Neurobiology of Aging

BackgroundDNAJC13 was initially linked to autosomal dominant (AD) Parkinsons disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13s role in the disease. ObjectivesExplore the association between common and rare variants in DNAJC13 and Parkinsons disease. MethodsWe leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Diseas...

BackgroundThe SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinsons disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited. ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB). MethodsWe examined common variants using four representative PD genome-...

Mitochondrial single-nucleotide variants (mtSNVs) can dysregulate cellular bioenergetics and have been increasingly implicated in susceptibility to Parkinsons disease (PD). These variants may impair oxidative metabolism and respiratory chain efficiency, thus contributing to neuronal dysfunction and degeneration. In peripheral blood, mtSNVs may also reflect systemic immunometabolic alterations associated with PD; however, this aspect remains poorly explored, particularly in admixed populations wi...

Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimers disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by prese...

White matter microstructural abnormalities are increasingly found to be associated with cognitive impairment in Alzheimers Disease (AD). Here, we investigated the relationship between visual short-term memory (VSTM) performance, measured using a digital cognitive task, and integrity of brain white matter tracts. 52 AD and 60 age-matched healthy controls were recruited from the Oxford Cognitive Disorders Clinic. An established digital VSTM test - the Oxford Memory Task (OMT) - was used to measur...

SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimers disease (AD). Studies suggest that restoring SORLA function or its trafficking pathways, particularly the SORLA-retromer recycling system, may offer a promising strategy to slow or halt AD progression. While both rare and common SORL1 variants have been associated with increased AD risk, recent evidence suggests a potential involvement of SORL1 in other neurodegenerative conditions. This study...

Following observations from a pilot study that, contrary to expectations, indicated that critical white matter (WM) connections were not more vulnerable to either SVD or AD pathologies than non-critical connections, we set out to systematically evaluate the relation between these pathologies and both connections types. For patients with CADASIL (n=59), Mixed pathology (n=57) and autosomal dominant AD (ADAD; n=50) we reconstructed WM networks based on diffusion tensor imaging and subsequently def...

This paper examines associations of atrophy in the amygdala, entorhinal cortex and hippocampus based on magnetic resonance imaging (MRI) and Positron Emission Tomography (PET) scans from two independent cohorts: Alzheimers Disease Neuroimaging Initiative (ADNI) and Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study. The amygdala and entorhinal cortex (ERC) are shown to change earlier in the disease than the hippocampus based on atrophy of laminar thickness of the ERC and am...

X chromosome-wide association studies (XWAS) have successfully identified risk loci on the X chromosome associated with Parkinsons disease (PD) susceptibility. However, only three such studies have been completed to date. Here, we present the first XWAS using an African cohort, comprising 690 PD cases and 826 controls. We applied an established XWAS workflow to perform male- and female-stratified analyses, as well as a combined meta-analysis. The male-stratified analysis identified five signific...

Background and ObjectivesIdentifying proteomic biomarkers associated with neuroimaging endophenotypes of cerebrovascular dysfunction and generalized neurodegeneration may provide insights into pre-Alzheimer disease pathological processes. This study aims to examine a broad panel of circulating proteins in relation to two diffusion tensor imaging (DTI) measures:free water (FW) and peak width of skeletonized mean diffusivity (PSMD), which are sensitive indicators of early white matter injury. Met...

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between...

INTRODUCTIONAlzheimers disease (AD) diagnostic guidelines emphasize subjective cognitive decline (SCD) preceding mild cognitive impairment (MCI), implicitly assuming awareness of cognitive decline (ACD) is preserved in preclinical AD. This study aimed to evaluate associations of decreased ACD with multimodal core AD biomarkers in cognitively unimpaired (CU) individuals. METHODSWe analyzed data from CU individuals with baseline CSF biomarkers and 3-year longitudinal neuropsychological assessment...

INTRODUCTIONPeople with mild cognitive impairment (MCI) are candidates for early intervention, but not all progress to Alzheimers disease (AD) dementia. Identifying a subgroup at highest risk may improve treatment targeting. METHODSWe analyzed data from participants with MCI enrolled in the Alzheimers Disease Neuroimaging Initiative (ADNI). Cognitive domains included memory, executive functioning, language, and visuospatial abilities. We evaluated baseline performance and 6-month change scores,...

Sleep disturbances represent a potentially modifiable risk factor for Alzheimer disease (AD). The extent to which changes in rapid eye movement (REM) sleep are related to the accumulation of AD pathology and brain tissue loss is not well understood. In the current study, ninety-four individuals 74 clinically unimpaired [CU] and 20 clinically impaired [CI]) underwent polysomnography (PSG), cognitive assessments, and neuroimaging. Cross-sectional and longitudinal models examined the associations b...

Alzheimers disease (AD) arises from synergistic interactions between amyloid-{beta}, tau, and neurodegeneration, yet it remains unclear how these mechanisms reshape the hierarchical organization of large-scale brain dynamics. Here, we quantified directed causal interactions across 134 participants spanning the AD continuum, comprising 46 amyloid-negative healthy controls (HC-), 36 amyloid-positive healthy controls (HC+), 31 amyloid-positive individuals with mild cognitive impairment (MCI+), and ...

BackgroundMild cognitive impairment (MCI) precedes Alzheimers disease (AD) in [~]40% of cases, with early language deficits distinguishing converters. This study develops a DTI radiomics model from language network gray matter to predict MCI to AD conversion and identify preclinical biomarkers. MethodsThis retrospective case-control study analyzed diffusion tensor imaging (DTI) data from 97 individuals with MCI (29 converters, 68 non-converters) from the Alzheimers Disease Neuroimaging Initiati...

INTRODUCTIONAlzheimers disease (AD) is heterogeneous, complicating diagnosis and prognosis. Uncovering patterns that link abnormalities across amyloid-tau-neurodegeneration (A-T-N) framework may improve prediction of clinical diagnosis. METHODSWe applied SuperBigFLICA (SBF), a semi-supervised multimodal data fusion method, to maps of gray matter density, cortical thickness, pial surface area, amyloid PET, and tau PET in 274 ADNI-3 participants. The model was trained to derive 50 latent componen...

Genome-wide association studies (GWAS) have identified numerous risk loci for Parkinsons disease, yet identifying specific causal genes remains a major challenge due to non-coding associations and complex linkage disequilibrium. Here, we present a systematic framework integrating machine learning-based gene prioritization with high-resolution rare variant burden analysis. Using an XGBoost machine-learning model trained on 285 multi-omic features, including brain-specific eQTLs and single-cell ex...

INTRODUCTIONBilingualism is among several lifestyle factors associated with protection against cognitive decline, yet the biological mechanisms through which it exerts these effects remain poorly understood. METHODSWe compared neuropsychological functioning and biofluid markers of brain health between active (n = 280) and passive (n = 287) Spanish-Catalan bilinguals with biomarker-confirmed Alzheimers disease (AD). RESULTSActive bilinguals outperformed passive bilinguals on tests assessing att...

BACKGROUNDEpisodic memory declines early with aging, reflecting reduced neural resources and diminished memory specificity. However, few studies have created a cognitive challenge with multiple levels of task demand to investigate this early subtle decline. Furthermore, it is unclear whether the genetic Alzheimers disease risk factor APOE4 and early Alzheimers pathology constrain the neural resources required to cope with increasing task demands. METHODSIn this preregistered behavioral study na...