Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study

Abstract

Background: Neurofibrillary pathology has a stereotypical progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme; however, some AD cases are atypical and do not fit into this scheme. We aimed to compare clinical and neuropathological features between typical and atypical AD cases.

Methods: AD cases with a Braak neurofibrillary tangle stage of more than IV were identified from a brain bank database. By use of thioflavin-S fluorescence microscopy, we assessed the density and the distribution of neurofibrillary tangles in three cortical regions and two hippocampal sectors. These data were used to construct an algorithm to classify AD cases into typical, hippocampal sparing, or limbic predominant. Classified cases were then compared for clinical, demographic, pathological, and genetic characteristics. An independent cohort of AD cases was assessed to validate findings from the initial cohort.

Findings: 889 cases of AD, 398 men and 491 women with age at death of 37-103 years, were classified with the algorithm as hippocampal sparing (97 cases [11%]), typical (665 [75%]), or limbic predominant (127 [14%]). By comparison with typical AD, neurofibrillary tangle counts per 0.125 mm(2) in hippocampal sparing cases were higher in cortical areas (median 13, IQR 11-16) and lower in the hippocampus (7.5, 5.2-9.5), whereas counts in limbic-predominant cases were lower in cortical areas (4.3, 3.0-5.7) and higher in the hippocampus (27, 22-35). Hippocampal sparing cases had less hippocampal atrophy than did typical and limbic-predominant cases. Patients with hippocampal sparing AD were younger at death (mean 72 years [SD 10]) and a higher proportion of them were men (61 [63%]), whereas those with limbic-predominant AD were older (mean 86 years [SD 6]) and a higher proportion of them were women (87 [69%]). Microtubule-associated protein tau (MAPT) H1H1 genotype was more common in limbic-predominant AD (54 [70%]) than in hippocampal sparing AD (24 [46%]; p=0.011), but did not differ significantly between limbic-predominant and typical AD (204 [59%]; p=0.11). Apolipoprotein E (APOE) ɛ4 allele status differed between AD subtypes only when data were stratified by age at onset. Clinical presentation, age at onset, disease duration, and rate of cognitive decline differed between the AD subtypes. These findings were confirmed in a validation cohort of 113 patients with AD.

Interpretation: These data support the hypothesis that AD has distinct clinicopathological subtypes. Hippocampal sparing and limbic-predominant AD subtypes might account for about 25% of cases, and hence should be considered when designing clinical, genetic, biomarker, and treatment studies in patients with AD.

Funding: US National Institutes of Health via Mayo Alzheimer's Disease Research Center, Mayo Clinic Study on Aging, Florida Alzheimer's Disease Research Center, and Einstein Aging Study; and State of Florida Alzheimer's Disease Initiative.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Photomicrograph of thioflavin S fluorescent microscopic images of neurofibrillary tangles (A), used in the operational classification algorithm, and of senile plaques with dense core (B) or neuritic elements (C). Magnification bar = 20 μm.

Figure 2

This diagram demonstrates the classification system used by the algorithm (dotted lines) and the resultant sample size of each subtype (solid line). The ratio between the hippocampal and cortical NFT was used to determine the cases with relative sparing of the hippocampus or cortex, however, this would have only classified cases in the 25th and 75th quartiles. By using NFT median counts, regional pathology and over/underestimation of these regional differences could be used to further differentiate the groups. The resultant asymmetry in the sample population of AD subtypes is a product of the differences in each of the hippocampal (i.e. CA1 and subiculum) and cortical areas (i.e. superior temporal, inferior parietal, and mid-frontal) individually evaluated.

Figure 3

The CA1 and subiculum of the posterior hippocampus and three association cortices were sampled, stained with Thioflavin-S, and reviewed at x400 to obtain neurofibrillary tangle counts. An algorithm was developed to operationally define relative hippocampal sparing AD, typical AD, and limbic predominant AD. These cases were analyzed for differences in averaged hippocampal (A) and cortical NFT counts (B). The HpSp group had a higher cortical density than both typical and limbic predominant AD. Converesly, limbic predominant AD had higher hippocampal NFT compared to typical and HpSp AD.

Figure 4

Longitudinal progression of cognitive decline in hippocampal sparing (A), typical (B), and limbic predominant AD (C) differs greatly amongst the groups with regard to MMSE total score. Age of onset was stratified in each graph according to the discovery set's median age at disease onset [<70 years (red) and ≥70 years (blue)]. A moving average was plotted to illustrate overall longitudinal decline in MMSE for each of the three AD subtypes.