The hippocampal sparing subtype of Alzheimer’s disease assessed in neuropathology and in vivo tau positron emission tomography: a systematic review

Abstract

Neuropathology and neuroimaging studies have identified several subtypes of Alzheimer’s disease (AD): hippocampal sparing AD, typical AD, and limbic predominant AD. An unresolved question is whether hippocampal sparing AD cases can present with neurofibrillary tangles (NFT) in association cortices while completely sparing the hippocampus. To address that question, we conducted a systematic review and performed original analyses on tau positron emission tomography (PET) data. We searched EMBASE, PubMed, and Web of Science databases until October 2022. We also implemented several methods for AD subtyping on tau PET to identify hippocampal sparing AD cases. Our findings show that seven out of the eight reviewed neuropathologic studies included cases at Braak stages IV or higher and therefore, could not identify hippocampal sparing cases with NFT completely sparing the hippocampus. In contrast, tau PET did identify AD participants with tracer retention in the association cortex while completely sparing the hippocampus. We conclude that tau PET can identify hippocampal sparing AD cases with NFT completely sparing the hippocampus. Based on the accumulating data, we suggest two possible pathways of tau spread: (1) a canonical pathway with early involvement of transentorhinal cortex and subsequent involvement of limbic regions and association cortices, and (2) a less common pathway that affects association cortices with limbic involvement observed at end stages of the disease or not at all.

The diagnostic and prognostic value of tau‐PET in amnestic MCI with different FDG‐PET subtypes

“…This finding is consistent with MRI studies in AD dementia patients which identified a malignant subtype characterized by great atrophy in the associative cortices and the worst cognitive progression 3,5,27 and with our previous FDG‐PET study, showing a comparable hippocampal sparing subtype with high positivity of AD‐CSF biomarkers and the highest level of cognitive decline and progression to AD dementia (73%) 12 . Contrary to the clinical comparability of our subtypes, previous studies reported more commonly atypical AD non‐amnestic presentations such as posterior cortical atrophy (PCA), logopenic primary progressive aphasia (LPPA), and the frontal variant of AD in hippocampal‐sparing than in typical and limbic‐predominant AD 28,29 that can possibly explain the faster longitudinal cognitive decline in this subtype. Moreover, dysexecutive AD has been recently clinically described initially presenting as a progressive and predominant degradation of core executive functions in the absence of prominent behavioral features and, from the imaging side, patients usually report hypometabolism and tau deposition in posterior parietal cortices and variably in the frontal cortices with the MTL sparing in most patients 30,31 …”

Multi-pathological contributions toward atrophy patterns in the Alzheimer’s disease continuum

“…This finding suggests that the relationship between atrophy-based typicality and severity in the AD continuum was driven by the later stages of the disease (AD dementia) aligning toward diffuse or limbic predominant atrophy patterns and pre-dementia cases aligning toward hippocampal sparing or minimal atrophy patterns. This finding is akin to the report suggesting that hippocampal sparing pattern in tau pathology may occur at earlier disease stages ( Ferreira et al, 2022 ). Thus, the current study highlights that typicality and severity can be related when characterizing subtypes or patterns of atrophy in individuals across disease stages.…”

The Adult Neurogenesis Theory of Alzheimer’s Disease

“…Interestingly, recent in vivo tau-PET imaging studies in AD have revealed substantial heterogeneity in tau deposition patterns with significant deviations from Braak's scheme [334,341,342]. These findings are in line with the four subtypes previously identified from neuropathology and neuroimaging studies based on the distribution of NFTs and patterns of brain atrophy, respectively: hippocampal-sparing AD, limbic-predominant AD, typical AD, and minimal atrophy AD [343][344][345][346][347][348][349][350][351][352][353][354]. In addition, some studies confirmed atypical patterns of tau deposition with elevated tau-PET signal in the occipital and parietal cortex [355], left temporo-parietal areas (logopenic) [356] and, similarly, perirolandic areas (corticobasal syndrome due to AD) [357,358] reflecting the clinical variants most frequently associated with EOAD [359,360].…”