The p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease.

Truncating genetic variants of , encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the coding missense variant rs772677709, that leads to a p.

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method.

Background: Epileptic seizures are an established comorbidity of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG.

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.

Rare exonic variant affects GRN splicing and contributes to frontotemporal lobar degeneration.

Heterozygous loss-of-function (LOF) mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. For most missense mutations, the contribution to FTLD is however unclear. We studied the pathogenicity of rare GRN missense mutations using patient biomaterials.

Biomimethics: a critical perspective on the ethical implications of biomimetics in technological innovation.

Biomimetics, bioinspiration, biomimicry, and related nature-inspired activities-collectively known as biom*-are witnessing an unprecedented surge in popularity, as they offer unparalleled opportunities for technological advancement, innovation, and sustainable development. The growing prevalence of biom*, however, has sparked moral debates regarding their approaches, emphasizing the need for universally applicable ethical guidelines that can effectively guide practitioners in their work. In this perspective, we outline some of the moral, ethical, and legal challenges associated with biom*, particularly the scientific discipline of biomimetics, focusing on various issues surrounding our motivations for pursuing these approaches, the valuation of nature within them, and regulations in the commercialization of biological knowledge.

Mutated Toll-like receptor 9 increases Alzheimer's disease risk by compromising innate immunity protection.

The development of Alzheimer's disease (AD) involves central and peripheral immune deregulation. Gene identification and studies of AD genetic variants of peripheral immune components may aid understanding of peripheral-central immune crosstalk and facilitate new opportunities for therapeutic intervention. In this study, we have identified in a Flanders-Belgian family a novel variant p.

Chromosome-Level Genome Assembly of the Cape Cliff Lizard (Hemicordylus capensis).

Squamates represent a highly diverse and species-rich vertebrate group that is remarkably understudied from a genomic perspective. A scarcity of genomic data is particularly evident for scincomorph lizards, which encompass over 10% of all living squamates, and for which high-quality genomic resources are currently lacking. To address this knowledge gap, we present the first chromosome-level reference genome for this group, generated from a male Cape cliff lizard (Hemicordylus capensis), using highly accurate PacBio HiFi long-read sequencing data, long-range Omni-C chromosomal conformation capture data and transcriptomic data for annotation.

TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism.

Introduction: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies.

Methods: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712).

Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

Purpose: CAG/CAA repeat expansions in TBP are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease.

Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study.

Background: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy.

Objective: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis.

Methods: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses.

Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.

How network-based approaches can complement gene identification studies in frontotemporal dementia.

Frontotemporal dementia (FTD) is a primary cause of dementia encompassing a broad range of clinical phenotypes and cellular pathologies. Genetic discoveries in FTD have largely been driven by linkage studies in well-documented extended families, explaining most of the patients with a known pathogenic mutation. In the context of complex diseases, it is hypothesized that mutations with reduced penetrance or a combination of low-effect size variants with environmental factors drive disease.

Intraspecific competition: A missing link in dermal armour evolution?

Predation is widely regarded as an important selective force in the evolution and maintenance of dermal armour; yet, the basic premise that predation and armour are strongly linked to each other has proven to be difficult to assess. In this concept, I put forward the fighting-advantage hypothesis, the view that aggressive interactions with conspecifics, not predation, might have been a key selective pressure in the evolution of dermal armour. Considering intraspecific competition as a potential explanation could not only reveal previously overlooked aspects of the functional and evolutionary significance of dermal armour, but also advance the emerging field of biomimetics in which such knowledge forms the starting point of technological innovation.

Protein interaction network analysis reveals genetic enrichment of immune system genes in frontotemporal dementia.

Interactors of protein products of known genes for frontotemporal dementia (FTD) are likely to be involved in the molecular pathways towards disease. We therefore applied protein interaction network (PIN) analysis to prioritize candidate genes for rare variant association analysis. We created an FTD-PIN starting from known FTD genes downloading their physical interactors and performed functional enrichment analyses.

Osteoderms as calcium reservoirs: Insights from the lizard Ouroborus cataphractus.

The functional significance of osteoderms-bony elements embedded in the dermis-remains a topic of much debate. Although many hypotheses have been put forward in the past, the idea that osteoderms can serve as calcium reservoirs has received little experimental attention thus far. In this study, we use micro-computed tomography to investigate inter- and intrasexual variation in osteoderm density in the viviparous lizard Ouroborus cataphractus and conduct histochemical analyses to unravel the potential mechanism involved in mineral resorption from the osteoderms.

The role of ATP-binding cassette subfamily A in the etiology of Alzheimer's disease.

Background: Alzheimer's disease (AD) is the leading cause of dementia, clinically characterized by memory deficits and progressive cognitive decline. Despite decades of research effective therapies are lacking, and a large part of the genetic heritability remains unidentified. ABCA7 and ABCA1, members of the ATP-binding cassette subfamily A (ABCA), were identified as AD risk genes in genome-wide association studies.

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis.

Rare missense mutations in ABCA7 might increase Alzheimer's disease risk by plasma membrane exclusion.

The adenosine triphosphate-binding cassette subfamily A member 7 gene (ABCA7) is associated with Alzheimer's disease (AD) in large genome-wide association studies. Targeted sequencing of ABCA7 suggests a role for rare premature termination codon (PTC) mutations in AD, with haploinsufficiency through nonsense-mediated mRNA decay as a plausible pathogenic mechanism. Since other classes of rare variants in ABCA7 are poorly understood, we investigated the contribution and pathogenicity of rare missense, indel and splice variants in ABCA7 in Belgian AD patient and control cohorts.

Frontotemporal Lobar Degeneration Case with an N-Terminal Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology.

Recently, disease-associated variants of the gene were identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we present the neuropathological report of a patient with the semantic variant of primary progressive aphasia with a family history of Parkinsonism, harboring a novel frameshift mutation c.187del (p.