Alzheimer's Biomarker Linked to Major Depression

Deborah Brauser

April 05, 2012

April 5, 2012 — Cognitively intact elderly patients with major depressive disorder (MDD) may have low levels of amyloid beta 42 (Aß-42), a biomarker that has been implicated in Alzheimer's disease (AD), new research suggests.

In a small study of older adult volunteers who had no mild cognitive impairment (MCI), those with MDD had significantly lower cerebrospinal fluid (CSF) levels of Aß-42 than those without depression.

In addition, levels of F2-isoprostane, considered a biomarker of oxidative stress, were higher for the participants with MDD.

"Current treatments for depression are not very satisfactory," lead author Nunzio Pomara, MD, director of the Geriatric Psychiatry Division of the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, and professor of psychiatry at the New York University School of Medicine, told Medscape Medical News.

Dr. Nunzio Pomara

"That's why, in my opinion, it's important to explore novel mechanisms which would underlie the development of depression in humans," said Dr. Pomara.

He noted that this study was an "interesting first step" and that if its findings bear out in further research, it may lead to the development of better therapeutic interventions.

"One must be very cautious because this was a small study. But I believe its importance lies not so much in finding a final truth about pathogenesis of depression but really in setting the stage for future studies of this molecule as a possible factor in both the development of depression and in shaping Alzheimer's disease."

The study was published online March 28 in the American Journal of Psychiatry.

Common Links

According to the investigators, Aß-42 is a main component of plaques often found in patients with AD. In past research, Aß peptides have been associated with depressive states in rodents.

"Depression and depressive symptoms have been linked to Alzheimer's disease. So we wanted to look at the biological basis for this link," explained Dr. Pomara.

"It is now generally believed that amyloid disturbances may contribute to the pathogenesis of [AD]. And it seemed very reasonable to me to see if these disturbances might also exist in cognitively intact individuals with major depression."

Although previous studies, including 1 reported by Medscape Medical News, have used positron emission tomography (PET) to examine Aß levels as a potential marker for late-life depression, Dr. Pomara and colleagues write that that this is the first study to use CSF levels to examine this issue in both men and women.

The investigators enrolled 47 older adult volunteers. Of these, 28 had clinically diagnosed MDD (36% women; mean age, 66.5 years) and 19 did not (63% women; mean age, 68.1 years).

Inclusion criteria included being "cognitively intact," as determined on the basis of several measures, including the Clinical Dementia Rating Scale.

Lumbar punctures were administered to all participants to obtain CFS samples. All samples were measured for soluble Aß, as well as for isoprostanes and total and phosphorylated tau protein.

Lower Amyloid Levels

Results showed that the participants with MDD had significantly lower levels of Aß-42 than those without the disorder (P = .02). In further analysis, the investigators found that use of antidepressants was not associated with this difference.

However, lower levels of Aß-42 were associated with greater MDD symptom severity.

Those with MDD also had lower levels of Aß-40, but this difference was not deemed statistically significant (P = .07).

In addition, the MDD group had significantly higher levels of isoprostanes than did the non-MDD group (P = .001).

There were no significant between-group differences found in tau proteins, and no differences in any of the measures between the sexes.

"Reduction in CSF levels of [Aß-42] may be related to increased brain amyloid beta plaques or decreased soluble [Aß] production," write the investigators, adding that the increase in isoprostanes suggests that oxidative stress is also associated with depression.

"These results may have implications for our understanding of the pathophysiology of major depression and for the development of treatment strategies," they add.

Dr. Pomara reported that he hopes to conduct further research "to really confirm these preliminary findings" and hopes that other researchers will also look into this area.

"It's not enough just to show that we have changes in CSF. It would be important to demonstrate that the reduction in [Aß-42] found in spinal fluid is truly accompanied by increases in brain amyloid deposits, as measured by novel PET techniques."

Dr. Pomara said that he also hopes that follow-up studies will include a bigger patient population and a follow-up period.

Vigilance Needed

"There is always this question of what the significance is of depression in older people," Christopher Marano, MD, geriatric psychiatrist and assistant professor in the Division of Geriatric Psychiatry and Neuropsychiatry at Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape Medical News.

Dr. Christopher Marano

"Is depression a risk factor for Alzheimer's or is it the first symptom of Alzheimer's-type pathology? This study looked at a biomarker we know is for Alzheimer's and found that older patients with depression had similar reductions in Aß-42 levels," he said.

"So this well-done study gives more evidence to the idea of this pathophysiologic link between late-life depression and Alzheimer's."

However, Dr. Marano, who was not involved with this research, noted that he would not advocate measuring Aß levels at this point.

"If we had disease-modifying treatments for Alzheimer's, it may be more appealing to do a lumbar puncture and measure amyloid beta. If we had these definitive treatments, then potentially in the future, this might be worthwhile — especially if we could also find imaging or blood-based biomarkers," he said.

"Instead, I think the message to clinicians now is that if you see someone with late-life depression, you need to be vigilant in seeing if that is the first symptom of a dementia syndrome or not. Pay close attention, do a thorough evaluation, and really monitor people through time."

The study was supported by grants from the National Institute of Mental Health and from the National Institutes of Health. Dr. Pomara reports holding "a joint patent with New York University School of Medicine and a patent application related to this study." Dr. Marano has disclosed no relevant financial relationships.

Am J Psychiatry. Published online March 28, 2012. Abstract


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