Neurobiology of Aging

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...

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...

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...

IntroductionPhosphorylated tau-217 (p-tau 217) is widely used as a plasma-based biomarker for Alzheimers Disease (AD) detection, demonstrating superior accuracy for detecting brain amyloid pathology. However, 30-50% of patients fall within an intermediate diagnostic "gray zone" where biomarker results are indeterminate, often decreasing physician confidence and requiring subsequent diagnostic workup. To address this, we developed a two-stage machine learning algorithm GRAD: Gatekeeper & Reflex ...

Parkinsons disease (PD) is a disabling neurodegenerative disorder with a substantial heritable component. Despite major advances in genome-wide association studies (GWAS), polygenic risk scores (PRS) show reduced predictive performance outside European populations, limiting equitable translation. Latin American populations represent a particularly difficult case because of their characteristic three-way admixture. We evaluated the cross-ancestry transferability of PD PRS in 1,872 PD cases and 1,...

Trade-offs form a key constraint in many aspects of organismal evolution, though they may help maintain genetic diversity. Late-onset Alzheimers disease (LOAD) shows features in common with the male-female health survival paradox: females suffer from higher prevalence and risk, as well as faster rates of cognitive decline while males suffer higher mortality. Though antagonistic pleiotropy could explain the tendency of LOAD to appear late in life, the sexually dimorphic profile suggests a role fo...

Subtle alterations in awareness may emerge in the preclinical stage of Alzheimers disease (AD), yet their clinical significance and translational relevance remain unclear. This study aimed to evaluate associations of distinct awareness trajectories with clinical and multimodal AD biomarker measurements in cognitively unimpaired (CU) older adults. This prospective study analyzed data from the Anti-Amyloid Treatment in Asymptomatic Alzheimers (A4) and Longitudinal Evaluation of Amyloid Risk and N...

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkins...

IntroductionGenome-wide association studies (GWAS) have identified over 130 risk loci for Parkinsons disease (PD), yet the majority derive from studies performed in European ancestry populations. African (AFR) and African admixed (AAC) ancestry individuals remain underrepresented in PD genetics research, limiting our understanding of ancestry-specific genetic architecture and the generalizability of known risk factors. MethodsWe conducted GWAS in AFR and AAC populations by integrating individua...

Individuals who carry two copies of the apolipoprotein E {varepsilon}4 (APOE{varepsilon}4) allele are at high risk of developing Alzheimers disease (AD), yet the effects of APOE {varepsilon}4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes of APOE {varepsilon}4/{varepsilon}4 individuals with and without AD-related cognitive impairment (n=413) and compared them to the proteomes of cognitively unimpaired individuals with APOE {...

Parkinsons disease (PD) is a progressive movement disorder that affects over ten million individuals worldwide. While the involvement of genetically-driven cellular mechanisms in PD pathogenesis is well-established, there is increasing evidence that epigenetic dysregulation also plays a key role. We profiled genome-wide DNA methylation in isolated neuronal, oligodendrocyte and other glial nuclei populations from the prefrontal cortex of 71 PD and 56 control individuals. We identified seven sign...

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)--the rhythmic heart rate modulation accompanying respiration--has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortic...

Functional neuroimaging studies suggested a biphasic trajectory of neuronal activity in Alzheimers disease (AD), with early hyperactivity followed by later hypoactivity. However, the underlying neurochemical mechanisms in humans remain unclear. Animal studies suggested that amyloid-beta (A{beta}) causes intrasynaptic glutamate increases through impaired astrocytic clearance. This study aimed to build a mechanistic bridge between findings from human neuroimaging studies and preclinical models by ...

BackgroundCommunity-based clinical-pathologic studies have been instrumental to examine the association of Alzheimers disease and related disorders (AD/ADRD) with age and dementia in very-old non-Latino Whites. Here, we show the age distribution of four AD and three additional common neuropathologies across the adult lifespan and examine their relation to dementia and cognitive impairment in old and young Brazilian adults. MethodsWe examined 5,376 brains from decedents age 18 years or older (52...

Plasma p-tau217 closely tracks amyloid-{beta} (A{beta}) pathology, yet its ability to predict long-term clinical progression in cognitively unimpaired (CU) adults remains uncertain. We analyzed harmonized data from 2,705 CU participants (Agemean=69.8{+/-}7years; Female=63%) across six longitudinal cohorts with up to 13.5 years of follow-up. Cox models evaluated associations between p-tau217 and progression to a clinical diagnosis of cognitive impairment, while natural cubic spline models assesse...

BackgroundAPOE-{rho}.4 is the strongest genetic risk factor for Alzheimers disease (AD), and plasma phosphorylated tau217 (P-tau217) is a highly sensitive and specific biomarker for AD pathology. Their combined utility to predict cognitive decline before onset of AD has not been systematically evaluated. MethodsUsing longitudinal data from multiple cohorts, we evaluated plasma P-tau217 as a predictor of when cognitive impairment occurs in AD. P-tau217 concentrations were analyzed as continuous ...

BackgroundNeurodegenerative diseases, including Alzheimers disease (AD), exhibit substantial clinical and molecular heterogeneity, complicating accurate diagnosis and development of effective therapies. Although multi-omics profiling provides unprecedented molecular resolution, systematic integration of high-dimensional, imbalanced data modalities with disease-relevant biological networks remains a methodological challenge. MethodsWe developed a network-informed multi-omics integration framewor...

The molecular basis of cognitive resilience in Alzheimers disease (AD), wherein individuals harbor substantial neuropathology yet maintain cognition, remains poorly understood. To systematically decode the regulatory logic underlying divergent cognitive outcomes, we constructed the largest cell-type-resolved gene regulatory network (GRN) atlas of AD to date, profiling 1.7 million nuclei from 687 individuals classified as Controls, cognitively Resilient, or AD dementia across 27 cell types in the...

Body mass index (BMI), type 2 diabetes (T2D) and associated cardiometabolic features modify Alzheimers disease (AD) risk, yet shared mechanisms remain poorly understood. Using sex- and age-stratified genotyping data for BMI and T2D, we investigate how these traits converge on shared genetic pathways to AD risk. Employing multi-trait, machine learning and single-cell transcriptomics, we identify sex-specific cardiometabolic liability linked to higher BMI-associated risk in women and T2D-driven ri...