•Vascular endothelial growth factor (VEGF) signaling is implicated in Alzheimer's disease.•The VEGF family exhibits differing effects across brain regions and cell types.•VEGF-related processes in AD ...are hard to interpret due to signaling complexity.•VEGFB and FLT1 are associated with worse neuropathological progression of AD.•FLT4 and NRP2 expressed in the caudate nucleus exhibit protective effects.
The vascular endothelial growth factor (VEGF) signaling family has been implicated in neuroprotection and clinical progression in Alzheimer's disease (AD). Previous work in postmortem human dorsolateral prefrontal cortex demonstrated that higher transcript levels of VEGFB, PGF, FLT1, and FLT4 are associated with AD dementia, worse cognitive outcomes, and higher AD neuropathology. To expand prior work, we leveraged bulk RNA sequencing data, single nucleus RNA (snRNA) sequencing, and both tandem mass tag and selected reaction monitoring mass spectrometry proteomic measures from the post-mortem brain. Outcomes included AD diagnosis, cognition, and AD neuropathology. We replicated previously reported VEGFB and FLT1 results, whereby higher expression was associated with worse outcomes, and snRNA results suggest microglia, oligodendrocytes, and endothelia may play a central role in these associations. Additionally, FLT4 and NRP2 expression were associated with better cognitive outcomes. This study provides a comprehensive molecular picture of the VEGF signaling family in cognitive aging and AD and critical insight towards the biomarker and therapeutic potential of VEGF family members in AD.
Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci ...mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer’s dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.
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•Dlgap2 QTL associates with working memory decline in Diversity Outbred (DO) mice•DLGAP2 variants associate with AD by GWAS in human populations•DLGAP2 gene and protein expression are associated with cognitive decline in humans•Results highlight translational relevance of DO mice for studying complex traits
Ouellette et al. identify Dlgap2 as a potential modifier of working memory in an aged Diversity Outbred (DO) mouse population. The cross-species significance of this finding is highlighted by the association between human DLGAP2 and Alzheimer’s disease phenotypes at the variant, gene expression, and methylation levels.
To investigate a new surgical and signal processing technique that provides apical stimulation of the cochlea using a cochlear implant without extending the length of the electrode array.
Three adult ...patients who underwent cochlear implantation using this new technique.
The patients received a cochlear implant. The surgery differed from the standard approach in that a ground electrode was placed in the cochlear helicotrema via an apical cochleostomy rather than in its typical location underneath the temporalis muscle. Clinical fitting was modified such that low frequencies were represented using the apically placed electrode as a ground.
Pitch scaling and speech recognition.
All surgeries were successful with no complications. Pitch scaling demonstrated that use of the apically placed electrode as a ground lowered the perceived pitch of electric stimulation relative to monopolar stimulation. Speech understanding was improved compared with preoperative scores.
The new surgical approach and clinical fitting are feasible. A lower pitch is perceived when using the apically placed electrode as a ground relative to stimulation using an extracochlear ground (i.e., monopolar mode), suggesting that stimulation can be provided more apically without the use of a longer electrode array. Further work is required to determine potential improvements in outcomes and optimal signal processing for the new approach.
Background
Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying these “resilient” individuals may lead to ...the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of AD neuropathology, with recent studies highlighting notable sex‐specific genetic drivers of AD pathogenesis. We sought to extend this work by elucidating sex‐specific genetic factors underlying resilience to AD.
Method
We used our published genetic resilience pipeline to assess sex‐specific genetic predictors (Dumitrescu et al., 2020). Briefly, we used modern psychometric approaches to harmonize cognitive measures across four cohorts of cognitive aging (N=5054), in‐vivo amyloid PET across two studies, and leveraged autopsy measures of amyloidosis (CERAD staging) across two studies. A continuous measure of resilience was quantified using a latent variable framework whereby higher scores reflected better‐than‐predicted cognitive performance given amyloidosis level and lower scores reflected worse‐than‐predicted performance. We then performed sex‐stratified GWASs and sex‐interaction GWASs, covarying for age and the first three principal components and meta‐analyzed across cohorts. Finally, we performed sex‐stratified genetic correlation analyses (GNOVA) between our meta‐analysis results and summary statistics from 63 complex traits.
Result
Among individuals with normal cognition, we identified a female‐specific locus on chromosome 10 (rs827389, p(females)=7.4E‐09, p(males)=0.64, p(interaction)=8.3E‐05, MAF=0.46). This variant is a modest eQTL for KIN (p=0.003), a gene encoding a DNA/RNA binding protein (http://www.braineac.org). In our genetic correlation analyses, we observed male‐specific correlations between resilience and two heart rate‐related traits, whereby higher resilience was associated with lower genetic risk for poor heart health. We also observed opposing genetic correlations between resilience and multiple sclerosis such that females with higher resilience scores had lower susceptibility for multiple sclerosis (p.FDR=0.009), whereas males with higher resilience had higher susceptibility (p.FDR=0.001).
Conclusion
Our results highlight sex‐specific genes and pathways that may drive resilience in a biological sex‐dependent manner, although independent replication is needed. The best target to enhance resilience to AD neuropathology may depend on sex and genetic context of an individual. Future work should continue to evaluate sex differences in the genetic architecture of the AD neuropathological cascade.
Background
Previous work has implicated associations between the angiogenic vascular endothelial growth factor (VEGF) gene family and Alzheimer’s disease (AD) and associated cognitive decline. ...Specifically, we have shown that mRNA expression of VEGFB, PGF, FLT1, and FLT4 are associated with AD diagnosis, lower cognition prior to death, faster cognitive decline, and higher AD neuropathology at death. However, we wanted to explore whether these associations persisted at the protein level.
Method
Detailed cognitive and neuropathological data were obtained from 1,084 participants in the Religious Orders Study and Rush Memory and Aging Project. Selected reaction monitoring mass spectrometry was used to quantify VEGF protein levels in dorsolateral prefrontal cortex tissue. A total of 22 peptides representing five VEGF family proteins were available for analysis. Linear regression assessed VEGF proteomic associations with cognition adjacent to death and with amyloid and tau burden at autopsy. Mixed‐effects regression quantified VEGF associations with cognitive decline. Models covaried for age at death, sex, post‐mortem interval, and interval to death, with secondary models covarying for post‐mortem amyloid and tau burden. P‐values were corrected using the false discovery rate (fdr) procedure.
Result
Higher levels of VEGFB and FLT1 peptides were associated with lower cognition prior to death (p.fdr≤0.031), as well as with faster cognitive decline (p.fdr≤0.016), while NRP1 peptides were associated with slower cognitive decline (p.fdr=0.010). VEGFB, VEGFA, and FLT1 peptides were positively associated with higher amyloid burden (p.fdr≤0.012), while NRP1 peptides were negatively associated (p.fdr=0.003). VEGFB and FLT1 peptides were also associated with higher tau burden at death (p.fdr≤0.041). Cognitive associations remained when covarying for neuropathology burden. Finally, only FLT1 peptides were differently expressed in AD cases and controls (β≥0.12, p.fdr≤0.024).
Conclusion
Proteomic results are highly consistent with previous mRNA findings, strengthening the hypothesis that VEGF’s role in AD‐related cognitive decline centers on VEGFB‐FLT1 signaling. The associations remained largely significant even when covarying for pathological burden, suggesting VEGF family signaling independently contributes to the clinical manifestation of AD. Interestingly, since NRP1 amplifies VEGF family angiogenic signaling, NRP1’s association with slower cognitive decline at the protein level may reflect a partially‐successful attempt to rescue cognition by increasing blood flow.
Background
APOE‐ε4 is the strongest common genetic risk factor for Alzheimer’s disease (AD) and contributes to worse cognition. However, many carriers of the APOE‐ε4 allele remain cognitively normal ...throughout life, suggesting resilience factors may exist that protect the brain. We leverage a unique statistical design to identify modifiers of APOE effects on cognition by first discovering gene modifiers leveraging RNA sequencing (RNAseq) from whole blood and then replicating any observed modifiers with brain RNAseq from an independent cohort. Transcripts that modify the association between APOE and cognitive decline may highlight pathways of risk or resilience that could be repurposed as targets for intervention.
Method
Cognition, RNAseq from whole blood, and APOE genotype were obtained from 336 individuals from the Vanderbilt Memory and Aging Project (VMAP; mean(SD) age=72.9(7.3), % male=59, % mild cognitive impairment=39). RNAseq data were quantile normalized and batch corrected. Regression and mixed‐effects regression models assessed the interaction between baseline gene expression and APOE‐ε4 or APOE‐ε2 positivity on both baseline and longitudinal decline in memory, adjusting for baseline age and sex. Results were replicated using bulk dorsolateral prefrontal cortex RNAseq data in 618 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP). Results were corrected for multiple comparisons (60,669 genes) using the false discovery rate method.
Results
Cross‐sectionally, RNASE6 interacted with APOE‐ε4 status on memory (β=‐1.16, p=4.35x10‐8) whereby low RNASE6 expression was associated with better memory performance at baseline among APOE‐ε4 carriers, but high RNASE6 expression was associated with worse memory performance among APOE‐ε4 carriers (Figure 1). These results replicated in brain RNAseq data from ROS/MAP (β=‐0.2, p=0.0009, Figure 2). There were no significant interactions longitudinally or with APOE‐ε2.
Conclusion
RNASE6 encodes a protein involved in innate immunity, including antimicrobial and antiviral activity. It has not been previously associated with AD or AD‐related cognitive decline, though it has been identified in a co‐expression network module with other inflammatory genes, such as TYROBP (DAP12), previously linked to AD. Together, these data implicate neuroinflammatory regulation in cognitive decline, and suggest that innate immune signaling may contribute to the regulation of resilience and susceptibility to AD among APOE‐ε4 carriers.
Background
There are notable sex differences in the clinical manifestation of Alzheimer’s disease (AD), including differences in baseline and longitudinal changes in memory performance. However, ...sex‐stratified models have not been routinely incorporated into genetic studies of cognitive performance or decline. We sought to identify sex‐specific genetic predictors of memory performance in aging adults.
Method
We obtained harmonized memory scores from 11,601 females and 8,885 males from 7 cohorts of cognitive aging. We calculated scores using latent variable modeling techniques anchored on overlapping neuropsychological test items across datasets to perform both sex‐stratified and sex‐interaction genome‐wide association studies in each cohort using mixed‐effects regression models to assess genetic associations with baseline memory score and rate of memory decline. Covariates included age at baseline and population principal components. We then combined results in a fixed‐effect meta‐analysis.
Results
As expected, we observed robust associations at the APOE locus in males and females in both baseline and longitudinal models. Additionally, we identified a sex‐specific locus for longitudinal memory performance (interaction‐p=2.54e‐6) on chromosome 7 within LINC‐PINT that was genome‐wide significant in males (index SNP= rs66754621; p=1.62e‐8; MAF=0.20), but not females (p=0.65). This variant is in an enhancer region within several brain regions, as well as within a promoter‐anchored chromatin interaction loop and a methylation eQTL in the prefrontal cortex. No female‐specific loci were identified. Interestingly, we did observe nominal associations in baseline memory at some known AD loci, including male‐specific effects at MS4A6A, FERMT2, and KAT8 (interaction ps=0.0026, 0.027, and 0.0058, respectively) and opposing effects between males and females at INPP5D (interaction p=0.0021).
Conclusion
These results highlight a novel male‐specific locus of memory performance on chromosome 7 near the LINC‐PINT gene. LINC‐PINT is upregulated in the substantia nigra in Parkinson’s disease and is downregulated in multiple brain regions over the course of normal aging, making it a fascinating male‐specific candidate gene. Replicate and functional analyses of the region are ongoing to verify our finding and elucidate the biological mechanism. Our results add to the growing body of literature suggesting that there are sex‐specific genetic contributors to cognitive decline.
While telomere shortening, a marker of cellular aging, may impact the progression of age-related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of ...Alzheimer's disease (AD) pathology.
Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid-β, tau, and APOE-ε4. Secondary analyses assessed brain volume and thickness outcomes.
Longer telomeres at baseline were associated with faster executive function decline. Amyloid-β and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker-positive individuals.
Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.
Abstract
Preclinical Alzheimer’s disease describes some individuals who harbour Alzheimer’s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect ...some individuals from Alzheimer’s-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume.
We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including APOE-ɛ4 and APOE-ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n = 808) where amyloid burden was assessed by Pittsburgh Compound B (11C-PiB) positron emission tomography.
In this study, we found that APOE-ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P = 1.46 × 10−8; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P = 0.0112) where amyloid burden was assessed by positron emission tomography.
In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.
Seto et al., report a novel locus on chromosome 3 that modulates the association between baseline amyloid levels and neurodegeneration. Minor allele carriers of rs62263260 exhibit faster hippocampal atrophy among high brain amyloid burden. Functional annotation links rs62263260 to the SEMA5B gene, which is involved in axonal guidance and neurodevelopment.
Graphical Abstract
Graphical Abstract
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