Citations

Abstract Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer’s disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer’s disease and Parkinson’s disease (Stanford Alzheimer’s Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer’s disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 ‘hub’ protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.

Abstract Histopathological assessment has served as the gold standard for diagnosing Alzheimer’s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10−11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10−10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10−201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10−8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10−8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10−7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Abstract Introduction: Evidence increasingly shows small nerve fibre pathology in subsets of people with fibromyalgia through skin biopsy, corneal confocal microscopy, and microneurography. However, blood-based biomarkers of ongoing neuronal damage, particularly neurofilament light chain (NfL), an axonal structural protein, are not well established. Objectives: The aim of this study was to evaluate serum NfL concentrations in fibromyalgia compared with other chronic pain conditions and assess their relationship with neuropathic-like pain. Methods: We measured serum NfL using Simoa SR-X NF Light v2 digital-immunoassay in 60 participants with fibromyalgia, 61 with endometriosis (another traditionally considered non-neuropathic pain condition), 24 with small fibre neuropathy (a recognised neuropathic pain condition), and 30 healthy controls. Serum NfL concentrations were compared between the groups controlling for age and body mass index. Neuropathic-like pain was assessed using the painDETECT questionnaire for fibromyalgia and endometriosis and NeuPSIG grading criteria for small fibre neuropathy. Results: Compared with healthy controls (mean concentration = 6.77 pg/mL, Z-score = −1.15), serum NfL concentrations were significantly elevated in fibromyalgia (mean concentration = 8.52 pg/mL P = 0.048; Z-score = −0.30, and P = 0.006) and small fibre neuropathy (mean concentration = 8.98 pg/mL, P = 0.004; Z-score = 0.23, P = 0.0001), with endometriosis representing an intermediate phenotype (mean concentration = 5.57 pg/mL, P = 0.44; Z-score = −0.41, P = 0.024). Using PainDETECT, 44% of fibromyalgia and 26% of endometriosis participants met likely neuropathic pain criteria; using NeupSIG grading, 96% of small fibre neuropathy participants met probable/definite criteria. Conclusion: Our study provides serological evidence of nerve pathology in fibromyalgia at comparable levels with small fibre neuropathy, although this did not correlate with neuropathic-like pain presence or severity. These findings highlight the need for subgroup-specific treatment strategies.

Abstract INTRODUCTION The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1 , FLT4 , and VEGFB on AD outcomes. However, these analyses have focused within the non‐Hispanic White (NHW) population. METHODS The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT‐MS) proteomic data. Outcomes included measures of AD pathology and diagnosis. RESULTS Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4 , whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity. DISCUSSION This multi‐omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD. Highlights Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi‐omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

Abstract Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance ( p <5×10 ‐8 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ‐5 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ‐6 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ‐6 ) was linked to diffuse plaques. All three SVs associated with AD ( p <5×10 ‐6 ) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

Abstract INTRODUCTION New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS Harmonized amyloid PET data from 4216 participants were used in genome‐wide survival, tissue‐specific gene expression, and genetic covariance analyses of EAOA. RESULTS Variants in apolipoprotein E ( APOE ), ABCA7 , and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7 , associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7 , which was associated with increased amyloid pathology at autopsy. Multiple immune‐related diseases shared genetic covariance with EAOA. DISCUSSION APOE , ABCA7 , and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue‐specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E ( APOE ) , ABCA7 , and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue‐specific expression analyses.

Abstract Introduction: Hyperexcitability, particularly of DRG neurons, is a key driver of persistent pain states including neuropathic pain. Contactin-associated protein-like 2 (CASPR2) is transmembrane protein known to interact and regulate the function of Kv1 channels, important determinants of neuronal excitability. Patients with autoantibodies (-Abs) against CASPR2 commonly have neuropathic pain, and these patient-Abs enhance the excitability of DRG neurons secondary to Kv1 channel disruption, leading to pain-related hypersensitivity. This is also observed after genetic ablation of CASPR2. Conversely, increasing CASPR2 levels in DRG neurons reduces excitability. Objectives: The aim of this study was to assess whether overexpressing CASPR2 could be a potential approach to treat pain. Methods: We generated a Cre-dependent mouse line to express human CASPR2 (R26 LSL:hCNTNAP2(+/+) (CASPR2 OE )) and crossed this with either Hoxb8 Cre or Nav1.8 Cre mice for CASPR2 overexpression in either all DRG neurons or to target nociceptors more selectively. Results: In both lines, CASPR2 was significantly overexpressed in DRG neurons, including at the cell membrane. In comparison to control littermates, overexpression of CASPR2 did not affect acute pain–related behaviour to mechanical or thermal stimulation or nerve injury–induced pain-related hypersensitivity. However, in both overexpression mouse lines, there were significantly reduced nocifensive responses to capsaicin. Although CASPR2 overexpression increased the contribution of α-dendrotoxin–sensitive Kv1 channels to the slowly inactivating outward current I KD , it did not affect total I KD. Conclusion: CASPR2 overexpression in DRG neurons can affect nociception, reducing pain-related behaviours to the noxious stimulant capsaicin, yet is insufficient to reduce mechanical pain–related hypersensitivity caused by nerve injury.