Elsevier

The Lancet Neurology

Volume 10, Issue 9, September 2011, Pages 785-796
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(11)70156-9Get rights and content

Summary

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 mm2 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.

Introduction

Hippocampal atrophy rates have been used as a biomarker to track progression of Alzheimer's disease (AD) and to predict cognitive decline.1, 2, 3, 4, 5 However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy.6 These cases challenge existing concepts of disease progression, as encapsulated in the Braak and Braak staging scheme of neurofibrillary changes.7

Neurofibrillary tangles and senile plaques are the characteristic structural lesions assessed in neuropathological diagnosis of AD;8 although their spatial pattern is predictable,7, 9 variability can be found in neuroimaging and neuropathological studies.1, 2, 6, 10, 11, 12, 13 An early report evaluating interhemispheric asymmetry noted one case with sparing of the hippocampus relative to widespread cortical degeneration.6 In a later report, pathology was more severe in occipital-parietal cortices than in frontal and temporal cortices in a subset of AD cases presenting with posterior cortical atrophy.12 Typically, neurofibrillary degeneration in AD originates in the transentorhinal cortex and progresses through the hippocampus to eventually target the association cortices and finally the primary cortices; however, observations from the above mentioned studies,6, 7, 8, 9, 10, 11, 12 although small case series, suggest that this pattern of pathological progression might not be the only pattern of neurofibrillary degeneration.7

In a previous study from our laboratory, we noted a subset of AD cases, usually in patients with Lewy body disease, that had relative sparing of the hippocampus from neurofibrillary pathology compared with neocortical neurofibrillary pathology.14 The frequency and clinical significance of this subtype of AD has not been explored. By contrast with hippocampal sparing cases, we refer to cases of AD with severe and fairly restricted medial temporal neurofibrillary tangles15 as limbic-predominant AD. The frequency and clinical implications of atypical AD have been neglected in research on large series of autopsied samples. We aimed to develop an operational classification method to separate typical and atypical AD on the basis of counts of neurofibrillary tangles in the hippocampus and the cortex, and to establish the clinical, pathological, and genetic implications of the subtypes of AD in a large series of pathologically confirmed AD cases. To this end, we also studied: differences in neurofibrillary tangle and senile plaque densities in regions not used in the classification algorithm; structural differences in the hippocampus and entorhinal cortex; differences in clinical diagnosis and disease progression; and genetic differences with respect to microtubule-associated protein tau (MAPT), α-synuclein (SNCA), and apolipoprotein E (APOE). Finally, we studied the same factors in an independent validation cohort of patients with AD from a community-based prospective longitudinal study.

Section snippets

Study samples

We searched the brain bank database at the Mayo Clinic, Jacksonville (FL, USA) for AD cases with a Braak neurofibrillary tangle stage of more than IV, absence of hippocampal sclerosis, presence of data on neurofibrillary tangles with thioflavin-S fluorescence microscopy, and presence of paraffin blocks for further studies. These AD cases came from several referral sources: the State of Florida Alzheimer's Disease Initiative; the Memory Disorder Clinic and Movement Disorder Clinic at the Mayo

Results

889 patients, 398 men and 491 women, who died at an age of 37–103 years, were eligible for inclusion in the study. AD cases were mostly from two sources: the State of Florida Alzheimer's Disease Initiative (589 cases [66%]), and the Memory Disorder Clinic at Mayo Clinic, Jacksonville (155 [17%]). The remaining 145 cases were from a variety of referral sources: 21 (2%) from the Einstein Aging Study; 29 (3%) from the Society of Progressive Supranuclear Palsy; 22 (2%) from the Movement Disorder

Discussion

By use of an algorithm to classify AD subtypes on the basis of quantitative methods to measure neurofibrillary tangle burden in the hippocampus and the association cortices, we identified pathological, demographic, structural, genetic, and clinical differences between typical AD and atypical AD (hippocampal sparing and limbic predominant; panel). Compared with the other subtypes, hippocampal sparing cases were younger at death and a higher proportion of them were men. Hippocampal regions not

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