Genetic risk factors that underlie depression may also lead to Alzheimer’s disease

Some cases of Alzheimer’s disease may be driven by genetic risk factors that can underlie depression, according to a NIA-backed data extraction study by researchers at Emory University School of Medicine. The results are published in Biological Psychiatrysuggests that the activity of at least seven genes may help explain why depression increases one’s chances of developing Alzheimer’s disease.

An old woman with Alzheimer's disease looks depressed

First, the researchers sought links between the two disorders by analyzing data from more than 1.2 million individuals of European ancestry who participated in several genome-wide association studies (GWAS). These types of studies aim to find single-letter changes in the DNA sequence, called “single nucleotide polymorphisms” – or “SNPs” for short – that often appear on the chromosomes of individuals with a specific disease.

Although several other studies have suggested an association between depression and Alzheimer’s disease, previous attempts to search for genomic links between the two disorders have yielded mixed results. But those investigations relied on one GWAS per disease.

In contrast, in this study, scientists looked at the combined results of several GWAS studies of depression and Alzheimer’s disease. In general, data merging increases the chances of detecting reliable signals. They also used advanced analysis techniques to assess how polymorphisms affect gene activity.

At first, the team discovered that the two disorders shared a genetic risk. In other words, they saw an association between the polymorphisms carried by people with Alzheimer’s disease and those observed in individuals who experienced depression.

The researchers then used a different analysis technique to determine if there was a causal relationship between the diseases. They found that polymorphisms associated with depression also increase an individual’s chances of developing Alzheimer’s disease. However, the opposite was not observed. SNPs associated with Alzheimer’s disease did not raise an individual’s risk of depression either.

Further support for these findings was gained when researchers re-analyzed pooled results from two other studies on aging known as ROS/MAP. Here, they found an association between participants who had higher genetic risk scores for depression and the appearance of several hallmarks of dementia, including a faster decline in the ability to recall past experiences. Those with higher scores experienced faster memory decline.

To understand the genes that might be behind this association, the researchers studied the brains of individuals who participated in ROS/MAP studies. Specifically, they studied proteins and messenger RNA (mRNA) transcripts. When a gene is turned on, its DNA sequence is transcribed, or transcribed, into mRNA and then often translated into a protein. So, measuring the levels of both proteins and mRNA can help scientists measure gene activity.

They found that changes in the activity of at least seven proteins may underlie the genomic causal link between depression and Alzheimer’s disease discovered in this study. Notably, changes in the levels of two of these proteins, called RAB27B and DDAH2, were associated with every hallmark of Alzheimer’s disease measured in studies of aging.

In a similar type of data mining study published in Nature ConnectionsAnd the The researchers found Alzheimer’s disease and other neurodegenerative disorders may share at least 13 genetic links with many psychiatric disorders.

Overall, the Emory study findings not only reinforce the apparent links between the two disorders, but also provide insight into how specific genes may play an important role in increasing the risk of Alzheimer’s disease associated with depression. These genes may be important targets for developing drugs to treat depression and dementia.

This research was supported in part by National Institutes of Health grants R01AG056533, U01AG046161, U01AG061356, P50AG025688, P30NS055077, R01AG017917, R01AG015819, U24NS072026, U01MH115484, RF1AG057470, U01AG056 (IK4)(1IK4 BX00).

These activities relate to:

AD + ADRD Research Implementation Achievements in NIA 1Enabling precision medicine research by supporting deep molecular and longitudinal endotyping of existing and new at-risk cohorts as well as cohorts and/or individuals who are resistant to disease despite high genetic risk (eg, Down syndrome, homozygous ApoE4 mutation carriers, and FAD).

AD + ADRD Research Implementation Achievements in NIA 2Create new research programs that use data-driven, systems-based approaches to integrate the study of the basic biology of aging with the neurobiology of aging and research on neurodegeneration, Alzheimer’s disease and Alzheimer’s-related dementia to better understand the mechanism(s) of vulnerability and resilience in Alzheimer’s disease across all levels of complexity. biological (from the cellular to the population level) and gain a deeper understanding of the complex biology and integrative physiology of healthy and pathological brain aging.”

references:
Harerimana NV, et al. Genetic evidence supporting a causal role for depression in Alzheimer’s disease. Biological Psychiatry. 2022. Epub December 16, 2021. doi: 10.1016/j.biopsych.2021.11.025.

Wingo TS et al. Shared mechanisms across major psychiatric and neurological diseases. Nature Connections. 2022; 13 (1): 4314. doi: 10.1038/s41467-022-31873-5.

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