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Research Highlights

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

Some cases of Alzheimer’s disease may be driven by the genetic risk factors that can underlie depression, according to an NIA-supported data-mining study by researchers at Emory University School of Medicine. The results, published in Biological Psychiatry, suggest that the activity of at least seven genes may help explain why depression appears to increase the chances one may experience Alzheimer’s.

Older adult woman with Alzheimer's appears depressed

First, the researchers sought links between the two disorders by analyzing the data of more than 1.2 million individuals of European descent who took part in several genome-wide association studies (GWAS). These types of studies aim to find one-letter changes in DNA sequences, called “single nucleotide polymorphisms” — or “SNPs” for short — that appear often on the chromosomes of individuals who experience a particular disease.

Although several other studies have suggested that there is a relationship between depression and Alzheimer’s, previous attempts to search for genomic links between the two disorders have produced mixed results. But those investigations relied on single GWAS of each disease.

In contrast, for this study, the scientists searched the combined results of several depression and Alzheimer’s GWAS studies. Generally, combining data increases the chances of detecting reliable signals. They also used advanced analysis techniques for assessing how the SNPs may influence genetic activity.

Initially, the team discovered that there is a shared genetic risk between the two disorders. In other words, they saw a correlation between the SNPs carried by people with Alzheimer’s and those observed in individuals who experienced depression.

The researchers then used a different analysis technique to determine whether there may be a causal link between the diseases. They found that the SNPs associated with depression also raised the chances that an individual may develop Alzheimer’s. However, the opposite was not observed. The SNPs associated with Alzheimer’s did not raise the risk that an individual would also experience depression.

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

To understand which genes may be behind the association, the researchers studied the brains of individuals who participated in the ROS/MAP studies. Specifically, they looked at proteins and messenger RNA (mRNA) transcripts. When a gene is turned on, its DNA sequence is copied, or transcribed, into mRNA and then often translated into a protein. So, measuring the levels of both proteins and mRNA can help a scientist gauge 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 discovered in this study. Notably, changes in the levels of two of these proteins, called RAB27B and DDAH2, were associated with every Alzheimer’s hallmark measured in the aging studies.

In a similar type of data-mining study published in Nature Communications, the researchers found that Alzheimer’s and other neurodegenerative disorders may share at least 13 genetic links with several psychiatric disorders.

Overall, the results of the Emory study not only strengthened the apparent links between the two disorders but also provided insights into how certain genes may play a critical role in driving the increased risk for Alzheimer’s associated with depression. Such genes may be important targets for developing drugs to treat both depression and dementia.

This research was supported in part by NIH grants R01AG056533, U01AG046161, U01AG061356, P50AG025688, P30NS055077, R01AG017917, R01AG015819, U24NS072026, U01MH115484, RF1AG057470, U01AG061357, R56AG062256, R56 AG060757, and by the Department of Veterans Affairs (Grant Nos. I01 BX003853 and 1IK4 BX005219).

These activities relate to:

NIA’s AD+ADRD Research Implementation Milestone 1.A, “Enable precision medicine research by supporting deep and longitudinal molecular endophenotyping of existing and new at-risk cohorts as well as cohorts and/or individuals who resist disease despite high genetic risk (e.g., Down Syndrome, ApoE 4 homozygous, FAD mutation carriers).”

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

Harerimana NV, et al. Genetic Evidence Supporting a Causal Role of Depression in Alzheimer’s Disease. Biological Psychiatry. 2022. Epub Dec. 16, 2021. doi: 10.1016/j.biopsych.2021.11.025.

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

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