Depression Is a Risk for Alzheimer’s: We Need to Know Why.

Studies have consistently shown that people with a history of depression, particularly recurrent or chronic depression, have about twice the risk of developing Alzheimer’s disease later in life. Why is this?

It’s not a life history that anyone would choose. Depression itself, as we all know, is a disorder that can have hugely disabling effects on careers, relationships and, above all, on quality of life. That is bad enough: add to this the prospect of later life being disfigured by dementia, and you have a trajectory that no-one would want. If we could understand why it is that depression represents a risk for Alzheimer’s, we might be able to devise interventions that reduce or eliminate that risk. And such an understanding might also add badly-needed extra knowledge about the causes of Alzheimer’s itself.

But there are big questions. Depression in also part of Alzheimer's, and is sometimes the first sign, so we need to separate an episode of depression as a symptom of Alzheimer's from one that represents an independent risk for it. Careful analysis shows the latter really is the case. There is another consideration: the risk that earlier depression poses might actually be much greater than it appears. This is because it has become obvious that what we call major depression may be a symptom of a number of different underlying brain disorders, rather than, as presently defined, a single disorder (though with a number of variations). Unlike any other branch of medicine, depression (as with other psychiatric disorders) is diagnosed by symptoms alone. There are no scans, blood tests and other investigations that allow other branches of medicine - neurologists, for example - a more precise definition of the cause and nature of the brain disorders that falls within their remit. This is not the case for psychiatrists. We already know that depression may be a symptom of more than one disorder: for example, those with bipolar disorder can have episodes of depression that are not really distinguishable from unipolar depression. So symptoms alone are not accurate enough for recognizing different brain disorders that may underlie the overt state of depression.

If what we currently define as ‘depression’ is actually, as many suspect, a manifestation of several brain disorders, then this suggests that there may be particular categories or sub-types of depression that are risks for later Alzheimer’s, whereas other types may not be such a risk. But this has another consequence: if these sub-types exist, then the risk they represent may be much greater than the twofold overall risk, since this is diluted by forms of depression that may not be such a risk. Who knows what risk such people face; it might be four, eight times the general risk, equivalent, then, to one of the known genetic risk factors. We need to know.

What do we know about the evident link between depression and Alzheimer’s? We know something about the genetic risks for Alzheimer’s, but there is much less certainty about depression, though genetic risks are known to exist for that disorder as well. But the genes identified so far for the two conditions are not the same. So a genetic risk for depression seems different from that for Alzheimer’s. Being at risk for one does not mean you are at risk for the other.

The stress hormone cortisol is known to be raised in both depression and Alzheimer’s. Raised cortisol is a risk for depression, but its role is not yet established in Alzheimer’s, though there is a suspicion that it may accelerate cognitive decline. There is experimental evidence that high cortisol exacerbates brain damage, including that seen in Alzheimer's. We don't yet know whether persistent alterations in cortisol, maybe as one result of chronic stress or persistent depression, predisposes to later Alzheimer's

Some people with depression also show evidence of inflammatory changes in their blood (this may be one sub-type). Inflammation in the brain is being implicated in Alzheimer’s, so this might be a link. But whether inflammation actually occurs in the brain in at least some cases of depression is still controversial. So is the contribution of inflammatory changes in the brain to either the onset or course of Alzheimer's, though there is increasing evidence that it may. But if some sub-types of depression are caused by, or related to, inflammation in the brain, this is a plausible link.

Another possibility is brain aging. Age is a major risk factor for Alzheimer's, so does depression - particularly repeated or chronic depression - accelerate the aging of the brain? It's quite difficult to define brain age, other than using tests of cognition or memory, though recently there have been reports that gene function may alter in predictable ways in the brain as we age. So in future it may be possible to see if this is accelerated by depression. If this is the case, we need to know why, and how this predisposes to Alzheimer's. All these various possibilities may only apply to certain types of depression, so these, if they exist, need to be defined.

It is obvious that we are at an early stage in our understanding of the link between the two conditions. This can only be resolved by more research. In particular, long-term studies on carefully characterized cases of depression to see if we can separate sub-types that are the real risk for Alzheimer’s. If we could, and then discover what it is about this sub-type(s) that is the real risk, then it becomes much easier to develop interventions that might reduce this risk. For example, if inflammation in the brain is the link, then being able to detect which cases of depression are accompanied (or caused) by inflammation would allow us to treat it in such a way that might both help depression (though anti-inflammatory drugs have not proved effective so far) but also remove or reduce the risk of later Alzheimer’s. Or it might be that disordered cortisol is the culprit: in which case, there are ways of counteracting the detrimental actions of excess cortisol that might be beneficial as a preventative measure.

These are not the only possibilities: only careful research will lift the curtain of ignorance. Such studies are urgently required: since both depression and Alzheimer’s are common conditions, if there is a group of patients in whom Alzheimer’s could be prevented, this might have a substantial effect on the overall incidence of dementia, as well as shifting at least one dark cloud from the lives of these people.

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Psychiatry by itself is unlikely to be able to provide what is needed. Here is an obvious case for the kind of inter-disciplinary research that has been so beneficial in other areas of medicine. All that is needed is a conviction that there is a worthwhile problem to be addressed, an open mind about how to approach it, and a meeting of those minds across the boundaries of medical, psychological and biological research[1].

[1] Those interested in reading a technical account of the link between depression and Alzheimer’s, see: J Herbert and PJ Lucassen (2016) Depression as a risk for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis –what do we need to know? Frontiers in Neuroendocrinology. (in press).