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 ) ε4 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.