This initial imaging study of AD neuropathology in elders with major depression supports growing clinical and epidemiologic data that late-life depression may be either a substantial risk factor or in some cases a potential early manifestation of AD. Among 9 nondemented subjects with treated depression and variable cognitive impairment (7 with MCI), approximately one-half demonstrated PiB retention indicative of brain β-amyloid accumulation in cortical areas in a pattern characteristic of early AD (3 of 8 with arterial lines were definitely PiB-positive, 1 of the remaining 5 had intermediate levels of PiB). Thal and colleagues61
described 5 distinct, sequential phases of brain amyloid deposition, where phase I demonstrates exclusively neocortical involvement (frontal, parietal, temporal, occipital) and later phases progressively show β-amyloid deposits in the entorhinal region and insula, thalamus, putamen, caudate nucleus, cholinergic nuclei of the basal forebrain, and brainstem nuclei. The latest phases indicate β-amyloid in the cerebellum and additional brainstem nuclei. Although both β-amyloid deposition and altered tau metabolism leading to neurofibrillary tangle formation are hallmarks of AD, it is pathologically defined by the presence of β-amyloid–containing neuritic plaques.62
The bulk of our knowledge of the pathophysiology of neurodegenerative disorders is based on postmortem studies, which are biased toward end-stage disease. However, a postmortem study in Down syndrome, in which early AD is common, supports the hypothesis that β-amyloid deposition may occur as early as a decade before clinical symptoms.22
In vivo data with PiB-PET imaging further support the accumulation of β-amyloid in the brains of individuals with only mild cognitive dysfunction.30–32
Demonstration of this new capability to detect the presence of AD pathologic changes in vivo has important implications for patient prognosis and differential management of individuals with late-life depression.
The clinical relevance of identifying those individuals at greatest risk of developing AD is growing as new therapeutic approaches directed at modifying AD progression evolve. Among subjects with MCI in memory disorders clinics, the overall rate of progression to dementia seems to be approximately 15% per year across several studies.13–16
The Alzheimer’s Disease Cooperative Study Group reported an annual rate of progression to AD of 16% among 769 MCI subjects followed over 3 years.63
Approximately 50% of individuals with MCI progress to develop AD over a 5-year period, indicating that a diagnosis of MCI alone is not a sufficient predictor of dementia prognosis.14,16,64,65
On the basis of recent reports of individuals labeled with MCI reverting to normal, Gauthier and Touchon66
argue against the use of MCI as a clinical entity or “predementia stage of AD.” Notably, a recent study by Forsberg et al30
reported that 7 of 21 MCI subjects converted to AD after 2 years, and moreover, at baseline (when adjudicated as having MCI), all 7 had PiB retention levels similar to AD subjects.
Most of the focus on MCI as a high-risk AD group has focused on the amnestic (memory impaired only) form of the disorder, originally described by Petersen and colleagues.13
However, depressed elders often have prominent deficits in other domains such as executive functioning or mild impairment in MCDs that may or may not include memory. In a study by Bhalla and colleagues,20
approximately one-half of elderly depression patients in remission met the cognitive criteria for MCI, with most of them exhibiting the MCI-MCD subtype, some with and some without memory impairment. One may hypothesize that MCI-MCD may represent a combination of the cognitive deficits associated with late-life depression and those owing to superimposed AD neuropathology. Notably, if we examine the relative PiB retention in frontal cortex in the depressed subjects in this study by cognitive diagnosis, there is a trend toward higher PiB DVR values among those with amnestic-MCI relative to nonamnestic MCI (). Larger future studies will be needed to further evaluate the relationship between cognitive impairment subtyping and amyloid binding measures in elders treated for major depression.
A recent study by Rapp and colleagues67
demonstrated that the brains of patients with AD and lifetime history of depression showed higher levels of both plaque and tangles in the hippocampus than AD patients without depression. Those AD patients with depression also had a more rapid cognitive decline than nondepressed demented subjects. Our in vivo findings are consistent with evidence that late-life depression may be either a risk factor for AD—in cases where depression may present many years before cognitive impairment—and/or a potential AD prodromal state in some individuals. Indeed, postmortem studies by Sweet et al68
have confirmed a predominance of AD neuropathology among well-characterized late-onset depressed patients with varying cognitive impairment who were followed longitudinally.
The heterogeneity of late-life depression and its association with cerebrovascular risk factors,69
physiologic changes related to aging,70
structural brain changes,72
and medical burden73
suggest that clinical expression of dementia may be related to a confluence of brain insults and diminished cognitive reserve. Future large prospective studies can address the relationship between the magnitude and distribution of amyloid load as measured by in vivo PET imaging and clinical and demographic factors that may contribute to the manifestation of cognitive impairment and clinical dementia. This information will likely shed further light on the complex neurobiologic mechanisms underlying depression and AD and guide future approaches to early intervention.