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COMMENTARY |
Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore.
Drs. Rasgon and Jarvik (1) propose that insulin resistance (IR) may link affective disorder (ad) with Alzheimer's disease (AD), at least partially. This hypothesis implies three things: first, that ad is associated with AD; second, that ad is associated with IR; and third, that AD is associated with IR. Certain important definitional issues are skirted in the presentation of the hypothesis. What is meant by ad? This is a heterogeneous category, which includes "primary" or "idiopathic," bipolar or unipolar affective (mood) disorders; the latter may be "major" or "minor" depression. It also includes "secondary" affective disorders due to a general medical condition or the use of psychoactive substances. The age of onset of mood disorders is also important. There are two incidence peaks for mood disorders, one in early adulthood and one in late middle-life, after age 50 (2). This suggests the possibility of a different etiopathogenesis for early onset or later-life onset mood disorders, with brain diseases, such as vascular disease and Alzheimer's disease playing a more important role later in life. It is unclear whether the hypothesis proposes a link between early onset or later-life onset ad, or both, and AD.
Next, what is meant by AD? Does the hypothesis refer to a clinical syndrome such as "Dementia of the Alzheimer type" (DSM-IV) or "Probable (Possible) Alzheimer disease" (NINDS/ADRDA) or even the concept of dementia itself? Or does it refer to a brain pathology, with characteristic plaques and tangles, and a specific brain distribution at different stages of the disease? There is not a 1:1 correspondence between the two, with many older persons exhibiting the brain pathology in the absence of cognitive symptoms, and with factors other than the AD pathology being critical to the manifestation of dementia, such as brain vascular disease (3,4). While this distinction is important, Drs. Rasgon and Jarvik do not address it. Affective disorder is a clinical syndrome and not a brain pathology, so that the hypothesis may be proposing an underlying biologic link between two clinical syndromes by suggesting that they may arise from damage to the same brain regions (hippocampus and other limbic areas) through a common process, in this case IR. Or, the hypothesis may be proposing that ad leads to IR, which in turn leads to the pathology underlying AD. The latter would be proposing a causal link whereas the former suggests a common cause that may manifest clinically in different ways at different points in life (e.g., with depression earlier and with cognitive change later on). The causal link idea is along the lines of efforts to explain the relationship between depression and cardiovascular disease via altered blood platelet function, or heart rate variability (5).
What is most critical to this discussion is whether there is an association between ad and AD. Several case-control studies have demonstrated that people with dementia are more likely to report a premorbid history of a depressive episode than controls (6–10). However, these case-control studies have serious methodological limitations since they rely on participant recall for past history of depression. The recall and dating of past episodes of psychopathology is notoriously inaccurate (11). Thus, the reliability of "caseness" of ad, date of onset, and duration of depression are limited due to recall bias, with recall further back in time being less reliable. Further, all these studies were of clinical samples or case registries subject to selection bias, hence more likely to show a false association between two conditions.
Several prospective studies have suggested that depression precedes dementia (12–16). However, these prospective studies are also limited in that all investigated people aged older than 65 years, so that the ascertainment of exposure (depression) was not entirely prospective since participants had to recall their life history of depression prior to that age (when most of the onset occurs). Due to the close temporal relationship between depressive symptoms and subsequent dementia in these studies, they fail to test the hypothesis that depressive episodes during earlier decades in life may be associated with the development of dementia in later years. This hypothesis can best be tested when the duration of follow-up encompasses the adulthood of each participant. Only one study has reported that an early history of affective disorder prospectively ascertained increases the risk of dementia in later life (17). This finding requires replication.
Thus, an association between ad in later life and later dementia seems reasonably well established. It is very likely that this is, in part, because depression in later life is the first clinical manifestation of a brain disease, such as Alzheimer's, which later goes on to also cause the clinical syndrome of dementia (18). However, while the notion has some supportive evidence, it is far from proven that ad with onset in early and middle life is associated with later dementia. There is no evidence of an association between bipolar disorder, minor depression, dysthymia, or secondary mood disorders and dementia, or between ad at any point in life and the development of AD pathology in the brain.
In contrast to the uncertainties about a link between ad and AD, the association between ad and IR is better established. A recent review (19) points out the extensive evidence linking major depression to diabetes mellitus (DM), and possibly milder forms of IR. In fact the evidence is such that treatment of depression, through either pharmacological or psychological methods, may well lead to improved glucose control and be a key aspect of the management of DM. Thus, at least some patients with ad are more likely to exhibit impairment of glucose control, which may be persistent and lead to DM and its long-term complications.
Turning to the link between IR and AD (20), this remains a matter of debate. The idea has face validity in the argument that IR may be associated with chronic "undernourishment" of neurons such that those most sensitive to it may eventually be injured or die (1). While the epidemiologic evidence suggests that DM is associated with a higher risk of AD incidence, this has not been universally replicated (20). Further, population studies depend on participant self-report to classify the exposure, in this case DM. Individuals who report that they have DM are more likely to be treated, adding the confounding of whether it is the treatment and not the disease that increases the risk of AD. Both insulin (20) and tolbutamide (21) appear to increase ß-amyloid deposition or to inhibit its degradation increasing the likelihood of AD. As many as two out of three individuals with IR and DM are not diagnosed or treated (22). Such individuals would report in population studies that they do not have DM, where they may in fact have worse glucose control than individuals who report that they have DM and are being treated for it.
Other arguments supporting the link between IR and AD include findings that induced hyperglycemia enhances cognitive performance in early AD dementia, but not more severe AD dementia, as well as an association between insulin levels and the progression of AD dementia (20). However, replication of these findings has not been reported by other groups. They also do not demonstrate an association between IR and the later onset of AD. Rasgon and Jarvik also point to functional imaging studies of reduced glucose metabolism in AD dementia and in persons at high risk for AD as further evidence of the IR–AD link (1). While, in fact, this hypometabolism may be reflective of reduced uptake of glucose by brain neurons, it is more likely that it reflects existing neuronal loss, since the same brain areas also show reduced H2O uptake in functional imaging studies (1). Finally, the strong link between vascular disease and dementia or AD (4) confounds the association between IR and AD.
The hypothesis proposed by Drs. Rasgon and Jarvik has merit, but its time has yet to come. The association between ad in later life and subsequent dementia could be, as noted, because depression is the first symptom of a brain disease that later goes on to cause dementia. This, in part, might be mediated by brain vascular disease. In fact, brain vascular disease has greater support for being a link between ad and AD dementia than IR. Brain vascular disease is widely accepted as a major cause of depression in later life (23), and is well known to cause dementia, possibly also AD dementia (3,4). In addition, should an association between ad in earlier life and AD be confirmed by future study, vascular disease may be the missing link. It has been well established that depression is a risk factor for cardiovascular disease (5). Hypercortisolism associated with depression has been known to induce hypercholesterolemia, hypertriglyceridemia, and hypertension (24,25), and to cause injury to vascular endothelial cells, intima, and inhibition of normal healing (26–29). Depression in earlier life is also a strong risk factor for stroke (30–35).
While a link between IR and AD is an interesting proposition, it remains in its nascent phases. The precise relationship between ad and AD remains to be defined, especially with regard to depression earlier in life and AD. While IR is well associated with depression, its relationship with AD is still uncertain. On balance, the evidence would suggest that brain vascular disease is a more likely link between ad and AD than IR, although the two are not mutually exclusive and may be synergistic. In order to test these hypotheses, future research should develop better methods of measuring IR, and, for that matter, brain vascular disease, especially methods that can be used in population-based studies.
Acknowledgments
Supported by U01-MH-66136 (DIADS-2) and by T32-MH-14592.
Address correspondence to Constantine G. Lyketsos, MD, MHS, Osler 320, The Johns Hopkins Hospital, Baltimore, MD 21287. E-mail: kostas{at}jhmi.edu
References
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