To the Editor: Drugs currently used to treat cognitive impairment and dementia have limited therapeutic value and cover mainly management of psychiatric and behavioral rather than cognitive symptoms. In the last decade, advances in understanding the neurobiology of Alzheimer's disease (AD) have been translated into an increase in clinical trials assessing several potential AD treatments. Only cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartic acid (NMDA)-receptor antagonist memantine have received Food and Drug Administration (FDA) approval for symptomatic treatment of AD, although ChEIs and memantine only slightly delay the inevitable symptomatic progression of the disease, leading some to question their clinical utility.1 Evidence from controlled clinical trials suggests that ChEIs in particular can stabilize patients' symptoms for periods of time ranging between 1 and 3 years but without modifying the progression of the disease.1 A recent meta-analysis was conducted on ChEIs to determine the effect of these drugs on mild cognitive impairment (MCI) with data from three published and five unpublished trials that met the inclusion criteria (3 on donepezil, 2 on rivastigmine, and 3 on galantamine).2 The duration of these trials ranged from 24 weeks to 3 years. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated and placebo groups. The rate of conversion ranged from 13% (over 2 years) to 25% (over 3 years) of treated patients and from 18% (over 2 years) to 28% (over 3 years) of those in the placebo groups.2 Only for two studies was it possible to derive point estimates of the relative risk of conversion (0.85, 95% confidence interval (CI)=0.64–1.12, and 0.84, 95% CI=0.57–1.25).2 Statistically significant differences emerged for three secondary end points, although after adjusting for multiple comparisons, only one difference remained significant (the rate of atrophy in the whole brain).2 In conclusion, the use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible.

A recent 3-year, longitudinal clinical trial study suggested that depressive symptoms were predictive of progression from amnestic MCI (aMCI) to AD.3 Furthermore, this study demonstrated that donepezil treatment delayed the progression to AD in subjects with depression without affecting symptoms of depression.3 These findings suggested that late-life depressive syndromes or symptoms may be early manifestations of dementing disorders and that depressive symptoms might be included in MCI diagnostic criteria.4 Subjects may have depressive symptoms related to cognitive impairment or to the underlying process. Depressive symptoms may be high in patients with MCI who remain dementia-free and in patients with MCI who progress to dementia or AD. In the first group of subjects, MCI could be related to an underlying psychiatric disorder, and in the second group, MCI and depression may be associated with neurodegeneration.4 Recently, in the Italian Longitudinal Study on Aging (ILSA), a population-based study with a sample of 5,632 subjects aged 65 to 84, a higher prevalence and incidence of depressive symptoms was found in subjects with MCI after a follow-up of 3.5 years,5 confirming that depressive symptoms could be frequent in subjects with MCI. However, in the ILSA, no significant association was observed between depressive symptoms and incident MCI6 or between depressive symptoms and rate of progression from MCI to dementia.7

The results of the earlier study3 are similar to the finding of lower risk of progression to AD in apolipoprotein E (APOE) ɛ4 carriers treated with donepezil.3 Therefore, although the presence of a APOE e4 allele anticipates the onset of AD in patients with MCI,8 the presence of depressive symptoms in patients with MCI constitutes a distinct subpopulation that more often represents early-stage AD, with a similar predictive function and response to donepezil.3 In conclusion, the critical question is determining the extent to which depression is a true risk factor rather than an early symptom occurring in the prodromal phase of dementia, particularly AD (e.g., aMCI). Substantial support exists for both hypotheses, and they are not mutually exclusive. Some findings suggest that, when depressive and cognitive symptoms appear close in time, they probably arise from common neuropathological processes.9 The previous study showed that the proportion of subjects with depression progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 and 2.2 years and remained marginally lower at 2.7 years.3 Therefore, depressive symptoms may be an early manifestation rather than a risk factor for dementia and AD,10 indicating that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms, rather than depressive symptoms causing or exacerbating MCI. At least in certain subsets of elderly patients (e.g., dysexecutive MCI plus anxiety-related or apathetic symptoms of depression), late-life depression, MCI, and dementia could represent a possible clinical continuum with indefinite bounds,4 and the findings of the previous study demonstrated that donepezil treatment may modify this continuum.


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Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. This work was supported by the ILSA (Italian National Research Council—CNR-Targeted Project on Ageing—Grants 9400419PF40 and 95973PF40) (Dr. Panza, Dr. C. Capurso, Dr. D'Introno, Dr. Colacicco, Pr. A. Capurso, and Dr. Solfrizzi).

Author Contributions: Dr. Solfrizzi and Dr. Panza: concept, interpretation, and manuscript preparation. Dr. V. Frisardi, Dr. C. Capurso, Dr. D'Introno, Dr. Colacicco, Dr. Chiloiro, Dr. Dellegrazie, Dr. Di Palo, and Pr. A. Capurso: interpretation and manuscript preparation.

Sponsor's Role: The funding agencies had no role in design or conduct of the study.


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  • 1
    Panza F, Solfrizzi V, Frisardi V et al. Disease-modifying approach to the treatment of Alzheimer's disease: From alpha-secretase activators to gamma-secretase inhibitors and modulators. Drugs Aging 2009;26:537555.
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    Raschetti R, Albanese E, Vanacore N et al. Cholinesterase inhibitors in mild cognitive impairment: A systematic review of randomised trials. PLoS Med 2007;4:e338.
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    Lu PH, Edland SD, Teng E et al. on behalf of the Alzheimer's Disease Cooperative Study Group. Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology 2009;72:21152121.
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    Panza F, D'Introno A, Colacicco AM et al. Late-life depression, mild cognitive impairment, and dementia: A possible continuum? Am J Geriatr Psychiatry; DOI: DOI: 10.1097/JGP.0b013e3181b0fa13.
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    Solfrizzi V, D'Introno AItalian Longitudinal Study on Aging Working Group. et al. Incident occurrence of depressive symptoms among patients with mild cognitive impairment. The Italian Longitudinal Study on Aging. Dement Geriatr Cogn Disord 2007;24:5564.
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    Panza F, Capurso C, D'Introno A et al., for the Italian Longitudinal Study on Aging Working Group. Impact of depressive symptoms on the rate of progression to dementia in patients affected by mild cognitive impairment. The Italian Longitudinal Study on Aging. Int J Geriatr Psychiatry 2008;23:726734.
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    Panza F, D'Introno A, Colacicco AM et al., for the Italian Longitudinal Study on Aging Working Group. Depressive symptoms, vascular risk factors, and mild cognitive impairment. The Italian Longitudinal Study on Aging. Dement Geriatr Cogn Disord 2008;25:336346.
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    Petersen RC, Thomas RG, Grundman M et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:23792388.
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    Butters MA, Young JB, Lopez O et al. Pathways linking late-life depression to persistent cognitive impairment and dementia. Dialogues Clin Neurosci 2008;10:345357.
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    Panza F, D'Introno A, Colacicco AM et al. Temporal relationship between depressive symptoms and cognitive impairment: The Italian Longitudinal Study on Aging. J Alzheimers Dis 2009 Jun 19. [Epub ahead of print].