New Data Support a Causal Role for Depression in Alzheimer's

Pauline Anderson

December 30, 2021

Researchers have known for some time that depression is associated with Alzheimer's disease (AD), but a causal link has been elusive. Now, using newly available data, they have uncovered genetic evidence of a causal role for depression in AD.

As depression typically affects those in early or midlife and dementia often occurs in later life, "it's fascinating to see a connection between the two brain illnesses that manifest in different time windows," co-investigator Aliza P. Wingo, MD, associate professor of psychiatry and behavioral science, Emory University, Atlanta, Georgia, told Medscape Medical News.

"If we can treat the depression early on, we may help reduce risk for dementia for our patients later in life," Wingo said.

The findings were published online December 16 in Biological Psychiatrry.

Postmortem Data

The investigators, who are all from the Emory University Center for Neurodegenerative Disease, wanted to clarify the genetic basis underlying the association between the established link between depression and dementia risk.

They used data from the largest and most recent genome-wide association studies (GWAS). These included a 2019 analysis of depression among 807,553 individuals and a 2019 study of AD among 455,258 individuals, all of European ancestry. For sensitivity analyses, they used results from two additional AD GWAS.

The researchers also accessed postmortem brain samples from participants in the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). These participants were cognitively normal at enrollment, underwent annual clinical evaluations, and agreed to donate their brains.

They also assessed brain samples donated by participants in the Banner Sun Health Research Institutelongitudinal study of healthy aging, Alzheimer's and Parkinson's disease.

The brain samples allowed researchers to use deep brain proteomic data to help determine molecular links between depression and AD.

After quality control, the analysis included 8356 proteins in 391 ROS/MAP participants and 7854 proteins in 196 Banner participants.

Results showed a small but significant positive genetic correlation between depression and AD, suggesting the two conditions have a shared genetic basis.

The investigators also applied a framework called "Mendelian randomization" to determine causality between depression and AD.

After assessing the effect of 115 independent single-nucleotide polymorphisms (SNPs) from the GWAS of depression, they uncovered significant evidence "that the SNPs cause depression, which in turn cause AD," said Wingo.

One-Way Relationship

The researchers conducted the same analysis on 61 significant SNPs from the GWAS of AD but did not find evidence to conclude AD causes depression.

"We found genetic evidence supporting a causal role of depression in AD but not vice versa," Wingo said.

In addition, the investigators identified 75 brain transcripts (messenger RNA) and 28 brain proteins regulated by the depression-predisposing genetic variants. Of these, 46 brain transcripts and seven proteins were significantly associated with at least one AD feature ― for example, beta-amyloid, tau tangles, and cognitive trajectory.

"These findings support the notion that the depression risk variants contribute to AD via regulating expression of their corresponding transcripts in the brain," the investigators write.

It is only recently that large enough studies have allowed researchers sufficient power to reach these conclusions, co-investigator Thomas Wingo, MD, said in an interview.

These additional "insights" into the relationship between depression and AD might "motivate" clinicians more to screen for and treat depressive symptoms, Wingo noted.

The new results also have implications for developing therapeutics to treat depression, she said. "If we target the genes, the brain proteins, that are shared risk between depression and AD, the medications that target that gene might mitigate risk for AD later on," she added.

However, the investigators advised caution. "A lot of this is still unknown," said Thomas Wingo.

For example, it is not clear whether successfully treating depression mitigates the eventual risk of dementia, which is "a very important topic of inquiry and one we continue to work on," he added.

He noted a significant number of patients do not respond well to existing antidepressants such as selective serotonin reuptake inhibitors (SSRIs).

Need for Further Research

Commenting on the findings for Medscape Medical News, Claire Sexton, DPhil, director of scientific programs and outreach, Alzheimer's Association, said the study contributes to the debate about whether depression increases risk for AD, whether AD increases risk for depression, or both.

"These newly published findings strengthen our understanding of the role of depression as a risk factor for Alzheimer's dementia," said Sexton, who was not involved with the research.

While experts do not yet fully understand the impact of treating depression on dementia risk, "the findings emphasize the importance of assessing mental health status, particularly depression, and getting it properly diagnosed and treated in a timely manner," she said.

However, she agreed more research in this area is needed. "Importantly, these findings need replication in broader, more diverse study populations," Sexton said.

A study funded by the Alzheimer's Association may provide more information on the link between depression and AD. It will investigate whether machine learning, an advanced computer science technique, can better predict cognitive decline compared with traditional methods.

Over a period of 6 months, researchers will collect smartphone conversations from 225 older adults with dementia, mild cognitive impairment, or no cognitive impairment. They will also have data from cognitive tests, brain scans, and biomarkers such as cerebrospinal fluid samples to study brain changes associated with AD.

The novel method of analysis should be able to identify subtle differences in speech quality to indicate which depressive symptoms an individual might be experiencing.

"The study could help us further understand the potential impact of depression in the risk of developing dementia," said Sexton.

Aliza Wingo and Thomas Wingo have reported no relevant financial relationships.

Biol Psychiatry. Published online December 16, 2021. Abstract

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