Although depression has been known for some time by scientists, a causal link between the two conditions remains undiscovered. Now, they have evidence genetically that depression is a causative factor in AD, from newly-released data.
Co-investigator Aliza Wingo, MD, associate professor in psychotherapy at Emory University, Atlanta, Georgia said in Medscape Medical News that depression is more common in the middle or early years of life, and dementia occurs is more common in later years.
“If we can treat the depression early we could reduce the risk of developing dementia in our patients later in the course of their lives,” Wingo said.
The results were published online on December 16, in the journal Biological Psychology.
Postmortem Data
The investigators who are all from the Emory University Center for Neurodegenerative Disease, wanted to clarify the genetic basis of the well-established link between depression and dementia risk.
They used data from the most recent genome-wide association studies (GWAS), to make their conclusions. They included a 2019 analysis of depression among 807 553 individuals , and a study in 2019 on AD among 455,258 people, all of European descent. For the sensitivity analysis, they used results from two additional AD GWAS.
The researchers also examined postmortem brain samples from participants in the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). Participants were cognitively normal when they joined. They also went through annual clinical assessments and agreed to donate 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 analyze deep brain proteomic information to identify the molecular connections between depression and AD.
After quality control after quality control, the analysis revealed 8356 proteins in 391 ROS/MAP participants, and 7854 proteins found in the 196 Banner participants.
Results revealed a tiny but significant genetic link between depression and AD and AD, suggesting that both conditions share common genetic causes.
The researchers also employed a framework called “Mendelian randomization” to establish the causality between depression and AD.
After assessing the effect of 115 independent single-nucleotide polymorphisms (SNPs) from the GWAS of depression, they found significant evidence “that the SNPs cause depression, which then cause AD,” said Wingo.
One-Way Relationship
The researchers carried out the same analysis on 61 significant SNPs from the GWAS of AD but did not find evidence to conclude AD causes depression.
Wingo stated that genetic evidence was discovered that supports a causal linkage between depression in AD however not vice versa.
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, seven proteins were connected to at least one AD characteristic — for instance, beta-amyloid, tau tangles and cognitive trajectory.
The researchers conclude that their findings support the notion that depression risk variants can contribute to AD by regulating expression of the corresponding transcripts in the brain.
In an interview, Thomas Wingo, MD co-investigator, mentioned that researchers have only recently conducted sufficient studies to arrive at these conclusions.
These additional “insights” into the relationship between depression and AD could “motivate” doctors to detect and treat depressive symptoms, Wingo noted.
She added that the latest findings could be a catalyst in the development of treatments for treating depression. “If we focus on the genes, the brain proteins that are associated with risk in depression and AD The medications targeted at this gene may reduce the risk of AD later on,” she added.
However investigators urged caution. Thomas Wingo stated that “a lot of this is still unsolved.”
For example, it is not clear whether successfully treating depression mitigates the eventual risk of developing dementia. This is “a extremely important subject of research and one that we will continue to study,” he added.
He also pointed that a significant number of patients aren’t responding well to 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 adds to the debate on whether depression is a risk factor for AD or if AD increases the risk of developing depression, or both.
Sexton who was not involved in the study, said that “These new findings have a positive impact on our understanding of depression as a possible risk factor for developing Alzheimer’s disease.”
Although the experts aren’t in a position to fully comprehend the effects of treating dementia and depression risk, she noted that the findings “underline the importance of taking a look at your mental health especially depression, and having it properly diagnosed, treated and monitored promptly.”
She also agreed that more research is required in this area. Sexton declared that these findings need to be replicated in larger population of study subjects that are more diverse.
The Alzheimer’s Association funded a study which could provide more information regarding the relationship between depression and AD. It will investigate whether machine learning, which is a sophisticated computer science technique, can better predict cognitive impairment than traditional methods.
Researchers will collect phone conversations from 225 older adults suffering from dementia, mild cognitivities, and no cognitive impairment for a six-month period. Data from brain scans, cognitive tests and biomarkers, such as cerebrospinal fluid, will be available to them. These data will enable them to study brain changes in connection with AD.
The innovative method of analysis should be able to identify subtle differences in the quality of speech to indicate which depressive symptoms an individual may be experiencing.
“The study could help us understand the potential effect of depression on the risk of developing dementia,” said Sexton.
Thomas Wingo and Aliza Wingo have not disclosed any financial relationships.
Biol Psychiatry. Online publication on December 16 2021. Abstract
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