Associations between Alzheimer’s disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants

Foo, Heidi; Thalamuthu, Anbupalam; Jiang, Jiyang; Koch, Forrest; Mather, Karen A.; Wang, Wen; Sachdev, Perminder S.

doi:10.1016/j.neurobiolaging.2020.11.002

Cited by 23 publications

(19 citation statements)

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“…Further studies are needed with larger patient cohorts to differentiate the proposed underlying mechanisms of AD in HippSub volume loss. The aforementioned literature suggests other mechanisms of HippSub volume degeneration in the AD spectrum such as genes, iron accumulation, or even neuroprotective factors (Foo et al, 2020;Foster et al, 2020;Wang et al, 2020). Some of these factors may be partly responsible for the PreSub volume loss in AD, aMCI vs BD patients that we detected.…”

Section: Discussionmentioning

confidence: 66%

“…This evidence suggests that both tau-based neurodegeneration and ß-amyloid pathology are crucial for HippSub volume loss in patients with AD. Other mechanisms underlying the loss of hippocampal volume might be polygenic, as a higher polygenic risk score for AD was observed in cognitively normal patients in a study by Foo (Foo et al, 2020), possibly depicting preclinical AD. Protective mechanisms might also play a role, such as carrying the TREML2 rs3747742-C polymorphism, which seem related to higher CA1 volumes in cognitively normal subjects (Wang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline

Hansen

Singh

Bartels³

et al. 2021

Front. Aging Neurosci.

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Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases.Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups.Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode.Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline

Hansen

Singh

Bartels³

et al. 2021

Front. Aging Neurosci.

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“…For Sample 1, hippocampal subfield volumes were obtained by processing the T1w images. T1w scans of 1 mm 3 are commonly used in large cohort studies, such as the UK‐Biobank (Alfaro‐Almagro et al, 2018; for examples of hippocampal subfield volumetry studies: Foo et al, 2021; Majrashi, Ahearn, Williams, & Waiter, 2020) or the Dallas LifeSpan Brain Study (https://dlbsdata.utdallas.edu/StructuralMriProtocol; Zheng et al, 2018), where they represent optimized imaging sequence both in terms of spatial resolution and acquisition time, given the large size of the samples studied. A recent commentary has cautioned against using HsVol obtained from 1 mm isotropic T1w scans (Wisse et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Novel characterization of the relationship between verbal list‐learning outcomes and hippocampal subfields in healthy adults

Cremona

Mellet

Petit

et al. 2021

Human Brain Mapping

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The relationship between hippocampal subfield volumetry and verbal list‐learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list‐learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle‐aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list‐learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association‐based mnemonics mediated the relationship between verbal list‐learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list‐learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1.

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“…The atrophy of the hippocampus, essential for memory formation and consolidation [ 9 , 13 , 49 ], is associated with memory impairment in normal ageing [ 34 ] and is predictive of Alzheimer’s disease (AD) and associated dementia [ 3 , 26 ]. The hippocampus is one of the most severely affected brain regions in AD and dementia with Lewy Bodies (DLB) [ 4 , 20 , 28 , 64 ] but the causes of its vulnerability are still poorly understood. The hippocampal architecture has been widely studied for its tri-synaptic loop circuitry and its composition in five distinct subfields, the dentate gyrus (DG), as well as the four Cornu ammonis (CA) fields [ 8 ] dedicated to specific types or sequences of memory processes [ 18 , 82 , 94 ].…”

Section: Introductionmentioning

confidence: 99%

Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

Fixemer

Ameli

Hammer

et al. 2022

acta neuropathol commun

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The cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration pattern of the hippocampus differs between AD and DLB with the CA1 subfield being more severely affected in AD. The activation of microglia, the brain immune cells, could play a role in its selective volume loss. How subregional microglia populations vary within AD or DLB and across these conditions remains poorly understood. Furthermore, how the nature of the hippocampal local pathological imprint is associated with microglia responses needs to be elucidated. To this purpose, we employed an automated pipeline for analysis of 3D confocal microscopy images to assess CA1, CA3 and DG/CA4 subfields microglia responses in post-mortem hippocampal samples from late-onset AD (n = 10), DLB (n = 8) and age-matched control (CTL) (n = 11) individuals. In parallel, we performed volumetric analyses of hyperphosphorylated tau (pTau), amyloid-β (Aβ) and phosphorylated α-synuclein (pSyn) loads. For each of the 32,447 extracted microglia, 16 morphological features were measured to classify them into seven distinct morphological clusters. Our results show similar alterations of microglial morphological features and clusters in AD and DLB, but with more prominent changes in AD. We identified two distinct microglia clusters enriched in disease conditions and particularly increased in CA1 and DG/CA4 of AD and CA3 of DLB. Our study confirms frequent concomitance of pTau, Aβ and pSyn loads across AD and DLB but reveals a specific subregional pattern for each type of pathology, along with a generally increased severity in AD. Furthermore, pTau and pSyn loads were highly correlated across subregions and conditions. We uncovered tight associations between microglial changes and the subfield pathological imprint. Our findings suggest that combinations and severity of subregional pTau, Aβ and pSyn pathologies transform local microglia phenotypic composition in the hippocampus. The high burdens of pTau and pSyn associated with increased microglial alterations could be a factor in CA1 vulnerability in AD.

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Associations between Alzheimer’s disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 23 publications

References 50 publications

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline

Novel characterization of the relationship between verbal list‐learning outcomes and hippocampal subfields in healthy adults

Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

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