Stress, Depression and Alzheimer's, Part 1

For most of his life, my father was calm and happy. “No sweat,” he’d say when the furnace blew up or the car wouldn’t start. Even when his retail lumberyard burned down, or when his parents died, he seemed to take a Zen attitude towards life. But after he retired, I thought he was more pessimistic than usual. Was this somehow related to his later dementia?

I didn’t think much about mood, depression and dementia until I realized it was a topic of discussion on some of the caregiver blogs. In The Yellow Wallpaper, Deb Peterson writes about how her mother’s depression after the death of several family members seemed to mark the beginning of her dementia. Paula Martinac (Dementia Blues) reports both her parents were depressed before their declines into dementia. But many people with Alzheimer’s disease or dementia have no history of depression. Gail Rae Hudson (The Mom & Me Journals), who describes her mother’s condition as “dementia lite,” doesn’t think her mom has ever been depressed.

Was the change in Dad’s mood [I wouldn’t call it depression] a normal reaction to retirement? Or was it an understandable reaction to subtle signs of dementia the rest of us didn’t see? It makes sense that some dementia patients become melancholy when they realize they’re having memory problems.

But rather than dementia causing depression, it seems to be more of a two-way process. Several studies show a history of depression may increase your risk of developing dementia later in life:

• A large retrospective study at the University of Limburg in the Netherlands (published in 1996) and another at the University of Copenhagen in Denmark (2003) found associations between a history of depression and dementia
• When researchers at Rush Alzheimer's Disease Center in Chicago followed Catholic clergy aged 65+ for seven years, they concluded that each depressive symptom reported over the seven year period increased the risk of developing Alzheimer’s disease by an average of 19%, and increased average cognitive decline by 24%.
• Scientists at Boston University School of Medicine found a significant association between depression symptoms and Alzheimer’s in 1953 patients with Alzheimer’s disease and 2093 of their non-demented relatives. The association was most significant when depression symptoms first occurred within one year of the onset of Alzheimer’s, but there was still a modest association even when depression first happened more than 25 years before the onset of Alzheimer’s. [free registration required to view this article]

Other studies have not been as definitive. University of Ottawa researchers found a weak, but not statistically significant association between a history of depression and Alzheimer’s disease after following more than 4600 Canadians aged 65 and older over a five year period.

This year, a team of researchers from the University of Miami Miller School of Medicine and the Wien Center for Alzheimer’s Disease and Memory Disorders at Mt. Sinai Medical Center published the results of a systematic review and analysis of the research on this topic. Analyzing data from over 100,000 patients in 22 studies, the researchers concluded that a history of depression does seem to increase the risk of developing Alzheimer’s, although the absolute risk is still small. Their data also showed relatively long times between depressive episodes and the onset of Alzheimer’s, suggesting that depression may be an independent risk factor for developing Alzheimer’s rather than signaling the onset of the disease.

For dementia patients with a previous history of depression, it’s also likely their dementia will be more severe than that of patients with no such history. In a recent study, pathologists compared the brains of Alzheimer’s patients who had lifelong histories of depression to the brains of Alzheimer’s patients who hadn’t had depression. The pathologists found that the brains of patients with a history of depression had more of the plaques and tangles associated with Alzheimer’s disease than those of patients who hadn’t had depression. This increase in plaques and tangles seemed to correlate with the severity of memory loss.

If depression and Alzheimer’s are linked, then maybe there’s a common underlying cause. Several studies point to cortisol, a stress hormone, as the possible culprit. The thinking is that stress causes the body to release cortisol, and that chronic stress leads to the chronically high levels of cortisol sometimes associated with cognitive impairment and shrinkage of some areas of the brain.

The obvious question is whether lowering cortisol improves memory. I’ve always had trouble navigating, and this problem gets worse when I’m upset. Could I take something to lower my levels of this hormone before I drive an unfamiliar route? It turns out that for rats, lowering cortisol levels does improve their performance in mazes.

I was disappointed to find it’s not so simple for humans. In a small trial of seventeen people, a team headed by researchers from McGill University in Canada found that manipulating cortisol levels did have an effect on memory in some people, but that effect was dependent on historical cortisol levels in each participant or person. If the individual patient had had moderate cortisol levels for a period of five years, blocking cortisol levels actually decreased memory, and adding back cortisol reversed this problem. For patients with historically high cortisol levels and existing memory problems, blocking cortisol didn’t improve memory, although increasing cortisol levels made their memory problems worse. This could be because it’s the cumulative, long-term exposure to high levels of cortisol that hurt the brain, rather than the level at any one time. Some scientists think problems are caused by the malfunctioning of the receptors for cortisol, rather than the hormone itself.

So, the cortisol and stress connection is intriguing, but at least so far, hasn’t yielded the magic formula to fix dementia.

One of reasons it’s hard to untangle the relationship of depression and dementia or Alzheimer’s disease is that both diseases may have multiple underlying causes. “I think the evidence shows that there may be complex relationships among stress, cortisol (and other neuroendocrine substances), inflammatory markers, cardiovascular disease, and cognition,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine and the lead author of the scientific review of research on the topic. “Since cardiovascular disease may be related to Alzheimer's disease, it seems quite possible that stress, cortisol, inflammation, depression, and AD may all be related, but we don’t know how.”

Raymond L. Ownby, M.D., Ph.D., M.B.A.

But even if stress, cortisol and depression were only partially responsible for dementia, could they be considered “modifiable risk factors” for Alzheimer’s disease? I asked Dr. Ownby if treating depression could actually lessen a person’s chances of developing dementia.

“The possibility that treating depression might lower your risk for Alzheimer’s disease is intriguing,” he says, “but there simply isn't any evidence that I'm aware of on the subject, other than the possibility that antidepressants can lower levels of some chemicals that may be related to dementing illnesses.”

What about the idea that depression can masquerade as dementia? When I first started researching my father’s memory problems, several web sites mentioned “pseudo-dementia.” According to some of these sites, once you treat the depression, the dementia is reversed. But the diagnosis and prevalence of pseudo-dementia is now in question, and at least one study has shown that many people who seemed to have reversible dementia [their memory problems improved after their depression was treated] later developed [non-reversible] dementia.

Dad didn’t have a history of depression, and it’s pretty clear most of his dementia was related to cerebral amyloid angiopathy. But if he had lived long enough, depression might have been more of a problem. Treating any depression may have helped his dementia, at least for a while. I’ll talk more about that in my next post.

Comments

[Paula]

Mona - A very interesting post. In the past year, I've thought a lot about my mom's depression, which she suffered from her entire life. I'm not sure when my dad's started, but it certainly became noticeable after years of retirement in which they were pretty much shut away from everyone. But the fact is, in addition to depression, they both had physical problems that may have brought on the dementia. So it's a "chicken or the egg" kind of thing.

[Gail Rae Hudson]

This review (which is excellent, by the way) made me wonder if there are differences between people who "enjoy" their depressive episodes and those who don't. I'm not talking, here, about people who use their depression to garner attention they fear they would not otherwise receive, but those who find personal pleasure in a depressive outlook and/or use this outlook creatively and/or as a tool to sharpen their minds and expand their peculiar understanding of life. My father did this. I do this. Both of us had/have tendencies to become annoyed with people who tried/try to talk us out of (or sympathize with) our "blues", even the indigo and navy shades, thus tending to isolate ourselves when we want to muck about in our mud. My inept understanding is that creative people in many fields (not just the arts) embrace their depression, unless and until it interferes with their relationships...sometimes beyond this, though, allowing relationships to be sacrificed to their preference for the darkly askew. I've often wondered what might "happen" if mainstream U.S. culture were not so addicted to the idea of "the pursuit of [relentless] happiness". Believe me, I recognize that there is another side to this...highly creative people who are immobilzed by their depression. But, you know, this isn't a "31 flavors" culture, thus, it's hard for us to recognize that some people actually like the taste of sour over sweet. Anyway, I wonder if people with a taste for sour and who prefer to lap it up alone are more or less inclined to senile dementia and how their preference affects their experience of dementia.
My dad only lived to 68. Although he longed for dementia (I know, bizarre, but he would have liked to have blamed it for his advanced alcoholism), he never experienced it. Perhaps he would have if he'd lived longer. Then again, he also might have developed into a very crochety, unpleasantly sharp old man.
Provocative post, Mona! Thanks!

[Deb Peterson]

Mona--Once again, a very interesting and well-presented essay. I was also wondering if treating depression might reduce the risk of AD in later life--if possibly the "newer" anti-depressants (SSRIs) might cause some permanent realignment of brain chemicals? I'm not surprised it's as complex as you describe it. My mother has a history of depression, and was fairly open to trying "talk" therapy as well as medication. I think Gail's point is interesting and adds yet another layer to it all: how an individual's beliefs about depression affect the ramifications of the disease. If it weren't still considered (surreptitiously) a character flaw and if people felt freer to talk about it--if there was a place for it--would all that lessen its momentum? You've got us thinking...

[Gevera Bert Piedmont]

Very interesting. I know my dad is depressed as well as having AD--it's his depression/anti-anxiety medicine he ran out of when he flipped this weekend. Have you found any stats on suicide? I've been looking but haven't found any.
Thanks for the link, I'll give you one in return.
Bert

[Mona Johnson]

Bert,

I'm sorry to hear about your dad. I've not looked carefully for statistics on suicide. I have noticed one study at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=PubMed. You'll notice two things about that study:

1. It's relatively small, analzying the case histories of 28 people over age 60 who committed suicide versus 56 people who died naturally.

2. The conclusion is that Alzheimer's patients were "over-represented" in the suicide cases. At least in the abstract I can access, I don't see anything that would estimate suicide rates in Alzheimer's patients. I would think that might be a very difficult number to come by.

I've almost completed a post about depression in Alzheimer's patients, and will post it as soon as I can. I hope this information is at all helpful for you.

Here's the usual disclaimer - please remember that anything I write is my opinion only, and not a substitute for qualified medical advice! I'm really sorry you're having to deal with these difficult issues, and hope that you find the best possible care for your dad and the rest of your family!

Mona

[Ellana Livermore]

Thanks. I needed the information and just followed a link from Grand Rounds. Printed off part the second and the abstract about Mociobemide to take along to my mom's next appointment.

Question - should we be seeing a neurologist for AD?
We've just been going to an Internist who has a large geriatric practice.

Thanks

[Mona Johnson]

Ellana,

I'm glad this information was helpful for you! I can't really tell you whether you need to see a neurologist. Maybe your internist would have an opinion or a recommendation. If you decide a specialist is right for you and your mom, you might want to spend some extra time making sure the specialist has your mom's records from the internist, and vice versa. We had a very difficult time coordinating care for my father among various doctors. It would be very useful for you to have a copy of all the records yourself (you'll need your mom's written permission). It might also be helpful for you to summarize issues and medications for each doctor - in our case, they didn't always have the time to read a lot of records before each visit. For more about this part of caregiving, you may want to take a look at Gail Rae Hudson's site (http://themomandmejournals.net/index.html. She has several posts about record-keeping and acting as an advocate for her mother during doctor's appointments.

Good luck, Ellana.