Depression as a Risk Factor for Alzheimer Disease

Green, Robert C.; Cupples, L. Adrienne; Kurz, A.; Auerbach, Sanford; Go, Rodney C.P.; Sadovnick, Dessa; Duara, Ranjan; Kukull, Walter A.; Chui, Helena; Edeki, Timi; Griffith, Patrick; Friedland, Robert P.; Bachman, David; Farrer, Lindsay A.

doi:10.1001/archneur.60.5.753

Cited by 502 publications

(341 citation statements)

References 51 publications

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“…The relationship between major depressive disorder (MDD) and AD is controversial, with several studies reporting contradictory findings. The most consistent observation is that depression itself increases risk of AD (39)(40)(41). Interpretation of many MDD/AD risk studies, however, are complicated in that incipient or early AD can present clinically as apparent late-life depression in some cases (42).…”

Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

300

307

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Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

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Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

300

307

View full text Add to dashboard Cite

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“…Diabetes is an established risk factor for atherosclerosis and the frequently associated cerebrovascular diseases and has been found by other investigators to affect performance in the MMSE (35,36) . The links between cognitive impairment and depression are also well recognized (37)(38)(39) and make it necessary to simultaneously assess performance in the two neuropsychiatric dimensions in order to control, as far as possible, for mutual confounding. Hypertension has been linked to cognitive impairment (40)(41)(42) .…”

Section: Discussionmentioning

confidence: 99%

Diet, physical activity and cognitive impairment among elders: the EPIC–Greece cohort (European Prospective Investigation into Cancer and Nutrition)

Ψαλτοπούλου

Kyrozis

Stathopoulos

et al. 2008

Public Health Nutr.

152

112

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“…In our study, six of nine patients with neurodegenerative disease had histories of latelife depressive symptoms. Depression is believed to be a risk factor for the onset of Alzheimer's disease (Green et al, 2003;Chen et al, 1999;Kokmen et al, 1991;Kral and Emery, 1989). Affective disorders are often comorbid with neurodegenerative disorders that are associated with dementia (Allen and Burns, 1995;Schreinzer et al, 2004;Lauterbauch et al, 2004).…”

Section: Possible Relevance Of 5-htt Axon Degeneration To Symptoms Ofmentioning

confidence: 99%

Dystrophic serotonergic axons in neurodegenerative diseases

Azmitia¹,

Nixon²

2008

Brain Research

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Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and Diffuse Lewy-Body dementia (DLBD) have diverse neuropathologic features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathologically normal (control) brains (n=3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers of passage appeared thick, smooth, and un-branched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in number and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric analysis revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphologic evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n=3 slices for each region (3) from each brain (4), total slices was n=36) and lack of extensive clinical characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue

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Depression as a Risk Factor for Alzheimer Disease

Abstract: Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

Cited by 502 publications

References 51 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Diet, physical activity and cognitive impairment among elders: the EPIC–Greece cohort (European Prospective Investigation into Cancer and Nutrition)

Dystrophic serotonergic axons in neurodegenerative diseases

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