Copyright: © 2012 de Mendonça. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.Alzheimer’s disease (AD) is a neurodegenerative disorder with insidious onset and progressive course, which prevalence increases with the age. It is characterized by neuronal degeneration and death, related to the deposition in the brain of the amyloid β1–42 peptide and the hyperphosphorylated tau protein, and initially affects brain areas, namely the hippocampus and other medial temporal lobe structures, which are important for memory processes (Blennow et al., 2006). As a consequence of the aging of the population, the number of patients with AD and other dementias, as well as the number of elderly people who, although not demented, suffer from significant cognitive decline, is growing worrisomely (Alzheimer’s Disease International, 2009).info:eu-repo/semantics/publishedVersio

de Mendonça, Alexandre

English

PubMed

Alexandre de Mendonça

Frontiers - Publisher Connector

Alzheimer’s disease (AD) is a neurode-
generative disorder with insidious onset 
and progressive course, which prevalence 
increases with the age. It is characterized by 
neuronal degeneration and death, related to 
the deposition in the brain of the amyloid 
β
1–42
 peptide and the hyperphosphoryl-
ated tau protein, and initially affects brain 
areas, namely the hippocampus and other 
medial temporal lobe structures, which are 
important for memory processes (Blennow 
et al., 2006). As a consequence of the aging 
of the population, the number of patients 
with AD and other dementias, as well as the 
number of elderly people who, although 
not demented, suffer from significant 
cognitive decline, is growing worrisomely 
(Alzheimer’s Disease International, 2009).
Alzheimer’s disease is the most frequent 
cause for dementia. Indeed, the presence 
of dementia is presently required for the 
diagnosis of AD according to established 
diagnostic criteria, like the International 
Classification of Diseases (World Health 
Organization, 1992), Diagnostic and 
Statistical Manual of Mental Disorders 
(American Psychiatric Association, 1994), or 
those proposed by the National Institute of 
Neurological and Communicative Disorders 
and Stroke (McKhann et al., 1984), that is to 
say, the patient must have deficits in memory 
and other cognitive domains, representing 
a decline in relation to a previous level, and 
interfering significantly with the social and 
professional life.
However, AD begins insidiously, usually 
with memory difficulties, many years before 
the patient has a cognitive and functional 
decline compatible with the diagnosis of 
dementia. Furthermore, it is often difficult 
to appreciate the memory complaints in the 
initial phase of AD, because healthy people 
frequently report an unfavorable opinion 
about their own memory, and there is a slight 
decline in objective memory performance in 
the aging process (Mendes et al., 2008).
Several nosologic concepts were 
 proposed, in the last decades, to describe 
the patients who have cognitive deficits 
but are not demented. Of these, the one 
that became more popular was mild cog-
nitive impairment (MCI), as established 
by Petersen et al. (1999), and subsequently 
refined (Portet et al., 2006).
Certainly, clinicians interested in mem-
ory disorders have been in the last few years 
consulting younger patients and patients 
with more subtle complaints. The nosologic 
concept of MCI has been very useful to 
establish the probability of progression to 
dementia and promote an adequate follow-
up in these patients. However, the concept 
of MCI has important limitations. First of 
all, it represents a stage of cognitive decline 
between normality and dementia, rather 
than a disease (Gauthier et al., 2006). In 
second place, some patients with MCI are 
intriguingly stable and do not progress to 
dementia after many years (Petersen et al., 
2001). In third place, some patients with 
cognitive complaints who have no altera-
tions in the neuropsychological testing, and 
thus do not fulfill MCI criteria, do never-
theless progress to dementia (Nunes et al., 
2010). We must thus recognize that the con-
cept of MCI is unsatisfactory both from a 
diagnostic and prognostic point of view.
However, and very importantly, the stud-
ies performed in patients with the diagno-
sis of MCI allowed a better understanding 
of the initial phases of AD, and lead to the 
proposal of new AD criteria that can diag-
nose the disease at initial stages, before the 
patient is demented (Dubois et al., 2007; 
Albert et al., 2011). These criteria are still 
considered mainly appropriate for clinical 
research, but their use is certainly spread-
ing to specialized practice. The new criteria 
are based on the identification of patho-
logical alterations in the brain typical of 
AD, or biomarkers, namely: (1) decline in 
episodic memory, confirmed by neuropsy-
chological testing, (2) atrophy of the hip-
pocampus and other medial temporal lobe 
structures shown by magnetic resonance 
imaging using volumetric techniques, (3) 
detection of abnormal CSF biomarkers, 
namely low amyloid β1–42  concentrations, 
increased total tau concentrations, or 
increased  phosphorylated tau concentra-
tions, (4) reduced glucose metabolism in 
bilateral temporal parietal regions by posi-
tron emission tomography. In familial cases, 
the finding of a causative mutation in the 
genes responsible for autosomal dominant 
forms of the disease may establish the defi-
nite diagnosis of AD. Other genetic and 
biochemical biomarkers, as well as neu-
roimaging using radioligand compounds 
with affinity for the amyloid β
1–42
 peptide, 
are presently being developed.
We still do not know the combination 
of biomarkers most sensitive and specific 
for the early diagnosis of AD. Large mul-
ticentric studies are being conducted to 
answer this important question, but so far 
the follow-up times have been generally 
limited. In the large Alzheimer’s Disease 
Neuroimaging Initiative (ADNI) cohort, 
the use of neuropsychological, brain imag-
ing, and CSF neurochemical biomarkers 
could only reach a predictive accuracy for 
MCI conversion to dementia of 64% (Ewers 
et al., 2010). This is not surprising, since 
the average follow-up was 2.3 years, and 
presumably many converters just had not 
the time to progress to dementia. Longer 
follow-up times will decisively be needed to 
find the best combination of biomarkers for 
an accurate early diagnosis of AD.
In conclusion, the reliable identification 
of patients with memory complaints who 
already have Alzheimer’s disease opens new 
frontiers in the management of the disease, 
since it will allow these patients to undergo 
interventions that might involve manipula-
tion of risk and protection environmental 
factors, cognitive rehabilitation procedures, 
and clinical trials with putative neuropro-
tective drugs.
RefeRences
Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., 
Feldman, H. H., Fox, N. C., Gamst, A., Holtzman, 
D. M., Jagust, W. J., Petersen, R. C., Snyder, P. J., 
Carrillo, M. C., Thies, B., and Phelps, C. H. (2011). 
The diagnosis of mild cognitive impairment due 
to Alzheimer’s disease: recommendations from the 
Rethinking Alzheimer’s disease
Alexandre de Mendonça*
Laboratory of Neurosciences, Faculty of Medicine of Lisbon, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
*Correspondence: mendonca@fm.ul.pt
www.frontiersin.org March 2012 | Volume 3 | Article 45 | 1
OpiniOn Article
published: 27 March 2012
doi: 10.3389/fneur.2012.00045
National Institute on Aging-Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s 
disease. Alzheimers Dement. 7, 270–279.
Alzheimer’s Disease International. (2009). World 
Alzheimer Report. London: Alzheimer’s Disease 
International.
American Psychiatric Association. (1994). Diagnostic 
and Statistical Manual of Mental Disorders, 4th Edn. 
Washington, DC: American Psychiatric Association.
Blennow, K., de Leon, M. J., and Zetterberg, H. (2006). 
Alzheimer’s disease. Lancet 368, 387–403.
Dubois, B., Feldman, H. H., Jacova, C., Dekosky, S. T., 
Barberger-Gateau, P., Cummings, J., Delacourte, 
A., Galasko, D., Gauthier, S., Jicha, G., Meguro, 
K., O’Brien, J., Pasquier, F., Robert, P., Rossor, M., 
Salloway, S., Stern, Y., Visser, P. J., and Scheltens, 
P. (2007). Research criteria for the diagnosis of 
Alzheimer’s disease: revising the NINCDS-ADRDA 
criteria. Lancet Neurol. 6, 734–746.
Ewers, M., Walsh, C., Trojanowski, J. Q., Shaw, L. M., 
Petersen, R. C., Jack, C. R. Jr., Feldman, H. H., Bokde, 
A. L., Alexander, G. E., Scheltens, P., Vellas, B., Dubois, 
B., Weiner, M., Hampel, H., and North American 
Alzheimer’s Disease Neuroimaging Initiative (ADNI). 
(2010). Prediction of conversion from mild cognitive 
impairment to Alzheimer’s disease dementia based 
upon biomarkers and neuropsychological test per-
formance. Neurobiol. Aging. doi:10.1016/j.neurobio-
laging.2010.10.019. [Epub ahead of print].
Gauthier, S., Reisberg, B., Zaudig, M., Petersen, R. 
C., Ritchie, K., Broich, K., Belleville, S., Brodaty, 
H., Bennett, D., Chertkow, H., Cummings, J. L., 
de Leon, M., Feldman, H., Ganguli, M., Hampel, 
H., Scheltens, P., Tierney, M. C., Whitehouse, P., 
Winblad, B., and International Psychogeriatric 
Association Expert Conference on Mild Cognitive 
Impairment. (2006). Mild cognitive impairment. 
Lancet 367, 1262–1270.
McKhann, G., Drachman, D., Folstein, M., Katzman, R., 
Price, D., and Stadlan, E. M. (1984). Clinical diagnosis 
of Alzheimer’s disease: report of the NINCDS ADRDA 
Work Group. Neurology 34, 939–944.
Mendes, T., Ginó, S., Ribeiro, F., Guerreiro, M., de Sousa, 
G., Ritchie, K., and de Mendonça, A. (2008). Memory 
complaints in healthy young and elderly adults: reli-
ability of memory reporting. Aging Ment. Health 12, 
177–182.
Nunes, T., Fragata, I., Ribeiro, F., Palma, T., Maroco, 
J., Cannas, J., Secca, M., Menezes, C., Carmo, I., 
Cunha, G., Castelo Branco, M., Guerreiro, M., and 
de Mendonça, A. (2010). The outcome of elderly 
patients with cognitive complaints but normal neu-
ropsychological tests. J. Alzheimers Dis. 19, 137–145.
Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., 
Morris, J. C., Rabins, P. V., Ritchie, K., Rossor, M., 
Thal, L., and Winblad, B. (2001). Current concepts 
in mild cognitive impairment. Arch. Neurol. 58, 
1985–1992.
Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., 
Tangalos, E. G., and Kokmen, E. (1999). Mild cognitive 
impairment. Arch. Neurol. 56, 303–308.
Portet, F., Ousset, P. J., Visser, P. J., Frisoni, G. B., Nobili, F., 
Scheltens, P., Vellas, B., Touchon, J., and MCI Working 
Group of the European Consortium on Alzheimer’s 
Disease (EADC). (2006). Mild cognitive impairment 
(MCI) in medical practice: a critical review of the 
concept and new diagnostic procedures. Report of the 
MCI Working Group of the European Consortium 
on Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatr. 
77, 714–718.
World Health Organization. (1992). The ICD-10 
Classification of Mental and Behavioural Disorders. 
Geneva: World Health Organization.
Received: 19 February 2012; accepted: 09 March 2012; 
published online: 27 March 2012.
Citation: de Mendonça A (2012) Rethinking Alzheimer’s 
disease. 3:45. doi: 10.3389/fneur.2012.00045
This article was submitted to Frontiers in Dementia, a 
specialty of Frontiers in Neurology.
Copyright © 2012 de Mendonça. This is an open-access 
article distributed under the terms of the Creative Commons 
Attribution Non Commercial License, which permits non-
commercial use, distribution, and reproduction in other 
forums, provided the original authors and source are 
credited.
Frontiers in Neurology | Dementia  March 2012 | Volume 3 | Article 45 | 2
de Mendonça Rethinking Alzheimer’s disease


Rethinking Alzheimer’s Disease

Crossref

Frontiers in Neurology

De Mendonça, Alexandre

Universidade de Lisboa: Repositório.UL

Alzheimer’s disease (AD) is a neurode-generative disorder with insidious onset and progressive course, which prevalence increases with the age. It is characterized by neuronal degeneration and death, related to the deposition in the brain of the amyloid β1–42 peptide and the hyperphosphoryl-ated tau protein, and initially affects brain areas, namely the hippocampus and other medial temporal lobe structures, which are important for memory processes (Blennow et al., 2006). As a consequence of the aging of the population, the number of patients with AD and other dementias, as well as the number of elderly people who, although not demented, suffer from significant cognitive decline, is growing worrisomely (Alzheimer’s Disease International, 2009).Alzheimer’s disease is the most frequent cause for dementia. Indeed, the presence of dementia is presently required for the diagnosis of AD according to established diagnostic criteria, like the International Classification of Diseases (World Health Organization, 1992), Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994), or those proposed by the National Institute of Neurological and Communicative Disorders and Stroke (McKhann et al., 1984), that is to say, the patient must have deficits in memory and other cognitive domains, representing a decline in relation to a previous level, and interfering significantly with the social and professional life.However, AD begins insidiously, usually with memory difficulties, many years before the patient has a cognitive and functional decline compatible with the diagnosis of dementia. Furthermore, it is often difficult to appreciate the memory complaints in the initial phase of AD, because healthy people frequently report an unfavorable opinion about their own memory, and there is a slight decline in objective memory performance in the aging process (Mendes et al., 2008).Several nosologic concepts were  proposed, in the last decades, to describe the patients who have cognitive deficits but are not demented. Of these, the one that became more popular was mild cog-nitive impairment (MCI), as established by Petersen et al. (1999), and subsequently refined (Portet et al., 2006).Certainly, clinicians interested in mem-ory disorders have been in the last few years consulting younger patients and patients with more subtle complaints. The nosologic concept of MCI has been very useful to establish the probability of progression to dementia and promote an adequate follow-up in these patients. However, the concept of MCI has important limitations. First of all, it represents a stage of cognitive decline between normality and dementia, rather than a disease (Gauthier et al., 2006). In second place, some patients with MCI are intriguingly stable and do not progress to dementia after many years (Petersen et al., 2001). In third place, some patients with cognitive complaints who have no altera-tions in the neuropsychological testing, and thus do not fulfill MCI criteria, do never-theless progress to dementia (Nunes et al., 2010). We must thus recognize that the con-cept of MCI is unsatisfactory both from a diagnostic and prognostic point of view.However, and very importantly, the stud-ies performed in patients with the diagno-sis of MCI allowed a better understanding of the initial phases of AD, and lead to the proposal of new AD criteria that can diag-nose the disease at initial stages, before the patient is demented (Dubois et al., 2007; Albert et al., 2011). These criteria are still considered mainly appropriate for clinical research, but their use is certainly spread-ing to specialized practice. The new criteria are based on the identification of patho-logical alterations in the brain typical of AD, or biomarkers, namely: (1) decline in episodic memory, confirmed by neuropsy-chological testing, (2) atrophy of the hip-pocampus and other medial temporal lobe structures shown by magnetic resonance imaging using volumetric techniques, (3) detection of abnormal CSF biomarkers, namely low amyloid β1–42  concentrations, increased total tau concentrations, or increased  phosphorylated tau concentra-tions, (4) reduced glucose metabolism in bilateral temporal parietal regions by posi-tron emission tomography. In familial cases, the finding of a causative mutation in the genes responsible for autosomal dominant forms of the disease may establish the defi-nite diagnosis of AD. Other genetic and biochemical biomarkers, as well as neu-roimaging using radioligand compounds with affinity for the amyloid β1–42 peptide, are presently being developed.We still do not know the combination of biomarkers most sensitive and specific for the early diagnosis of AD. Large mul-ticentric studies are being conducted to answer this important question, but so far the follow-up times have been generally limited. In the large Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, the use of neuropsychological, brain imag-ing, and CSF neurochemical biomarkers could only reach a predictive accuracy for MCI conversion to dementia of 64% (Ewers et al., 2010). This is not surprising, since the average follow-up was 2.3 years, and presumably many converters just had not the time to progress to dementia. Longer follow-up times will decisively be needed to find the best combination of biomarkers for an accurate early diagnosis of AD.In conclusion, the reliable identification of patients with memory complaints who already have Alzheimer’s disease opens new frontiers in the management of the disease, since it will allow these patients to undergo interventions that might involve manipula-tion of risk and protection environmental factors, cognitive rehabilitation procedures, and clinical trials with putative neuropro-tective drugs.RefeRencesAlbert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., Gamst, A., Holtzman, D. M., Jagust, W. J., Petersen, R. C., Snyder, P. J., Carrillo, M. C., Thies, B., and Phelps, C. H. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the Rethinking Alzheimer’s diseaseAlexandre de Mendonça*Laboratory of Neurosciences, Faculty of Medicine of Lisbon, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal*Correspondence: mendonca@fm.ul.ptwww.frontiersin.org March 2012 | Volume 3 | Article 45 | 1OpiniOn Articlepublished: 27 March 2012doi: 10.3389/fneur.2012.00045National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 270–279.Alzheimer’s Disease International. (2009). World Alzheimer Report. London: Alzheimer’s Disease International.American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th Edn. Washington, DC: American Psychiatric Association.Blennow, K., de Leon, M. J., and Zetterberg, H. (2006). Alzheimer’s disease. Lancet 368, 387–403.Dubois, B., Feldman, H. H., Jacova, C., Dekosky, S. T., Barberger-Gateau, P., Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G., Meguro, K., O’Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway, S., Stern, Y., Visser, P. J., and Scheltens, P. (2007). Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734–746.Ewers, M., Walsh, C., Trojanowski, J. Q., Shaw, L. M., Petersen, R. C., Jack, C. R. Jr., Feldman, H. H., Bokde, A. L., Alexander, G. E., Scheltens, P., Vellas, B., Dubois, B., Weiner, M., Hampel, H., and North American Alzheimer’s Disease Neuroimaging Initiative (ADNI). (2010). Prediction of conversion from mild cognitive impairment to Alzheimer’s disease dementia based upon biomarkers and neuropsychological test per-formance. Neurobiol. Aging. doi:10.1016/j.neurobio-laging.2010.10.019. [Epub ahead of print].Gauthier, S., Reisberg, B., Zaudig, M., Petersen, R. C., Ritchie, K., Broich, K., Belleville, S., Brodaty, H., Bennett, D., Chertkow, H., Cummings, J. L., de Leon, M., Feldman, H., Ganguli, M., Hampel, H., Scheltens, P., Tierney, M. C., Whitehouse, P., Winblad, B., and International Psychogeriatric Association Expert Conference on Mild Cognitive Impairment. (2006). Mild cognitive impairment. Lancet 367, 1262–1270.McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., and Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease: report of the NINCDS ADRDA Work Group. Neurology 34, 939–944.Mendes, T., Ginó, S., Ribeiro, F., Guerreiro, M., de Sousa, G., Ritchie, K., and de Mendonça, A. (2008). Memory complaints in healthy young and elderly adults: reli-ability of memory reporting. Aging Ment. Health 12, 177–182.Nunes, T., Fragata, I., Ribeiro, F., Palma, T., Maroco, J., Cannas, J., Secca, M., Menezes, C., Carmo, I., Cunha, G., Castelo Branco, M., Guerreiro, M., and de Mendonça, A. (2010). The outcome of elderly patients with cognitive complaints but normal neu-ropsychological tests. J. Alzheimers Dis. 19, 137–145.Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., Morris, J. C., Rabins, P. V., Ritchie, K., Rossor, M., Thal, L., and Winblad, B. (2001). Current concepts in mild cognitive impairment. Arch. Neurol. 58, 1985–1992.Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., and Kokmen, E. (1999). Mild cognitive impairment. Arch. Neurol. 56, 303–308.Portet, F., Ousset, P. J., Visser, P. J., Frisoni, G. B., Nobili, F., Scheltens, P., Vellas, B., Touchon, J., and MCI Working Group of the European Consortium on Alzheimer’s Disease (EADC). (2006). Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedures. Report of the MCI Working Group of the European Consortium on Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatr. 77, 714–718.World Health Organization. (1992). The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: World Health Organization.Received: 19 February 2012; accepted: 09 March 2012; published online: 27 March 2012.Citation: de Mendonça A (2012) Rethinking Alzheimer’s disease. 3:45. doi: 10.3389/fneur.2012.00045This article was submitted to Frontiers in Dementia, a specialty of Frontiers in Neurology.Copyright © 2012 de Mendonça. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.Frontiers in Neurology | Dementia  March 2012 | Volume 3 | Article 45 | 2de Mendonça Rethinking Alzheimer’s disease

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