Neurobiology of Aging

PurposeSimilar vocal impairments occur in normative aging and Parkinsons disease (PD), making differential diagnosis challenging in early stages. The brains role in age and PD-related vocal dysfunction is unclear. This motivated our use of the zebra finch songbird model. We applied human acoustic analysis to evaluate aging and parkinsonian-like birdsong for shared and distinct features. MethodTwo open-access datasets of zebra finch song were analyzed using an expanded set of parameters that, in the case of humans, can detect subtle changes in voice. The aging dataset included younger, middle-aged, and older birds. The PD dataset included birds receiving viral injections into Area X to induce -synuclein overexpression or control treatment, recorded pre- and post-injection. Songs were automatically segmented into motifs using cross-correlation. Acoustic measures were extracted from harmonic, noisy, and mixed syllables. ResultsMiddle-aged birds differed from younger and older birds, showing non-linear trajectories in fundamental frequency measures and age-related increases in spectral slope, spectral emphasis, and intensity variability, whereas temporal parameters remained stable. In PD, pre-post changes occurred in both ASYN and controls, with ASYN birds exhibiting larger effects for fundamental frequency variability, decreasing frequency modulation, and vocal intensity measures. ConclusionsVocal aging in zebra finches was characterized by non-linear trajectories and prominent spectral and intensity-related changes. In a gene-driven PD state there were greater alterations in fundamental frequency variability and intensity regulation, features that may distinguish aging-from disease-related vocal variability. These findings further support the zebra finch as a translational model for vocal biomarker research.

NTRODUCTION: Alzheimer's disease (AD) shows sex differences in risk, clinical progression, and biomarker profiles, but whether inherited genetic liability to modifiable risk factors contributes differently to AD susceptibility in females and males remains unclear. We evaluated whether genetic relationships between several modifiable dementia risk factors and AD differ between females and males. METHODS: We integrated polygenic risk scores (PRSs) for modifiable risk factors, genome-wide genetic correlation, and two-sample Mendelian randomization (MR) analyses. PRS associations with AD diagnosis were evaluated in the Alzheimer's Disease Genetics Consortium (n=27,751) and with AD plasma biomarkers in the Health and Aging Brain Study-Health Disparities (n=2,307-2,737, depending on the biomarker). Primary analyses evaluated female- and male-specific associations and compared sex-specific estimates. RESULTS: Educational attainment and physical activity PRSs were associated with AD in both sexes. PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction. Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males. Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction. In HABS-HD, type 2 diabetes PRS was associated with higher NfL, BMI PRS with higher pTau181, and the composite PRS with higher NfL among males after FDR correction. DISCUSSION: Evidence that modifiable dementia risk factors relate differently to AD by sex was limited and depended on the genetic measure examined. Sex differences in genome-wide genetic overlap were not consistently reflected in PRS or MR, indicating that shared genetic architecture does not necessarily translate into sex-specific inherited liability or causal effects

Neuroticism, a personality trait characterized by the predisposition to experience intense and frequent negative emotions, has been associated with an increased risk of Alzheimer's disease (AD). However, the mechanisms underlying this association remain unclear. Our study investigated two potential pathways: (1) whether the relationship between neuroticism and AD is causal, and (2) whether it is mediated by health and behavioral factors associated with both neuroticism and AD risk. To assess causality, a two-sample Mendelian randomization (MR) was employed using publicly available genome-wide association studies (GWAS) for neuroticism (Nagel et al., 2018) and AD (Bellenguez et al., 2022). Mediation analysis was conducted in a subset of UK Biobank participants aged 60 and older, including 121,825 controls (mean age = 63.9 {+/-} 2.81; 61,993 females or 50.9%) and 1,277 individuals with AD (mean age = 65.6 {+/-} 2.71; 628 females or 49.2%). All participants had complete data on neuroticism and the potential mediators. MR analysis suggested that the neuroticism-AD relationship is unlikely to be causal. However, depression ({beta}=0.048, p=3x10-4), hypertension ({beta}=0.005, p=2x10-4), and alcohol consumption ({beta}=0.001, p=1x10-5) were identified as significant mediators of the relationship between higher neuroticism and increased AD risk. Overall, the association between neuroticism and AD may be largely explained by modifiable health and behavioral factors rather than a direct causal effect. A better understanding of these mediating pathways may inform targeted prevention and therapeutic strategies to reduce AD risk.

As the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the human APOE {varepsilon}4 allele alters neuronal physiology before overt pathology. However, how aging and sex modify these effects in the anterior olfactory nucleus (AON), an early AD-affected brain region, remains unclear. Here, we performed whole-cell recordings and post hoc morphological reconstructions of pyramidal cells (PCs) and interneurons (INs) in acute AON slices from adult and aged humanized APOE3 (E3) and APOE4 (E4) knock-in mice of both sexes with identification of context-dependent remodeling across structural, intrinsic, and synaptic domains. In PCs, morphology was broadly susceptible to APOE genotype x age x sex and their interactions. Functionally, aged E4 PCs exhibited a more depolarized resting membrane potential than aged E3 PCs. Additionally, afterhyperpolarization amplitude displayed a marked age x genotype interaction, reversing the direction of the E4 - E3 difference from adulthood to aging. Excitatory synaptic event frequency showed a complex genotype and age and sex interaction, whereas inhibitory synaptic event amplitude was elevated in E4 mice. In contrast, INs displayed far more restricted alterations. Morphological changes were limited to dendritic length, which was modulated by age and sex specifically in E4 mice. Physiologically, genotype effects were confined to action potential amplitude, while aging primarily altered membrane properties and excitatory synaptic inputs. Together, these findings demonstrate that APOE genotype cell-specifically shapes AON neuronal properties through interactions with age and sex, suggesting that APOE4 establishes altered cellular states that influence how this circuit responds to subsequent disease-related stress.

Older adults typically exhibit reduced episodic memory precision, while maintaining relatively preserved retrieval success. However, little is known about whether these age-related differences are influenced by internal biological factors (e.g., chronotype) or external testing conditions (e.g., experiment format, time of day). To address this question, younger and older adults completed an object-location memory task online, either in the morning or evening, and either with or without video-based supervision. Memory performance was assessed using mean absolute error and Bayesian hierarchical mixture modelling, which dissociated memory precision ({kappa}) from the probability of memory-based responding ({theta}). Immediate memory performance was high across age groups, irrespective of time of day. Greater encoding error predicted greater retrieval error, and participants tested in the video condition exhibited lower recall error and higher recognition performance than those tested without supervision. Consistent with prior studies, older adults exhibited reduced memory precision relative to younger adults, whereas retrieval success remained largely intact. However, Bayesian Hierarchical Modelling provided no evidence that time of day, experiment format, or their interactions with age influenced either memory precision or retrieval probability. Older adults reported stronger morning preferences than younger adults, and participants generally selected testing times that aligned with their chronotype. Nevertheless, alignment between chronotype and testing time did not modulate memory performance. The results indicate that age-related differences in episodic memory precision are robust across variations in testing context, including time of day, experiment format, and individual differences in chronotype. More broadly, the results support the feasibility of remote and unsupervised testing for memory precision research and suggest that chronotype and testing time are unlikely to be major sources of variability in immediate object-location memory performance.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and its incidence is rising rapidly with population aging. Pathologically, AD is characterized by the accumulation of amyloid-beta (Abeta) plaques and hyperphosphorylated Tau neurofibrillary tangles. Human genomic studies have identified numerous risk alleles, with the APOE4 variant representing the strongest and most common genetic risk factor, present in approximately 75 percent of AD patients. However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis. Emerging evidence highlights a central role for oxidized lipid metabolism in AD. Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility. To systematically investigate APOE function in vivo, we tested humanized Drosophila expressing the human APOE3 or APOE4 variants in place of the Drosophila ortholog Glial Lazarillo (GLaz). The lifespan of APOE3 and APOE4 flies does not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis. APOE4 flies exposed to rotenone exhibit several AD-associated phenotypes, including age-related memory loss and chemosensory deficits, supporting the use of this model to investigate AD pathogenesis. Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges. Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.

Age-related speech-in-noise difficulties have been associated with increased activity in prefrontal regions. Whether this upregulation reflects adaptive compensation, neural inefficiency, or changes in task engagement as listening demands increase remains unresolved. Most studies have relied on linear contrasts of task difficulty, limiting our understanding of how the role of prefrontal recruitment evolves with listening demand. The present study examined these competing accounts within a non-linear framework. Using functional near-infrared spectroscopy, we measured activity in the dorsolateral prefrontal cortex (DLPFC) while 36 young and 34 older adults performed a sentence-in-noise task across five signal-to-noise ratio conditions. We tested whether DLPFC recruitment followed a quadratic trajectory across listening demands and whether its relationship with performance changed accordingly. Dorsomedial and ventrolateral prefrontal activity was also recorded to assess regional specificity. Bilateral DLPFC responses followed an inverted U-shaped pattern, increasing from easier to intermediate conditions before declining at the most difficult levels. Greater left DLPFC activation was associated with poorer performance in older adults across the ascending and peak portions of the demand-response function. High-performing older adults showed more youth-like recruitment profiles characterized by lower overall activation. Within the older adult group, higher left DLPFC activation was associated with greater age but not with hearing or global cognition. These results clarify the neural mechanisms underlying age-related speech-in-noise difficulties, suggesting that the shape of DLPFC recruitment reflects a demand-sensitive trajectory broadly preserved across age groups, while the level of activation in older adults may reflect neural processing efficiency, with greater upregulation associated with poorer performance.

Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.

Healthy older adults are more susceptible to false memories than young adults. Traditional false memory paradigms leverage semantic overlap, shared meaning, to induce false memories, but experiences can also overlap temporally whereby they occur close together in time. Prior work shows that older adults have impaired episodic memory, memory for events within a spatiotemporal context, corresponding to an overall shift toward semantic memory and away from episodic memory across the lifespan. We hypothesize that compared to young adults, older adults rely more heavily on semantic versus episodic information, which promotes false memory. We collected behavioral data in young and older adults performing an old/new recognition memory task in which we manipulated the degree of semantic and temporal overlap between study words and included critical lures, unstudied words that semantically overlap with study words. We find that whereas young and older adults are similarly reliant on semantic relative to episodic information to support false memory, the two age groups differ in their reliance on semantic relative to episodic information to support true memory. These results suggest that differences in the orientation of attention -- toward semantic vs. episodic information -- may underlie age-related memory changes.

Background The genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease. Method Using extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed. Results Heritability estimates suggested that common variants explain much of genetic risk among APOE-{varepsilon}4 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed APOE-{varepsilon}4 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified. Discussion These findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the APOE-{varepsilon}4 non-carriers.

While loss of NMDA receptors (NMDARs) is associated with Alzheimers disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Exam (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the CA1 field. However, there was a significant diagnosis by sex interaction driven by sex-specific changes in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that changes in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.

INTRODUCTION: Alzheimers, Lewy body and vascular neuropathology underpin the most common forms of dementia. Large-scale genetic studies tend to rely on clinical diagnoses and therefore may be subject to misdiagnoses and co-neuropathologies that occur. METHODS: Utilising the extension neuropathology data available on the Brains for Dementia Research cohort, this study performed whole-genome association analyses based on common neuropathology present in dementia. Genetic data was generated on the Illumina Neurobooster array and analysed using standard analyses pipelines in PLINK. RESULTS: Several associations were observed in and around the APOE locus but only in relation Alzheimers neuropathology. Whilst there was a convergence of common gene associations across the different neuropathology groups, there were distinct associations of individual SNPs. DISCUSSION: Different neuropathological outcomes appear to be driven by distinct genetic variants but converge on shared genes and biological processes related to neuronal structure and communication. Understanding these common pathways may provide new insights into mechanisms underlying mixed neuropathology and age-related neurodegeneration.

PurposeDuring speech planning, the brain predicts the auditory consequences of its movements and modulates the auditory system--a process called pre-speech auditory modulation (PSAM). We investigated the link between PSAM and behavioral error correction and determined how aging influences these mechanisms. MethodsSeventeen young adults (18-32 years) and 13 older adults (50-85 years) performed a speaking task involving auditory feedback perturbations and a silent reading control. We measured electrophysiological responses (N1/P2) to auditory probes during speech planning and correlated these modulations with the magnitude of participants subsequent behavioral corrective responses. ResultsBoth groups showed significant modulation of N1 and P2. However, N1 modulation correlated with corrective responses only in young adults. Older adults showed reduced behavioral corrections and smaller, delayed P2 components. Despite these age-related behavioral differences and the loss of the modulation-correction correlation, older adults maintained modulation magnitudes comparable to those of younger adults. ConclusionsN1 modulation serves as a neural index of the brains predictive processes during speech planning. Aging appears to selectively disrupt the integration of these signals into motor output rather than the internal generation of the predictions themselves.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) frequently co-occurs with Alzheimer's disease (AD) pathology and has been studied mainly in older populations. We examined its frequency and expression in 196 individuals with autopsy-confirmed intermediate-to-high AD neuropathologic change, enriched for younger-onset cases, integrating neuropathology with antemortem clinical, cognitive and neuroimaging data. LATE-NC occurred in 31% overall and 19% of individuals with symptom onset [≤]65 years. Its frequency increased with older age at symptom onset, and its presence was associated with greater episodic memory impairment and smaller amygdala and hippocampal volumes. Among individuals with LATE NC, older age at symptom onset was associated with memory-first presentation and greater medial temporal involvement, including higher inferior-to-medial temporal metabolism ratios on FDG PET. Despite its lower frequency, LATE-NC co-pathology should still be considered in early-onset AD, where selected clinical features and neuroimaging markers described in older populations may be less applicable.

Despite extensive knowledge of the progressive sequence of cognitive and functional deficits in Alzheimer's Disease (AD), the impact of neurodegeneration on the conscious experience of patients remains largely unexplored. Understanding how the content of consciousness, particularly perceptual awareness, changes with the progression of AD is crucial to enable meaningful person-centred care. This is especially important in severe AD when impairments in language and other cognitive domains mean people are unable to report their experiences. We investigated whether electrophysiological (EEG) and fMRI signatures of perceptual awareness described in healthy older people are present in people with mild-moderate and severe AD using two "no-report" paradigms. Firstly, a visual masking paradigm examined visual awareness negativity (VAN) and late positive (LP) electrophysiological responses and activation in visual cortex and fronto-parietal regions that are characteristically associated with conscious perception of faces; and second, a complex audio-visual (movie) task examined activation in fronto-parietal networks previously associated with perceptual awareness. In healthy older controls we found cortical responses characteristic of awareness in both EEG and fMRI modalities, with VAN and LP markers and widespread occipital, fusiform face area and fronto-parietal activation. In people with mild-moderate AD, there were significant reductions in VAN and LP markers and reduced fronto-parietal activation. In participants with severe AD, who were behaviourally minimally responsive, there was only limited evidence of presence of frontoparietal markers of perceptual awareness, however this may reflect attentional and task insensitivity in people with advanced dementia. These results demonstrate that the brain mechanisms associated with perceptual awareness become increasingly impaired with progression of AD. Specifically, involvement of frontoparietal networks is reduced in AD, which may reflect reduced higher-level awareness. This suggests AD should be considered a disorder of consciousness and should motivate further investigation into the dimensions of awareness affected by the disorder with implications for treatment and management of people with dementia.

Background: ACE variants are genetic risk factors for Alzheimer's disease (AD), potentially through reduced enzymatic activity and impaired amyloid {beta} hydrolysis. Objectives: To create a publicly available database of ACE variants relevant to ACE deficiency and AD, and to estimate the population frequency of damaging ACE variants and their impact on blood ACE levels. Methods: ACE variants were compiled from literature, public databases (VarSome, dbSNP, ClinVar, gnomAD), and sequencing data (WES/WGS) from 5147 Russian individuals. Variants were classified using a consensus in silico score (AlphaMissense, MetaRNN, EVE). Blood ACE levels were measured in 330 carriers of 64 different ACE mutations. Results: We identified 1682 unique ACE variants. Of these, 608 (36.2%) were classified as functionally damaging, including 17 signal peptide, 210 loss of function, and 381 missense variants. The estimated carrier frequency of damaging ACE variants was 2 % (1/50). Notably, 24 variants associated with experimentally confirmed reductions in blood ACE levels had a combined estimated carrier frequency of 3.9 % in the general population, calculated from cumulative gnomAD v4.1.0 allele frequencies under a rare-variant independence model. An open-access browser is available at https://ace-browser.com/. Conclusions: Variants associated with reduced blood ACE levels were estimated to be carried by approximately 1 in 25 individuals in the general population. This frequency is of the same order of magnitude as the 13.2% prevalence of Alzheimer's dementia in individuals aged 75-84 years (Alzheimer's Association, 2025), consistent with the hypothesis that ACE deficiency may represent an underrecognized contributor to late-onset AD susceptibility. The ACE mutations-AD browser and integrated genotype-phenotype data presented here provide a novel resource for future basic, translational, and clinical research on ACE-dependent AD.

Olfactory decline is among the earliest signs of aging and predicts later cognitive decline and neurodegenerative disease. Age-related impairments in odor identification and discrimination implicate central olfactory brain regions in both mice and humans, but it remains unclear where in the processing hierarchy aging alters neural function relating to these cognitive and perceptual deficits. To resolve this, we acquired simultaneous Neuropixels recordings from olfactory bulb (OB) and piriform cortex (PCx) in young and old mice during awake, head-fixed odor presentation, allowing us to probe multiple levels of odor response features within each animal. Our recordings revealed a shift toward greater excitation in both regions and reduced inhibitory neuron activity in PCx. Aging also restructured odor-evoked local field potential (LFP) oscillations within and across regions, with strongly elevated beta power and coherence. Population odor representations were less discriminable in OB, but not in PCx. Thus, our results point to reduced discriminability of OB population odor representations as the clearest neural analog of previously reported discrimination deficits. Single-unit, LFP, and population measures did not collapse onto a single axis using dimensionality reduction, indicating that several partly independent processes reshape the dynamics of odor responses in central olfactory circuits with aging. Together, these findings identify central circuit excitation/inhibition (E/I) and oscillatory imbalances that parallel age-related olfactory dysfunction despite largely preserved odor responsivity.

Background: Aging-related changes in motor performance are associated with a widespread reorganization of the motor network. Despite extensive research on altered brain activity patterns in aging, the underlying neurophysiological mechanisms driving these reorganizational changes remain incompletely understood, particularly regarding the role of inhibitory control. Methods: We here combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to examine aging-related alterations in local excitability, oscillatory dynamics, and neural coupling in the motor system. Brain responsivity was probed by applying single-pulse TMS to the primary motor cortex (M1) in younger and older subjects at rest. Results: Our findings indicated reduced cortical excitability in the stimulated M1 of older participants, consistent with an age-related reduction of GABAergic inhibitory control. Phase-locking analyses revealed reduced intra- and interhemispheric coupling in lower frequency bands, suggesting decreased inhibitory output from the stimulated M1. Moreover, older individuals demonstrated less localized event-related desynchronization (ERD) with greater power decreases in the prefrontal cortex contralateral to the stimulation site, indicating enhanced prefrontal involvement in the aging motor system. Conclusions: Together, these findings underline the relevance of alterations in inhibitory processes in the motor network in aging and point to a shift from an automatic, locally driven towards a broader, putatively more cognitively controlled sensorimotor processing in older adults.

INTRODUCTION: Plasma p-tau217 is associated with Alzheimer's disease pathology and memory performance, but its implications for memory may depend on fibrillar tau topography. We examined whether tau-PET subtype modified the association between plasma p-tau217 and memory. METHODS: We analyzed 396 amyloid-positive, tau-positive participants spanning cognitively unimpaired, mild cognitive impairment, and dementia stages from six cohorts with tau-PET and plasma p-tau217; 301 had harmonized memory data. Tau-PET subtypes were derived using data-driven disease progression modelling. Primary cross-sectional models tested subtypexp-tau217 interactions for memory, adjusting for age, sex, education, APOE {epsilon}4 status, and cohort. Secondary and exploratory analyses examined latent global cognition, non-memory measures, and longitudinal cognitive change. RESULTS: Three tau-PET subtypes were retained: limbic-predominant, medial temporal lobe (MTL)-sparing, and posterior-predominant. Cross-sectionally, MTL-sparing participants had lower plasma p-tau217 than the other subtypes. The association between higher plasma p-tau217 and worse memory differed by subtype (interaction p=0.002) and was stronger in MTL-sparing (B=-0.191, p<0.001) than in limbic-predominant (B=-0.07, p=0.002) and posterior-predominant participants (B=-0.07, p<0.001). The interaction remained significant after additional adjustment for diagnostic group (p=0.015). This pattern also persisted after additional adjustment for PET tau burden, amyloid Centiloids, or plasma A{beta}42/40 none of these biomarkers showed comparable subtype modification. Subtype modification was also observed for a global cognitive composite (interaction p=0.004) and subsequent memory decline in an exploratory analysis conditioned on baseline memory (interaction p=0.016). DISCUSSION: Tau-PET subtype modified the p-tau217-memory association, suggesting that the cognitive implications of plasma p-tau217 may vary with tau topography.

Background: White matter hyperintensities (WMH) are prevalent in dementia, but lesion volume does not capture their microstructural heterogeneity. The T1-weighted to fluid-attenuated inversion recovery (T1w/T2w-FLAIR) ratio is sensitive to myelin, gliosis, and tissue water. We tested whether lesion-specific T1w/T2w-FLAIR ratio, referenced to each participant's normal-appearing white matter (NAWM), differs by diagnosis and reflects distinct amyloid and vascular mechanisms in Alzheimer's disease (AD) and vascular dementia (VD). Methods: We analyzed 576 participants from the multicentre BICWALZS cohort (seven South Korean sites), spanning subjective cognitive impairment (SCI, n=71), mild cognitive impairment (n=270), AD (n=125) and VD (n=88). WMH T1w/T2w-FLAIR ratio was regressed on NAWM ratio, yielding standardized residuals as the outcome. Regression and mediation models tested diagnosis, plasma biomarkers, APOE genotype, amyloid PET and vascular risk burden, adjusting for age, sex, education and site. We conducted regression and mediation analyses after multiple imputation for missing variables. We adjusted for hierarchical models using Bonferroni correction. We tested for insensitivity to site effects by applying ComBat harmonization. Results: Older age, AD, VD, and high vascular risk burden were associated with higher residualized T1w/T2w-FLAIR ratios relative to SCI. Lower plasma amyloid-beta 42 (greater amyloid burden) was associated with lower T1w/T2w-FLAIR ratios. Greater vascular burden was associated with greater T1w/T2w-FLAIR ratios, which partially mediated the VD association with T1w/T2w-FLAIR. Lower amyloid-beta 42 (greater amyloid) was associated with lower T1w/T2w-FLAIR, which partially mediated the effect between AD and T1w/T2w-FLAIR ratio. Findings were robust to harmonization. Conclusions: Residualized WMH T1w/T2w-FLAIR ratio captures lesion-specific microstructural variation missed by volumetric measures, consistent with vascular-gliotic injury in VD and coexisting amyloid-linked demyelination in AD. Limitations include the cross-sectional design, no cognitively normal comparison group, and a predominantly Korean sample.