Fig. 7.

Some prevalent brain pathologies in older individuals do not map well onto the preliminary Preclinical Alzheimer’s disease Workgroup (PADW) recommendations. Brains with medial temporal lobe neurofibrillary tangles (NFTs) but no amyloid plaques in the cortex, which we refer to as stage 0-N, comprise over 10% of preclinical Alzheimer’s disease (pAD) cases (A and B). This brain from a 78-year-old male (final Mini Mental State Examination [MMSE] score = 29) showed moderate densities of NFTs in the hippocampal formation and entorhinal cortex (A, stained with Gallyas stain) but there was no Aβ-positive plaques detected (B), in contrast to what is seen in Alzheimer’s disease (AD) brains using the same stain (C, at same magnification). Whereas stage 0-N was seen in 13/126 cognitively intact individuals, we found only a single case with hippocampal sclerosis in nondemented individuals, so this form of non-AD hippocampal atrophy appears more relevant to mild cognitive impairment and demented states. (D) An hematoxylin and eosin stained brain from an 88-year-old female with Clinical Dementia Rating (CDR) = 1 and clinical diagnosis of presumed early AD. The hippocampus appears shrunken, especially the subiculum (arrow). Immunohistochemical stain for TDP-43 (E; nuclei counterstained with hematoxylin) showed aberrant pattern of staining with cytoplasmic TDP-43 inclusions (arrows). Scale bars: (A and E) 25 µm, (B and C) 100 µm; (D) 2 mm.