Alzheimer's Gene Linked to Late-Life Depression

Pauline Anderson

August 04, 2017

The apolipoprotein E gene (APOE), which has been implicated in risk for Alzheimer's disease (AD), also increases risk for late-life depression, new research suggests.

The study showed that poor vascular health was also predictive of later-life depression, but independently of genetic risk.

"We found that vascular burden ― things like hypertension, diabetes, or other heart problems ― and having an APOE4 allele were both risk factors for developing depression as the cohort aged, but they were completely independent of one another in our sample," lead author Roseanna G. Scott, a doctoral candidate in clinical psychology at the University of Central Florida, Orlando, told Medscape Medical News.

Vascular risk also had greater influence on depression than genetics in the study. So although patients cannot change their genetic risk, "they can still modify their vascular risk to some extent" through such things as diet and exercise, said Scott.

"It's somewhat encouraging that the risk factor that makes more of a difference is the one that's modifiable."

The study was published online June 20 in the Journal of Clinical Psychiatry.

Adverse Late-Life Outcomes

APOE has been linked to several adverse late-life health outcomes, including major depressive disorder. It was first recognized for its role in lipoprotein metabolism and cardiovascular disease and has since become known for its role in cognitive function, immune regulation, and AD.

There are three common alleles of the APOE locus: ε2, ε3, and ε4. Prior studies have shown that persons with APOE4 are at significantly higher risk of developing AD, especially those who have two copies of the allele (odds ratio [OR] for ε4/ε4, 14.9).

APOE has also been linked to earlier AD onset. For individuals with the ε4/ε4 genotype, the mean age at onset of AD is 66.4 years. For individuals with all other APOE configurations, the average age at onset of AD is from 71.3 to 73.6 years.

In contrast, ε2 has been shown to reduce risk of developing AD (OR, 0.6.)

The new analysis used data from the Wisconsin Longitudinal Study (WLS), which includes more than 10,000 randomly selected representatives of Wisconsin's 1957 high school graduating classes. The researchers assessed 3203 WLS participants in the 1993, 2004, and 2011 waves.

Participants self-reported cerebrovascular health variables, including hypertension, diabetes, heart attack, coronary heart disease, angina, congestive heart failure, other heart problems, and stroke.

Those with a history of stroke were excluded from the study because of the possibility that they may be more likely to experience subsequent mood dysregulation.

Cardiovascular Burden

Total cardiovascular burden (CVB) was determined on the basis of participant scores on measures of hypertension, diabetes, and heart disease. Total scores ranged from 0 to 3.

Investigators performed DNA genotyping on saliva samples contributed by the study participants. The study operationalized APOE continuously. (As a measure of APOE-conferred risk, ε2/ε2 reflected least risk, and ε4/ε4 reflected most risk.)

Depression was measured using the Center for Epidemiology Studies Depression scale (CES-D), a self-reported measure of depressive symptoms experienced in the past week. A suggested cutoff for probable depression was a score of 16.

Researchers studied the effect of APOE on the relationship between CVB and depressive symptoms over time. They also assessed the cross-sectional relationship of APOE-conferred risk, CVB, and their interaction on clinically significant depression symptoms at the three time points.

The mean age of the participants was 53 years in 1993, 64 years in 2004, and 71 years in 2011.

The most common genotyping was ε3/ε3 (60%), followed by ε3/ε4 (23%) and ε2/ε3 (12.6%). About 2% of the study population had ε4/ε4 genotyping.

Predicting Depressive Symptoms

In the longitudinal analysis, APOE-conferred risk did not significantly predict depressive symptomatology at age 64 years, although this relationship approached significance in 2011, when participants were 71 years old (P = .079).

Other analyses showed that APOE-conferred risk significantly predicted clinically significant depressive symptoms in 2011 (P = .02), as did CVB in 2011 (P < .001).

"With respect to the 2011 logistic regression, a 1-unit increase in APOE-conferred risk increased the odds of a 71-year-old meeting the CES-D clinical cutoff for probable depression by 19.7%," write the authors.

The interaction between APOE-conferred risk and CVB was not significant with respect to depression in 2004 or 2011. This, said the authors, indicates that APOE does not moderate the demonstrated vascular depression effect.

"Based on our research, we now have a much better idea of how APOE is related to depression, but again, it's an aging process. This relationship is not significant when participants were 53 or when they were 64; it only emerged when they were 71," said Scott.

She noted that a similar age-related pattern is seen with AD. "We can't say for sure that the mechanism is the same, but it's interesting that both of these maladaptive aging processes come online as individuals typically age into their 70s and beyond."

Antidepressant Effect?

Would taking antidepressants help treat or prevent depression in older adults? Scott pointed out that these medications have different degrees of efficacy and side-effect profiles across age groups.

"Antidepressant drugs may not be the first line of treatment for older adults with depression, especially if they have vascular depression," said Scott.

Nondrug behavioral therapies are being developed specifically for later-life depression, she added.

Having information about a patient's APOE status could more precisely target patients whose depression may be modifiable.

"I would think that the more information we have, the more individualized we can make our treatments, and the more we can maximize prognosis," said Scott. "So it's really a precision medicine kind of approach."

She acknowledged, however, that the use of genetic testing can be a sensitive issue.

The new results fit well within the context of past research. The authors note that a recent 9-year follow-up study showed a significant relationship between APOE4 and incidence of depression in a sample of persons whose baseline mean age was about 74 years.

Another study showed an increased effect of APOE4 on late-onset depression in adults older than 80 years compared with their counterparts who were younger than 80.

One limitation of the current study was the use of a sample that was almost entirely white.

"A future direction would be to look at this relationship in different races," because the effect of APOE on AD has been shown to fluctuate between ethnic groups, said Scott.

Another limitation was the use of self-reported health data in measuring CVB. However, the authors point out that this approach is consistent with past research on clinically defined vascular depression, and subjective accounts of medical burden have yielded high concordance with objective measures.

Unclear Findings

When asked for comment, James Potash, MD,professor of psychiatry and behavioral sciences, Johns Hopkins Medicine, Baltimore, Maryland, told Medscape Medical News that the new study goes over previously covered ground.

Results of past research have been "pretty mixed," with some studies showing that APOE does increase risk for depression, whereas others show that it does not, said Dr Potash.

"This new paper does not, to my mind, make it any clearer."

He noted that some analyses in the study were negative. For example, APOE was not associated with depression in people in their 60s; APOE at an earlier stage was not predictive of depression at a later stage; and APOE did not interact with cardiovascular risk to cause depression.

And the positive finding ― that APOE was a predictor of depression in 2011 ― had a P value of .02, which Dr Potash called "pretty weak."

He also raised the issue of "multiple testing," whereby a positive finding could occur by chance after enough testing has been done.

"Jury Still Out"

"The new paper adds a little bit of incremental evidence in favor of the hypothesis that APOE4 contributes to depression, but the jury is really still out, in my mind," said Dr Potash.

From 20% to 25% of the population carries APOE4, and most of them will not develop AD, so "it's not inevitable," stressed Dr Potash. He added that an estimated one third of people who do develop AD do not carry APOE4.

It has only been in the past year or two that solid research has started to surface on the genetics of depression, said Dr Potash. Two "really important papers" were published last year that "strongly implicate a number of genetic variations in depression." These did not include APOE4.

In addition, Dr Potash is one of the authors of what he thinks is a pivotal article currently under review by the journal Nature. He said it will be "the most important paper ever done in this field of genetics and depression."

The field has opened up since investigators have determined the entire genome.

Researchers now estimate that roughly 35% of cases of depression have a genetic cause, compared with 75% for schizophrenia and a similar percentage for bipolar disorder, according to Dr Potash.

The study received no funding. Roseanna Scott and Dr Potash have disclosed no relevant financial relationships.

J Clin Psychiatry. Published online June 20, 2017. Abstract

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