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Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study
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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.
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“clinical features lack specificity for a pathologic process, but rather indicate brain regions or systems affected by the disease process [3, 4].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [3]
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“Three major subtypes of AD can be classified by the relative density of hippocampal neurofibrillary tangles with respect to neocortical tangles [3].”
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“Genetic analyses of APOE suggest APOE4 is more closely linked to typical or limbic predominant than hippocampal sparing AD [3].”
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“Nonamnestic clinical presentations, that is, language, visuospatial, and executive disorders, may also be due to AD [63–66].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [65]
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“Another challenge of CPC studies is that the molecular, anatomic, and clinical changes of AD may not progress in a uniform fashion (7, 12-15).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [12]
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“and that not all AD cases fall within the same spatial continuum with regard to brain NFT distributions (12, 15, 151).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [12]
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“Nevertheless, Braak staging also masks the fact that marked variability in pathologic lesion density across cases exists within a given Braak stage (7, 12)”
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Metadata
- Authors
- Murray, M. E., Graff-Radford, N. R., Ross, O. A., Petersen, R. C., Duara, R., & Dickson, D. W.
- Affiliations
- Mayo Clinic (US)
- Mount Sinai Medical Center (US)
- Corresponding author
- Dickson, Dennis W
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 10
- Issue
- 9
- Pages
- 785-796
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC3175379
- OpenAlex
- W2075444764
- Cited by
- 972
- References
- 44
- Citations by year
- 2026: 60 · 2025: 80 · 2024: 78 · 2023: 96 · 2022: 80 · 2021: 104 · 2020: 70 · 2019: 73 · 2018: 56 · 2017: 50 · 2016: 55 · 2015: 37 · 2014: 36 · 2013: 54 · 2012: 35
- FWCI
- 29.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Mayo Clinic
- National Institutes of Health
- National Institute on Aging (P50‐AG16574, U01AG06786, P50 AG215711, P01AG03949, U01AG006786, P01AG003949, R21AG038736, P50AG025711, P01AG017216, P50AG016574)
- National Institute of Neurological Disorders and Stroke (P50NS072187)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neurofibrillary tangles, Braak staging, hippocampal sparing, hippocampal atrophy, tau pathology, clinical features, atypical Alzheimer's disease, sex differences, age at death, genetic risk factors
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Hippocampus, Humans, Limbic System, Male, Middle Aged, Retrospective Studies, Cohort Studies, Neurofibrillary Tangles, tau Proteins, Apolipoprotein E4
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