Alzheimer's disease‐associated P460L variant of EphA1 dysregulates receptor activity and blood‐brain barrier function

Owens, Helen A.; Thorburn, Lauren E.; Walsby, Elisabeth; Moon, Owen R.; Rizkallah, Pierre; Sherwani, Subuhi; Tinsley, Caroline L.; Rogers, Louise; Cerutti, Camilla; Ridley, Anne J.; Williams, Julie; Knäuper, Vera; Ager, Ann

doi:10.1002/alz.13603

Cited by 2 publications

References 49 publications

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Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

Gunasekaran,

Reyes-Dumeyer,

Faber

et al. 2023

Preprint

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PURPOSEFew rare pathogenic variants have been identified in the 70+ genetic loci from genome wide association studies of late-onset Alzheimer’s disease (AD), limiting research on underlying mechanisms, risk assessment, and genetic counseling.METHODSUsing genome sequencing data from 197 families in The National Institute on Aging Alzheimer’s Disease Family Based Study (AD-FBS), and 214 families in The Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), we characterized rare coding variants predicted to highly damaging missense or loss of function variants (LoF) within known GWAS loci.RESULTSEight coding and one LoF variant segregated in 10 (5.1%) AD-FBS families and 16 coding and two LoF variants segregated in 18 (8.4%) EFIGA families.ABCA7 and AKAP9contained the most damaging variants. In 51 (25.9%) of the AD-FBS and in 26 (12.1%) of the EFIGA families,APOE-ε4was the only variant segregating with familial AD (fAD). NeitherAPOE-ε4nor missense or LoF variants were found in 44.1% of the AD-FBS and 62.1% of the EFIGA families.CONCLUSIONSAlthough rare variants were found in both family groups, many families had no gene variant segregating within the family, indicating that the genetic basis for AD has yet to be fully defined.

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Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

Gunasekaran,

Reyes-Dumeyer,

Faber

et al. 2023

Preprint

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Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?

Lista,

Imbimbo,

Grasso

et al. 2024

J Neuroinflammation

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Background Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD. Main body Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aβ reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aβ deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aβ (“A”), tau (“T”), and neurodegeneration (“N”), by incorporating a novel inflammatory component (“I”). Conclusions The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients.

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Alzheimer's disease‐associated P460L variant of EphA1 dysregulates receptor activity and blood‐brain barrier function

Cited by 2 publications

References 49 publications

Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?

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