Neuropathological subtypes of Alzheimer’s disease

Murray et al. [9], among 889 cases of autopsy-verified Alzheimer’s disease (AD) recently compared clinical and neuropathological features between typical and atypical AD cases, thus separating distinct clinicopathological subtypes. Based on the density of neurofibrillary tangles (NFT) in various brain regions, using thioflavin-S fluorescence microscopy [11] but not immunohistochemistry as suggested more recently [3], cases were classified as hippocampal-sparing with lower NFT counts in hippocampus (11%), limbic-predominant forms with lower cortical NFT counts (14%), and typical AD forms (75%). In a smaller AD validation cohort (n = 113), 71% were typical AD, while limbic-predominant and hippocampal-sparing type showed different frequencies (21 and 8%, respectively). Hippocampal-sparing cases were younger at death and a higher proportion of them were men, whereas those with limbic-prominent AD were older and had a higher proportion of women. Additional vascular pathology ranging from 16 to 36% was highest in limbic-predominant and lowest in hippocampal-sparing cases, while Lewy body pathology (11–26%) was lowest in the hippocampal-sparing form, but did not differ between limbic-predominant and typical AD cases. Disease duration was similar, while final Mini-Mental score (MMS) was lowest in hippocampal-sparing form but did not differ from typical AD. Some major pathological data of this extensive study can be confirmed from a personal study in 933 autopsyconfirmed cases of AD (all with neurofibrillary tangle stage of more than Braak IV) from the brain bank of the Institute of Clinical Neurobiology, Vienna, Austria (1989–2008). All cases underwent standardized neuropathological assessment including immunohistochemistry for tau (using antibody AT-8—Innogenetics, Ghent, Belgium, and not Thioflavin-S fluorescence microscopy as by Murray et al. [9]), b-amyloid and a-synuclein (methods see [7]). Tangle distribution was assessed using Braak neurofibrillary tangle stage [2, 3]. The classification of the different subtypes of AD followed those by Murray et al. [9], however, without performing local NFT counts, but using detailed histological description of NFT distribution. Cerebrovascular disease was assessed with a simple scheme [5], and Lewy body pathology by immunohistochemistry, as previously described [6]. The age at onset, duration of disease, initial MMS score, essential clinical data, APOE genotype, and brain weight were not systematically assessed in our series; final MMS score was only assessed in a rather small percentage of patients (10.1–25.3%). The major results are summarized in Table 1. Typical AD in our cohort was more frequent than in the Mayo series (82.5 vs. 75%), while both hippocampal sparing (8.2%) and limbic-predominant including tangle-predominant cases [4, 8] were less frequent (8.9%), the latter being similar to its frequency in their smaller validation AD cohort [9]. As stated by Murray et al. [9], the limbic-predominant AD cases share several morphologic characteristics with the subtype of late onset dementia, referred to as tangle-predominant dementia (TDP, [4, 8]), in which NFTs are frequently limited to allocortical regions with rather few isocortical NFTs, similar to the limbicpredominant AD. The major difference between the two subtypes is the virtual absence of neuritic plaques in TPD [8], whereas in the Mayo cohort the senile plaques (detected by thioflavin-S-fluorescence, non-differentiating the plaque types) showed little differences in their density K. A. Jellinger (&) Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria e-mail: kurt.jellinger@univie.ac.at