Alzheimer dementia (AD) represents a profound global health concern. By the year 2050, the prevalence of AD in the United States is expected to reach 15 million. At present, there are 4.5 million cases in the United States,1 which equals an estimated cost of $100 billion each year in medical and family expenses.2 Clinically, AD is characterized by the progressive deterioration of patients' cognitive and functional abilities over several years from the initial onset of symptoms.
Neuropsychiatric symptoms are highly prevalent in this patient population and often represent the greatest source of distress to both the patient and his or her caregivers. Depression is one of the most common of these symptoms and often presents differently from major depressive episodes in younger persons. Although the treatment of depression in AD remains challenging, both pharmacologic and nonpharmacologic approaches can offer relief to patients and caregivers. This article highlights the significance of depression of Alzheimer disease (dAD) as a diagnostic entity, elucidates the issues surrounding its recognition, and ultimately offers some practical treatment strategies to physicians dealing with these complex cases.
Symptoms of dAD
Neuropsychiatric symptoms in AD are a heterogeneous group, representing a spectrum of expressions including depression, agitation, hallucinations, delusions, insomnia, and others. Two recent population-based studies examined the epidemiology of these symptoms in AD. In the Cache County Study on Memory in Aging, 53% of AD patients exhibited at least one of the previously mentioned symptoms during the previous month, as defined by the Neuropsychiatric Inventory, with depression occurring in about 20%.3 Similar results were seen in the cardiovascular health study, with depression being the most prevalent symptom at 32.3%.4 Comparable studies in the United Kingdom reported similar findings.5
Additional analyses of the Cache County data found that despite the broad spectrum of neuropsychiatric symptoms, participants could be classified into 3 groups of symptom constellations: those with a monosymptomatic disturbance (19%; mostly delusions), those with a primarily psychotic syndrome (13%), and those with a primarily affective syndrome (28%).6 Studies from clinical settings reported that an estimated 30% to 50% of AD patients had depression. Neuropsy chiatric symptoms are reported to affect as many as 90% of AD patients over the course of their illness, with depression being among the most prevalent. These data confirm the overarching need for improved interventions in this area.
Depression can often be the first symptom in AD. Some evidence indicates that it is most common in mild to moderate illness but has a symptom constellation differing from that of depression in younger patients. For this reason, the National Institute of Mental Health (NIMH) sponsored a workgroup in 2002 to develop a set of criteria that would crystallize the cur rent consensus in the field.7 These criteria were predicated on the understanding that al though dAD has some similarities to major depressive disorder (MDD), it represents a unique clinical entity. Because of this qualitative distinction, existing criteria for the assessment of MDD consistently tend to underestimate the prevalence of dAD. Key differences in these criteria include: (1) dAD requires only 3 symptoms versus the 5 for MDD; (2) dAD symptoms can fluctuate more than those of MDD; (3) dAD includes symptoms of irritability and social isolation/withdrawal; and (4) dAD places greater emphasis on anhedonia (a decrease in positive affect or pleasure in response to social contact and usual activities). Generally speaking, patients with dAD tend to be more anxious, agitated, delusional, or inattentive but have less guilt and self-deprecation and are rarely suicidal. The hope among investigators is that the diagnostic criteria developed by the NIMH can more accurately capture these phenomena.
Causes of dAD
A commonly encountered belief among caregivers of patients with dementia is that receiving the diagnosis of Alz heimer disease will inevitably result in depression. This is the reason that families frequently protect their loved ones from hearing the details of their condition. However, there does not appear to be a clear association between a patient's insight into the disease and the risk of a mood disorder. In fact, many patients in whom an affective syndrome ultimately develops have little or no insight into their cognitive condition. In addition, dAD can occur at any stage in the disease process, including in advanced illness, where insight is almost universally absent.
Research is beginning to shed light on some of the proposed biologic foundations of dAD. Several pathologic studies8-10 consistently showed a relationship between depression in dementia and a loss of noradrenergic neurons in the locus caeruleus. A fluorodeoxy glucose positron emission tomography (PET) study found hypometabolism in the right superior frontal gyrus in patients with dAD as opposed to those without.11 A previous PET study also demonstrated frontal lobe hypometabolism that was most prominent on the left side in depressed patients with dementia.12 In addition, a recent autopsy study dem onstrated the consistent finding of Lewy bodies in the amygdala of dAD patients.13 The further elucidation of these underlying mechanisms may help to guide future treatment efforts.