Implementing recently approved disease-modifying treatments for Alzheimer's disease (AD) requires healthcare systems to adapt rapidly. ApoE genotyping and determination of phosphorylated tau at Thr217 ( p -tau217) levels are essential for accurate patient selection and treatment response monitoring, respectively. Simplified, decentralized access to these biomarkers could reduce patient burden and healthcare resource consumption. Here, we evaluated the performance of fingerstick sampling for ApoE genotyping and longitudinal plasma p -tau217 quantification. Participants were evaluated at the Memory Unit of Ace Alzheimer Center Barcelona and provided longitudinal dried plasma spots (DPS) from on-site fingerstick collection at baseline (V0), 6 months (V6), and 12 months (V12). Capillary DPS cards were shipped to Gothenburg, Sweden, within seven days, without temperature control or cooling, and processed using a custom extraction protocol. Paired venipuncture plasma samples were collected at each visit. p -tau217 levels were measured with the ALZpath Simoa assay. Cerebrospinal fluid (CSF) Aβ1-42/Aβ1-40 measurements were available for all participants. In a sub-cohort, an additional fingerstick sample was collected for ApoE genotyping, performed using real-time PCR. A total of 58 participants (mean age 75.0 years, 61% female, 38% ApoEε4 carriers) were included in the study. The levels of p -tau217 from capillary DPS and plasma samples showed significant correlations at the three time points (all p  <0.001). capillary DPS p -tau217 showed high accuracy to discriminate patients based on their CSF Aβ status at V0 (AUC=0.83, CI95% 0.76-0.91), V6 (AUC=0.79, CI95% 0.67-0.91) and V12 (AUC=0.73, CI95% 0.63-0.82), similar to the paired plasma. Changes in capillary DPS and venous plasma samples between V0 and V6 were significantly associated in the total sample (r s =0.571; p  <0.001), and in Aβ+ (r s =0.568; p  <0.001), but not in Aβ- individuals (r s =0.368; n.s.). The average percentage change of p -tau217 levels from V0 to V6 in Aβ− individuals was -25% for capillary DPS and -16% for plasma, while in Aβ+ individuals, it was 27% for capillary DPS and 6% for plasma. ApoE genotyping results were the same as those from whole blood analysis. Our findings demonstrate the capability of a fingerstick collection to accurately quantify p -tau217 levels longitudinally and genotype ApoE. This suggests that this simple, decentralized, temperature-independent, and reliable method could facilitate AD patient management.

IntroductionHippocampal atrophy is frequently observed in neurodegenerative diseases such as Alzheimer’s disease (AD) or hippocampal sclerosis of aging (HS-aging). Volume loss in the hippocampus is described as prodromal stage of dementia and has been associated with AD polygenic risk score (PRS). CA1 and subiculum atrophy have been suggested to be a promising in vivo biomarker for HS-aging. Recent studies suggest that some loci associated with AD may be more related to other brain diseases concomitant with AD. We aimed to find which significant single nucleotide polymorphisms (SNPs) in the latest AD genome wide association studies (GWAS) could be potentially related with early atrophy of specific hippocampal subregions related to HS-aging.Materials and methodsWe used regression models to assess the relation of the AD-PRS, and genome-wide significant AD variants, with CA1 and subiculum volumes assessed by magnetic resonance imaging (MRI) in 1,859 participants without dementia (with mild cognitive impairment or cognitively healthy). Co-regulatory network analyses and over-representation enrichment analyses were conducted to identify biological pathways enriched with co-regulatory networks of genes associated with hippocampal subregion volumes. We meta-analyzed data from seven cohorts to associate their AD-PRS with AD in the presence of concomitant brain pathologies.ResultsReduced volumes of CA1 and subiculum show association with higher levels of AD-PRS and with variant rs5848 in GRN. This variant was enriched in immune-related pathways. AD-PRS showed no significant association with AD pathology alone, but was strongly associated with AD in the presence of concomitant neurodegenerative pathologies, with HS-aging showing the largest effect size.DiscussionSpecific AD-SNPs enriched in immune-brain axis pathways rather than Aβ related processes, were associated with reduced volumes of CA1 and subiculum prior to dementia onset. This supports that AD-PRS may capture genetic susceptibility to concomitant neurodegenerative diseases frequently misdiagnosed as AD. Given that AD-PRS is most strongly associated with AD in cases with HS-aging, and that CA1 and subiculum are promising in vivo biomarker for HS-aging also linked with rs5848 in GRN, our findings are consistent with HS-aging related vulnerability. This insight links early hippocampal subfields atrophy to shared genetic mechanisms and biological pathways of interest.

Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer's disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.

OBJECTIVES:Cerebrospinal fluid (CSF) contains thousands of proteins, and some of them are useful biomarkers for brain diseases, including neurodegeneration. Our objective was to compare two state-of-the-art mass spectrometers in revealing non-Alzheimer's disease (AD) to AD CSF variability. METHODS:We qualitatively compared Orbitrap Astral and timsTOF Pro 2. We analyzed CSF and brain tissue extracts from non-AD individuals and patients with AD without prior fractionation of the samples. RESULTS:The Orbitrap Astral detected twice as many proteins as the timsTOF Pro 2. The combined CSF proteome included 2,317 proteins. The reproducibility of the analysis was 74-92 % with both machines. There were no significant sex differences in the number of CSF proteins detected, but there was an age-related increase. Fifty-two proteins were exclusively present in the CSF of non-AD but absent in AD patient samples. We compared our non-pathological CSF proteome data obtained by Orbitrap Astral with three previously published datasets. The combined CSF proteome was 5,861 unique proteins. Our study identified 558 proteins that were not found in any of the other studies. CONCLUSIONS:New mass spectrometers are significantly more sensitive and can be used to extend the proteome of biological fluids and tissues in the quest for new disease biomarkers.

Blood biomarkers have emerged as accurate tools for detecting Alzheimer's disease (AD) pathology, offering a minimally invasive alternative to traditional diagnostic methods such as imaging and cerebrospinal fluid (CSF) analysis. Yet, the logistics surrounding venipuncture for blood collection, although considerably simpler than the acquisition of imaging and CSF, require precise processing and storage specific to AD biomarkers that are still guided by medical personnel. Consequently, limitations in their widescale use in research and broader clinical implementation exist. The DROP-AD project investigates the potential of dried plasma spot (DPS) and dried blood spot (DBS) analysis, derived from capillary blood, for detecting AD biomarkers, including phosphorylated tau at amino acid 217 (p-tau217), glial fibrillary acidic protein and neurofilament light. Here, 337 participants from 7 centers were included, with 304 participants providing paired capillary DPS or DBS and venous plasma samples. We observed strong correlations between DPS p-tau217 and venous plasma p-tau217 (r(S) = 0.74, P < 0.001). DPS p-tau217 progressively increased with increasing disease severity, and showed good accuracy in predicting CSF biomarker positivity (area under the curve = 0.864). Similarly, we demonstrated the successful detection of glial fibrillary acidic protein and neurofilament light with strong correlations between DBS and DPS, respectively, using paired venous plasma samples. Notably, the method was also effective in individuals with Down syndrome, a population at high genetic risk for AD but in whom standard blood sampling by venipuncture may be more complicated, revealing elevated biomarkers in those with dementia compared with asymptomatic individuals. The study also explored unsupervised blood collection, finding high concordance between supervised and self-collected samples. These findings underscore the potential of dried blood collection and capillary blood as a minimally invasive, scalable approach for AD biomarker testing in research settings. Yet, further refinement of collection and analytical protocols is needed to fully translate this approach to be viable and useful as a clinical tool.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), share overlapping clinical and pathological features. We analyzed cerebrospinal fluid (CSF) and plasma proteomes from 2,705 and 3,009 samples, respectively, across these NDs, identifying disease-specific and shared molecular signatures. CSF showed more disease-associated proteins than plasma, with AD and DLB exhibiting the strongest cross-tissue similarity. Pathway analyses revealed shared dysregulation of immune-related processes in CSF and plasma across the NDs, as well as disease-specific impairment of glycosylation and apoptotic pathways in AD; ATF4 and PERK signaling in PD; fibroblast growth factor receptor (FGFR) and interleukin signaling in DLB; and glycoprotein hormones disruption in FTD. We developed disease-specific predictive models showing high accuracy (area under the curve [AUC]: 0.81-0.95 in CSF and 0.80-0.89 in plasma). These findings reveal distinct and convergent mechanisms across NDs, highlighting potential biomarkers and pathways for diagnostic and therapeutic strategies in neurodegeneration.

INTRODUCTION:Early Alzheimer's disease (AD) involves subtle cortical changes that may precede atrophy. Magnetic resonance imaging (MRI) microstructural markers may detect earlier pathology than classical morphometry. METHODS:We analyzed cross-sectional MRI and amyloid-β (Aβ) positron emission tomography (PET) data from 1323 non-demented AMYPAD participants. Cortical volume, thickness, gray-white matter contrast (GWC), and mean diffusivity (MD) were related to global Aβ burden and estimated time to Aβ-positivity using regression, correlation, and change-point analyses. RESULTS:Microstructural measures showed stronger age associations than macrostructural measures, whereas all measures were unaffected by apolipoprotein E (APOE) -ε4 carriership. GWC and MD showed minimal overlap with volume and thickness. Higher Aβ burden was most strongly associated with reduced GWC and cortical thinning. Change-point analyses showed GWC alterations preceded Aβ-positivity by several years. DISCUSSION:Cortical microstructural MRI, particularly GWC, changes earlier than atrophy and may serve as an early in vivo marker of AD pathology.

The Amyloid Imaging to Prevent Alzheimer’s Disease Prognostic and Natural History Study (AMYPAD-PNHS) multimodal magnetic resonance imaging (MRI) dataset provides open-access longitudinal MRI data of 2759 cognitively normal or mild cognitive impairment individuals, encompassing (micro-)structural, physiological, and functional MRI sequences from 10 European parent cohorts. Processed and raw images, and image-derived (endo-)phenotypes, are organized in Brain Imaging Data Structure (BIDS) standards and accessible upon request, to enhance generalizability and comparability between future neuroimaging studies. This dataset supports preclinical Alzheimer’s disease (AD) and aging-related research by enabling robust multimodal analyses of neurodegeneration, microvascular pathology, and structural and functional connectivity changes, facilitating advanced investigations into preclinical AD mechanisms, informing early intervention strategies and allowing reproducible and centralized neuroimaging (endo-)phenotyping.

Abstract Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer’s disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrate that these variants have significant association with Alzheimer’s disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE , coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.

INTRODUCTION:ABvac40 is an active immunotherapy targeting Aβ40, the main component of cerebrovascular deposition in Alzheimer's disease (AD). A 24-month randomized, placebo-controlled phase 2 study (Part A) showed favorable safety and robust immunogenicity, with exploratory signals of clinical efficacy. Here, we report results from Part B, an 18-month extension evaluating long-term safety and immunological memory. METHODS:Participants treated with ABvac40 in Part A received placebo plus a delayed booster, whereas previous placebo participants received ABvac40. Exploratory endpoints included safety, tolerability, and immunogenicity. RESULTS:Seventy-seven participants entered Part B. Treatment-emergent adverse events (TEAEs) occurred in 75.0% of participants in placebo + booster group and 81.1% in ABvac40 group; serious TEAEs were 5.0% and 16.2%, respectively. No ARIA-E or meningoencephalomyelitis were observed, with one ARIA-H event. ABvac40 induced robust antibody responses following delayed booster, with detectable anti-Aβ40 antibodies in CSF. DISCUSSION:ABvac40 showed favorable long-term safety and durable immunogenicity, supporting further clinical development. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03461276, registered March 2, 2018. EudraCT: 2016-004352-30, registered March 10, 2017.

Cerebrospinal fluid (CSF) biomarkers are central to Alzheimer's disease (AD) diagnosis and research. However, CSF composition is shaped not only by neurodegeneration, but also by underlying physiological and pathological processes that remain poorly characterized. By integrating multi-omics data from the deeply characterized memory-clinic ACE CSF cohort (N=1,372), the Global Neurodegeneration Proteomics Consortium (N=1,863), and publicly available quantitative trait loci data, we reveal that 73.2-85.9% of the molecular variance in CSF omics data is driven by two main factors: one reflecting CSF turnover rate, and another representing blood-brain barrier (BBB) integrity. CSF turnover mainly determines brain-derived molecules, while BBB damage leads to increased blood-derived protein abundance. CSF turnover/clearance severely impacted core AD biomarker levels, affecting the classification of subjects in the A/T framework. Adjusting biomarker levels for OPCML, a novel reference marker, improved biomarker-based prediction of AD progression and removed confounded associations, revealing a proteomic signature of sporadic AD pathology that closely resembles that of autosomal dominant AD. Finally, using the ACE CSF cohort as discovery (N=1,221) and Knight ADRC as replication (N=1,073), we report a curated AD signature comprising 446 unique proteins. Our findings identify CSF dynamics as a major source of molecular variation, reshaping the interpretation of CSF biomarkers.

Abstract INTRODUCTION Plasma biomarker rule‐out tests can be used early in the Alzheimer's disease (AD) diagnostic pathway to identify people with low likelihood of amyloid pathology. METHODS A care setting‐agnostic cutoff for the Elecsys ® Phospho‐Tau (181P) plasma (pT181p) immunoassay was determined and validated in two independent, diverse cohorts, representative of real‐world clinical practice ( N = 604; N = 787, respectively). An additional cutoff was assessed in a subset of people reflective of primary care ( n = 312). RESULTS At a care setting‐agnostic cutoff of 0.934 pg/ml, high negative predictive value (NPV) (93.8%) and acceptable positive predictive value (PPV) (46.6%) were observed against amyloid‐positron emission tomography (PET). A primary care‐specific cutoff of 0.722 pg/ml showed high NPV (97.9%) against amyloid‐PET. Amyloid positivity prevalence for each cutoff population was 22.5% and 13.1%, respectively. DISCUSSION The pT181p immunoassay is a high‐performance test that may substantially help improve access to amyloid pathology testing for people requiring confirmation, potentially leading to timely clinical decisions and better outcomes.

Background The accurate identification of individuals at risk of Alzheimer’s disease (AD) through blood-based biomarkers remains challenging. Objectives To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline. Design, setting and participants This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years. Measurements Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition. Results Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177–0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14–7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17–9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559–51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory. Conclusions Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.

IntroductionEarly detection of Alzheimer’s disease (AD) is critical for timely intervention, particularly during the mild cognitive impairment (MCI) stage. This study aimed to develop and evaluate a multidomain speech analysis framework to support cognitive screening, biomarker prediction within the amyloid, tau and neurodegeneration (ATN) framework, and estimation of cognitive function across the AD continuum.MethodsThis study analyzed speech from 2,320 individuals spanning the cognitive spectrum-including those with subjective cognitive decline (SCD), MCI, and Alzheimer’s disease dementia (ADD)-using three spoken tasks (∼3 min) and extracted multidomain features including acoustic, lexical, syntactic, and semantic features. Machine learning models were trained to classify cognitive status, predict amyloid, tau and neurodegeneration (ATN) biomarker positivity, and estimate scores across six neuropsychological domains.ResultsMultidomain speech models achieved high performance in differentiating cognitive stages, with AUC values of up to 0.94 for SCD vs. ADD and 0.82 for SCD vs. MCI classifications. In biomarker prediction, the models yielded AUCs of 0.71, 0.74, and 0.73 for ATN classification, respectively. Speech-based models also showed strong correlations (up to 0.83) with cognitive function scores. Feature importance analysis revealed that verbal fluency measures were the most predictive. Explainability analyses indicated minimal dependency on age, sex, or education, supporting model fairness.DiscussionThese findings show that multidomain speech features capture clinically and biologically relevant information across the AD continuum, enabling cognitive classification, biomarker prediction, and cognitive estimation. These results underscore the potential of speech analysis as a non-invasive, accessible tool for scalable cognitive screening and early detection of AD. These results underscore the potential of speech analysis as a non-invasive, accessible tool for scalable cognitive screening and early detection of AD.

INTRODUCTION:In Alzheimer's disease (AD), females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. METHODS:We comprehensively examined 6162 proteins in cerebrospinal fluid (CSF) from 2496 participants to identify sex-specific proteomic alteration by CSF amyloid beta (Aβ)42 and phosphorylated tau (p-tau) levels. RESULTS:We identified and replicated 68 male-specific and 116 female-specific proteins associated with Aβ42 and/or p-tau levels. Apolipoprotein E ε4 carrier status modified sex-specific alterations of multiple proteins including S100A9 and NEFL for Aβ42 and MAPK9 and MAPKAPK2 for p-tau. Male-specific proteins, enriched in microglia, were involved in activating innate immune response. The male network exhibited direct connections among 30 proteins and highlighted MAPKAPK2 as a hub. Female-specific proteins, enriched in endothelial cells, were involved in regulating protein metabolic process. The female network exhibited direct connections among 43 proteins and highlighted CSNK2A2 and PRKCA as hubs. DISCUSSION:Our findings provide insights into mechanistic understanding of sex differences in AD risk. HIGHLIGHTS:Our proteomic study of 6162 proteins (targeted by 7006 aptamers) in cerebrospinal fluid (CSF) from 2496 participants identified and replicated 68 male-specific and 116 female-specific proteins associated with cerebrospinal fluid amyloid beta 42 and/or phosphorylated tau levels. Male-specific proteins, enriched in microglia, were involved in activation of innate immune response. The male network highlighted MAPKAPK2 involved in chronic neuronal neuroinflammation as a hub. Female-specific proteins, enriched in endothelial cells, were involved in regulation of protein metabolic process and response to external stimuli. The female network highlighted PRKCA regulating synaptic plasticity and CSNK2A2 protein involved in neuroplasticity as hubs.

Aging remains the predominant risk factor for Alzheimer’s disease (AD) and other neurodegenerative disorders, yet the mechanisms linking systemic aging to brain dysfunction remain incompletely understood. Cellular senescence, a state of stable cell-cycle arrest coupled with metabolic and secretory reprogramming, has emerged as a pivotal and context-dependent driver of brain aging. Accumulation of senescent glial cells (astrocytes, microglia, and oligodendrocyte progenitors) and emerging evidence of “neurescence” in post-mitotic neurons contribute to neuroinflammation, impaired proteostasis, and synaptic dysfunction. This review synthesizes molecular, cellular, and translational findings that reframe senescence as an active process shaping brain vulnerability. We discuss SASP-mediated neurotoxicity, crosstalk among senescent glial subtypes, and context-specific pathways (NF-κB, p38 MAPK, mTOR, cGAS–STING) as therapeutic targets. Senomorphic and senolytic strategies, alongside emerging systemic interventions such as therapeutic plasma exchange with albumin replacement, are evaluated for their potential to mitigate senescence burden and restore homeostasis. Integrating evidence from fluid, imaging, and multi-omic biomarkers, we highlight how senescence can now be monitored in vivo and stratified across disease stages. Multi-omic and spatial transcriptomic data reveal that central and peripheral senescence signatures only partially overlap, suggesting bidirectional communication across the brain–body axis. This systemic dimension raises key questions about whether modifying peripheral senescence or proteostasis could reshape CNS trajectories. However, key uncertainties remain, particularly regarding the causal role of senescence in human neurodegeneration, the specificity of current biomarkers, and the distinction between adaptive versus maladaptive senescence responses. Notably, direct evidence linking senescent cells to functional alterations in the human brain microenvironment remains limited. This review distinguishes itself from prior literature by integrating a multi-scale brain–body axis perspective, combining molecular, cellular, and systemic evidence to propose senescence as a bidirectional and context-dependent driver of neurodegeneration rather than a purely cell-autonomous process.

Schizophrenia (SCZ) and bipolar disorder (BD) are complex psychiatric disorders with partially overlapping genetic architectures and shared features with neurodegenerative diseases. Short tandem repeats (STRs), particularly CAG expansions in HTT , ATXN1 and ATXN2 , are established causes of neurodegenerative disorders, yet their role as genetic modifiers in major mental disorders remains poorly understood. We analysed CAG repeat sizes in a cohort of 1,604 individuals, including 234 SCZ patients, 329 BD patients and 1,041 healthy controls. Repeat lengths were determined by fluorescent PCR and capillary electrophoresis, and associations with disease risk and clinical phenotypes were evaluated using non-parametric tests, multinomial logistic regression and survival analyses. Intermediate HTT alleles were more frequent in BD type I compared with controls (8.8% vs 4.4%, p = 0.033), whereas ATXN1 intermediate alleles were less frequent in SCZ than in BD (4.7% vs 11.2%, p = 0.02). Although overall differences in repeat size were modest, ATXN2 CAG length showed consistent shifts across diagnostic groups, with slightly larger repeats in BD and SCZ than in controls. Multinomial models identified the ATXN2 long allele as associated with disease risk with a non-linear effect. Intermediate ATXN2 alleles were also associated with shorter disease duration in BD (p = 0.00048). Functional enrichment analysis revealed convergence of these genes with SCZ- and BD-related networks involved in synaptic function and RNA metabolism. These findings support a role for CAG repeat variation as a genetic modifier influencing susceptibility and clinical trajectories in psychiatric disorders.