The <i>BIN1</i> rs744373 Alzheimer's disease risk SNP is associated with faster Aβ‐associated tau accumulation and cognitive decline

Franzmeier, Nicolai; Ossenkoppele, Rik; Brendel, Matthias; Rubinski, Anna; Smith, Ruben; Kumar, Atul; Mattsson‐Carlgren, Niklas; Strandberg, Olof; Duering, Marco; Büerger, Katharina; Dichgans, Martin; Hansson, Oskar; Ewers, Michael

doi:10.1002/alz.12371

Cited by 30 publications

(31 citation statements)

References 53 publications

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“…Even if our current study was not intended to directly assess functional consequences of AD risk-related BIN1 polymorphisms but to focus on BIN1 isoforms function in neurons, which are still insufficiently described and understood, it may provide a context for BIN1-associated risk, namely the dysregulation of early endosome size and function. Up to now and not exclusive from each other, BIN1 polymorphisms have been associated with Tau but not amyloid loads in post-mortem AD brain tissue [ 9 ] and they are consistently associated with faster Aβ-associated Tau-PET accumulation and cognitive decline in AD patient [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Lambert

Saha

Landeira

et al. 2022

acta neuropathol commun

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The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

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Section: Discussionmentioning

confidence: 99%

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Lambert

Saha

Landeira

et al. 2022

acta neuropathol commun

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“…Therriault et al [ 86 ] and Neitzel et al [ 89 ] independently evaluated different datasets and reported that APOE ε4 is associated with higher tau accumulation and that this association is independent of amyloid burden. Regarding other AD candidate genes, Franzmeier et al [ 87 , 90 ] and Neitzel et al [ 91 ] suggested that the BIN1 rs744373 SNP and Klotho-VS heterozygosity are associated with higher and lower pathologic tau levels, respectively, by analyses of variance and multiple linear regression.…”

Section: Implementation Of Ad Imaging Biomarker Genomics Studiesmentioning

confidence: 99%

“…The use of prior knowledge, such as the Allen Human Brain atlas (AHBA), can facilitate calculations in brain imaging biomarker genomics and correlate spatial variations at the molecular scale with macroscopic neuroimaging phenotypes. For example, Franzmeier et al [ 90 ] and Neitzel et al [ 91 ] have used the AHBA to explore associations of BIN1 rs744373 and KL-VS heterozygosity with tau accumulation, respectively. Moreover, Sepulcre et al [ 172 ] have developed a novel graph theory approach named directional graph theory regression (DGTR) to investigate the intersection of tau/Aβ pathological changes in the brain and the genetic transcriptome of AHBA.…”

Section: Key Considerations and Perspectives Regarding Ad Imaging Bio...mentioning

confidence: 99%

A review of brain imaging biomarker genomics in Alzheimer’s disease: implementation and perspectives

Sheng

et al. 2022

Transl Neurodegener

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with phenotypic changes closely associated with both genetic variants and imaging pathology. Brain imaging biomarker genomics has been developed in recent years to reveal potential AD pathological mechanisms and provide early diagnoses. This technique integrates multimodal imaging phenotypes with genetic data in a noninvasive and high-throughput manner. In this review, we summarize the basic analytical framework of brain imaging biomarker genomics and elucidate two main implementation scenarios of this technique in AD studies: (1) exploring novel biomarkers and seeking mutual interpretability and (2) providing a diagnosis and prognosis for AD with combined use of machine learning methods and brain imaging biomarker genomics. Importantly, we highlight the necessity of brain imaging biomarker genomics, discuss the strengths and limitations of current methods, and propose directions for development of this research field.

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“…in ADNI CNs. 9 Based on the power analysis, a sample of 59 individuals per group would be required to reach a power of 80% at α = 0.05 to replicate the reported BIN1 rs744373 effect on global tau burden (effect size = 0.26). Similarly, one would need to include 48 individuals per group to reach a power of 80% at α = 0.05 for detecting a BIN1 rs744373 effect on global tau burden (effect size = 0.29) in BioFINDER CNs.…”

Section: Statistical Analysesmentioning

confidence: 99%

“… 8 According to a follow‐up paper, BIN1 risk‐allele carriers show accelerated tau‐PET accumulation at higher Aβ levels. 9 …”

Section: Introductionmentioning

confidence: 99%

Lack of association between bridging integrator 1 (BIN1) rs744373 polymorphism and tau‐PET load in cognitively intact older adults

Schaeverbeke

Luckett

Gabel

et al. 2022

A&D Transl Res & Clin Interv

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Introduction The bridging integrator 1( BIN1) rs744373 risk polymorphism has been linked to increased [ 18 F]AV1451 signal in non‐demented older adults (ie., mild cognitive impairment [MCI] plus cognitively normal [CN] individuals). However, the association of BIN1 with in vivo tau, amyloid beta (Aβ) burden, and cognitive impairment in the asymptomatic stage of Alzheimer's disease (AD) remains unknown. Methods The BIN1 effect on [ 18 F]AV1451 binding was evaluated in 59 cognitively normal (CN) participants (39% apolipoprotein E [ APOE ε4]) from the Flemish Prevent AD Cohort KU Leuven (F‐PACK), as well as in 66 Alzheimer's Disease Neuroimaging Initiative (ADNI) CN participants, using voxelwise and regional statistics. For comparison, 52 MCI patients from ADNI were also studied. Results Forty‐four percent of F‐PACK participants were BIN1 rs744373 risk‐allele carriers, 21% showed high amyloid burden, and 8% had elevated [ 18 F]AV1451 binding. In ADNI, 53% and 50% of CNs and MCIs, respectively, carried the BIN1 rs744373 risk‐allele. Amyloid positivity was present in 23% of CNs and 51% of MCIs, whereas 2% of CNs and 35% of MCIs showed elevated [ 18 F]AV1451 binding. There was no significant effect of BIN1 on voxelwise or regional [ 18 F]AV1451 in F‐PACK or ADNI CNs, or in the pooled CN sample. No significant association between BIN1 and [ 18 F]AV1451 was obtained in ADNI MCI patients. However, in the MCI group, numerically higher [ 18 F]AV1451 binding was observed in the BIN1 risk‐allele group compared to the BIN1 normal group in regions corresponding to more progressed tau pathology. Discussion We could not confirm the association between BIN1 rs744373 risk‐allele and elevated [ 18 F]AV1451 signal in CN older adults or MCI. Numerically higher [ 18 F]AV1451 binding was observed, however, in the MCI BIN1 risk‐allele group, indicating that the previously reported positive effect may be confounded by group. Therefore, when studying how the BIN1 risk polymorphism influences AD pathogenesis, a distinction should be made between asymptomatic, MCI, and dementia stages of AD.

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The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ‐associated tau accumulation and cognitive decline

Cited by 30 publications

References 53 publications

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

A review of brain imaging biomarker genomics in Alzheimer’s disease: implementation and perspectives

Lack of association between bridging integrator 1 (BIN1) rs744373 polymorphism and tau‐PET load in cognitively intact older adults

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