research move forward. Identifying rare variants could enhance our ability to find novel therapeutic targets and advance precision medicine approaches for Alzheimer's disease."

By comparing the exomes (gene-coding portions of entire genetic sequences) of nearly 6,000 individuals with AD and 5,000 cognitively healthy older adults, the researchers were able to find rare variations in that they believe may contribute to the development of common AD. These newly discovered genes may suggest an inflammatory response and changes in the protein production. These combined changes are thought to contribute to the overall neurodegeneration witnessed in AD.

The researchers hope their work will help bridge the knowledge gaps of the genetic architecture related to AD, which is a necessary step toward a better understanding of mechanisms leading to AD and eventual therapeutic treatments. "Many of our findings will provide insight into disease mechanisms and targets for biological experiments to gain further understanding about the role of these genes in AD pathogenesis," explained corresponding author Lindsay A. Farrer, Ph.D., Chief of Biomedical Genetics and a professor of Medicine, Neurology, Ophthalmology, Epidemiology and Biostatistics at Boston University Schools of Medicine and Public Health.

The research team emphasizes that further research will need to be done to find other genes hidden throughout the genome, as the current paradigm is that many genes contribute to the development of AD.

These findings appear in Molecular Psychiatry.

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Journal information: Molecular Psychiatry

Citation: Researchers identify new genes that may contribute to Alzheimer's disease (2018, August 14) retrieved 20 September 2019 from
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Aug 14, 2018
AD is caused by chronic, aberrant activation of the NF-kB driven immune response. Many genetic variants can predispose to this, the most important known being the APOE4 allele. Genetic factors interact with environmental and lifestyle factors. For example, AD sufferers have a higher incidence of infection with herpes viruses, chlamydia pneumoniae and spirochetes.

The NF-kB response attempts to prevent infection by downregulaing receptors used by pathogens to enter cells. This can take the form of reduced expression, desentitization, or receptor blockade, and often occurs aberrantly in the absence of infection. In the case of AD, the receptors are the acetylcholine NACH and noradrenaline. Both are involved in learning, and this explains the early symptoms of short term memory impairment. When this is prolonged, the cells die.

Abeta deposition is an integral part of this response. Molecular fragments are cleaved from Abeta, and these bind to receptors, boosting Nf-kB activation

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