. Rates of decline in Alzheimer disease decrease with age. PLoS One. 2012;7(8):e42325. PubMed.

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  1. The paper by Dominic Holland et al. reporting that AD-associated decline slows with advancing age is interesting. Although no autopsy confirmation was available in this study, these data agree with neuropathologic studies in the oldest-old (Haroutunian et al., 2008).

    However, there are some limitations of this study, which only in part have been mentioned by the authors:

    1. The importance of confounding pathologies, in particular, cerebrovascular lesions including the importance of CAA (the authors only mentioned microvascular pathology), Lewy body pathology, argyrophilic grain disease, hippocampal atrophy, etc., which are frequent in aged human brains (see "mixed dementia," e.g., Kovacs et al., 2008; Jellinger and Attems, 2011). It should be emphasized that up to two-thirds of aged human brains contain non-AD type pathologies (Nelson et al., 2007, and others).

    2. A high percentage of demented persons aged 80+ do not meet the morphological criteria of AD and are classified "dementia of unknown etiology" (Crystal et al., 1988; Jellinger, 2001; Corrada et al., 2012), which cannot be detected without morphological verification.

    In general, density and pattern of neurofibrillary tangles (NFTs) show significant correlations with the severity of cognitive decline across old age including 90+ patients, at least in those without other pathologies superimposed (Nelson et al., 2007; Nelson et al., 2010; Nelson et al., 2012).

    It should further be considered that there are several morphological subtypes of AD, which differ in age, duration, and dementia severity (Murray et al., 2011; Jellinger, 2012).

    All together, these and other data indicate that clinical detection of AD and its distinction from normal (and "pathological") aging—the latter featured by generalized Aβ deposition with only little tau pathology limited to the limbic areas—are more difficult in the oldest old, as stated by the authors.

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    . Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology. 1988 Nov;38(11):1682-7. PubMed.

    . Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol. 2008 Sep;65(9):1211-7. PubMed.

    . Frequency of "dementia of unknown etiology" increases with age. Arch Neurol. 2001 Sep;58(9):1498-9. PubMed.

    . Neuropathological subtypes of Alzheimer's disease. Acta Neuropathol. 2012 Jan;123(1):153-4. PubMed.

    . Prevalence and pathology of dementia with Lewy bodies in the oldest old: a comparison with other dementing disorders. Dement Geriatr Cogn Disord. 2011;31(4):309-16. PubMed.

    . Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord. 2008;26(4):343-50. PubMed.

    . Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.

    . Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol. 2010 Jan;20(1):66-79. PubMed.

    . Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012 May;71(5):362-81. PubMed.

    . Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles "do count" when staging disease severity. J Neuropathol Exp Neurol. 2007 Dec;66(12):1136-46. PubMed.