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SAGE KE Bulletin Board

MCI: Earliest clinical manifestation of Alzheimer’s disease or a heterogeneous group of diseases?

30 January 2006

Dietmar R. Thal

Comment on Markesbery et al. “Neuropathologic substrate of mild cognitive impairment�? Arch Neurol (2006) 38-46

Markesbery and colleagues studied 10 clinically well-characterized individuals who died in the state of mild cognitive impairment (MCI) neuropathologically. They compared tangle and neuritic plaque pathology with cases of definite early Alzheimer’s disease (AD) and controls. Controls were non-demented elderly cases showing a maximum AD-related pathology of Braak-stage II. Thus, the authors have a selection bias in their control group because non-demented cases with higher Braak-stages were excluded from controls. The results presented show that the degree of AD-related pathology seen in MCI-cases represents an intermediate state between control and early AD. Therefore, the authors conclude that MCI appears to represent the first clinical manifestation of AD.

This conclusion will be correct for a high number of MCI cases exhibiting only AD-related pathology. Our analysis of two different large consecutive autopsy samples of a) 106 (Thal et al., 2000) and b) 204 cases (Thal et al., 2005) confirmed that cases with MCI (= CDR-score 0.5) showed lower Braak stages than definite AD-cases but higher Braak-stages than controls. In our large sample all non-demented cases were accepted to be controls. Thus, the use of a biased control group in the Markesbery study did not lead to a wrong conclusion when reviewing our own data. In addition to the neuropathological analysis of neurofibrillary lesions such as tangles and neuritic plaques, we also studied the expansion of amyloid ß-protein (Aß) plaques. We found that the expansion of Aß-plaques is not different from AD cases but strikingly larger than in non-demented cases. Thus, our results (Thal et al., 2000; Thal et al., 2005) as well as those of other authors (Petersen et al., 2001) support the conclusion that MCI can be the first manifestation of AD. However, we found that in addition to AD argyrophilic grain disease (AGD) significantly contributed to the development of dementia including MCI (Thal et al., 2005). Similarly, cerebrovascular lesions (CVL) can also contribute to the development of MCI and dementia (Esiri et al., 1999). The study by Markesberry et al. (Markesbery et al., 2006) does not contradict these findings since they reported 3/10 MCI and 2/10 AD cases to exhibit AGD and 7/10 MCI and 9/10 AD cases to show CVL.

In summary, MCI can represent the first clinical manifestation of AD but often also represents the first manifestation of a mixed form of dementia with AGD and CVL contributing significantly to the development of dementia.


Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 354:919-920.

Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38-46.

Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B (2001) Current concepts in mild cognitive impairment. Arch Neurol 58:1985-1992.

Thal DR, Holzer M, Rüb U, Waldmann G, Gunzel S, Zedlick D, Schober R (2000) Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp Neurol 163:98-110.

Thal DR, Schultz C, Botez G, Del Tredici K, Mrak RE, Griffin WS, Wiestler OD, Braak H, Ghebremedhin E (2005) The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology. Neuropathol Appl Neurobiol 31:270- 279.

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