Neuropathologically defined subtypes of Alzheimer's disease differ significantly from neurofibrillary tangle-predominant dementia

Abstract

Alzheimer's disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.

Fig. 1

Neurofibrillary tangle-predominant dementia (NFTD) was objectively diagnosed with a mathematical algorithm that used hippocampal and cortical NFT and SP counts in cases with a gestalt diagnosis of NFTD to set standards. A flowchart of the algorithm illustrates inclusion and exclusion criteria

Fig. 2

Four scatter plots of thioflavin-S hippocampal neurofibrillary tangle (NFT) density are plotted against cortical NFT density. The four plots show minimal overlap between groups, with no interrelationships between hippocampal and cortical NFT for hippocampal-sparing AD (HpSp, red down triangle) or neurofibrillary tangle-predominant dementia (NFTD, yellow square). Significant interrelationships were found for both typical AD (black circle) and limbic-predominant AD (LP, cyan up triangle). The scatter plots were separated based on a MAPT H1H1 carriers and b non-carriers

Fig. 3

CP13 immunohistochemistry detecting early neuritic and tangle pathology in the middle frontal cortex of a hippocampal-sparing Alzheimer’s disease (HpSp AD) reveals both neurofibrillary tangles (NFT, arrow) and extensive neuritic pathology (arrowhead) compared to e typical AD, which shows fewer NFT and neurites, i but not as scarce as that seen in limbic-predominant (LP) AD. m Neurofibrillary tangle-predominant dementia (NFTD) has no NFT and only rare tau-positive neurites. NFT immunohistochemistry using a conformational epitope (Ab39) reveals b frequent mature and extracellular NFT (arrows), as well as neuritic elements (arrowhead) in HpSp and f to a lesser extent in typical AD. j Ab39 staining in LP AD showed rare extracellular NFT and neuritic pathology, n while none were observed in NFTD. c, g, k Amyloid immunohistochemistry using a pan-Aβ marker reveals a range of plaques across groups, but differences in total β-amyloid burden. c Compact plaques can be found in HpSp AD (inset; top and bottom, respectively), but many lightly staining plaques (arrow) are more common. d Aβ40 was found to correspond with some of these plaques, suggesting that the lightly stained plaques were not all “diffuse plaques”, commonly found in aging brains. g Typical AD often had a higher amyloid burden than HpSp and tended to have a wider range of plaque morphology (inset) that could be found to be h Aβ40 positive (g arrow, h arrowhead). k Limbic-predominant cases had the highest plaque burden with stereotypic compact and cored plaques (inset; top and bottom, respectively), but more often had amorphous plaques that were immunopositive for l Aβ40. o, p Neither amyloid stain revealed notable positive structures in NFTD. Scale bars 100 μm (d, h, l, p)

Fig. 4

Box plots of immunohistochemical burden measured using digital microscopy are plotted for hippocampal-sparing Alzheimer’s disease (HpSp AD), typical AD, limbic-predominant (LP) AD, and neurofibrillary tangle-predominant dementia (NFTD). a The phospho-tau burden (CP13) was twofold higher in HpSp AD compared to typical AD and sixfold higher than LP AD. b The conformational-epitope burden (Ab39) was 4-fold higher in HpSp AD compared to typical AD and 19-fold higher than LP AD. Box plots show median (interquartile ratio) and error bars represent the 10–90th percentile