Beta-amyloid Burden Research Articles

Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer’s Disease in Down Syndrome

Background/Objectives: Mitochondrial dysfunction is increasingly recognized as a central contributor to neurodegenerative diseases and age-related cognitive decline. Individuals with Down syndrome (DS) are at high risk of neurodegeneration due to Alzheimer’s disease (AD). This study aims to explore the relationship between mitochondrial dysfunction, brain amyloid-beta (Aβ) deposition, and cognitive decline in this population. Methods: We investigated mitochondrial function, brain amyloid-beta burden, and cognitive performance in a pilot study of a cohort of 10 eligible adults with DS selected from a sample of 28 individuals with DS. Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was used to assess mitochondrial function in skeletal muscle using a post-exercise paradigm, while positron emission tomography using 11C-Pittsburgh compound B (PiB-PET) measured brain Aβ deposition. Cognitive performance was evaluated using the Cambridge Cognitive Examination adapted for individuals with Down syndrome (CAMCOG-DS) and executive function batteries. Results: Significant correlations were observed between slowed phosphocreatine (PCr) recovery in muscle and increased Aβ deposition in key brain regions, particularly the striatum. Cognitive performance inversely correlated with mitochondrial function, with pronounced deficits in memory and executive function tasks. Notably, an individual carrying the APOE-ε4 allele exhibited the poorest mitochondrial function, highest Aβ burden, and most severe cognitive impairment, suggesting a potential interaction between genetic risk and mitochondrial health. Conclusions: These findings highlight the role of mitochondrial dysfunction in DS-associated AD (DSAD) and its impact on cognition in adults. The results support targeting mitochondrial pathways as a potential therapeutic strategy to mitigate AD progression in DS populations. Further research with larger cohorts and longitudinal designs is needed to clarify causative mechanisms and develop effective interventions.

Association of rapid eye movement sleep latency with multimodal biomarkers of Alzheimer's disease.

Sleep disturbances are associated with Alzheimer's disease (AD)and Alzheimer's disease and related dementias (ADRD), but the relationship between sleep architecture, particularly rapid eye movement (REM) sleep, and AD/ADRD biomarkers remains unclear. We enrolled 128 adults (64 with Alzheimer's disease, 41 with mild cognitive impairment [MCI], and 23 with normal cognition [NC]), mean age 70.8±9.6 years, 56.9% female, from a tertiary hospital in China. Participants underwent overnight polysomnography (PSG), amyloid β (Aβ) positron emission tomography (PET), and plasma biomarker analysis: phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and brain-derived neurotrophic factor (BDNF). After adjusting for demographics, apolipoprotein E (APOE) ε4 status, cognition, and comorbidities, the highest tertile of REM latency was associated with higher Aβ burden (β=0.08, 95% confidence interval [CI]: 0.03 to 0.13, p=0.002), elevated p-tau181 (β=0.19, 95% CI: 0.02 to 0.13, p=0.002), and reduced BDNF levels (β=-0.47, 95% CI: -0.68 to -0.13, p=0.013), compared to the lowest tertile. Prolonged REM latency may serve as a novel marker or risk factor for AD/ADRD pathogenesis. Rapid eye movement latency (REML) may be a potential marker for Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) pathogenesis. Prolonged REML was associated with higher amyloid beta (Aβ) burden, phosphorylated tau-181 (p-tau181), and lower brain-derived neurotrophic factor (BDNF) levels. Intervention trial is needed to determine if targeting REML can modify AD/ADRD risk. Slow-wave sleep was not associated with AD/ADRD biomarkers.

Identifying gait differences between Alzheimer's disease and dementia with Lewy bodies and their associations with regional amyloid deposition.

We aimed to compare gait between individuals with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and cognitively unimpaired (CU) individuals and to evaluate the association between gait and regional amyloid beta (Aβ) burden in AD and DLB. We included 420 participants (70 AD, 70 DLB, 280 CU) in the Mayo Clinic Study of Aging (MCSA). Gait was assessed using a pressure-sensor walkway. Aβ deposition was analyzed with Pittsburgh compound B (PiB) positron emission topography (PET). The DLB group had reduced stride velocity, step length, and stride width variability, as well as increased double support percentage (%DS) and variability in step length, swing time, and step time compared to the AD and CU groups. Aβ burden was not associated with any gait outcomes. This study provides additional evidence that gait differs between AD and DLB. Larger studies are needed to investigate associations between Aβ burden and gait outcomes in dementia. Gait was more impaired in dementia than in cognitively unimpaired (CU) controls. Compared with Alzheimer's disease (AD), Dementia with Lewy bodies (DLB) had more impaired pace, variability, and postural control. Step length and double support (%) distinguished DLB and AD with moderate accuracy.

Association Between Late‐Life Depression and Amyloid Beta Burden in Older Adults Without Cognitive Impairment: A. Systematic Review and Meta‐Analysis

AbstractBackgroundLate‐life depression (LLD) is a risk factor for cognitive impairment. Some studies have shown an association between higher amyloid‐beta (Aβ) burden, a known marker of Alzheimer’s Disease (AD), and LLD, but research findings are mixed. We performed a systematic review and meta‐analysis to compare the Aβ burden between cognitively unimpaired subjects with and without LLD.MethodWe searched MEDLINE, Embase, and ScienceDirect for studies comparing Aβ burden between LLD patients and controls (molecular imaging and/or fluid‐biomarker confirmation) and included subjects aged ≥60 years with LLD, and absence of cognitive impairment (MMSE ≥24 and/or description of normal cognition). The review process was performed by 2 independent reviewers (Covidence‐software). A random effects meta‐analysis was executed to evaluate the pooled difference of Aβ burden between LLD and control groups (JASP‐software).Result372 studies were identified and eight met the inclusion‐exclusion criteria (combined sample: 725 LLD subjects and 885 controls). The weighted‐mean age was 69.3 and 68.9 years for subjects and controls. Six studies evaluated Aβ in blood (4 on serum and 2 on plasma, one of them also evaluated PET‐Aβ), and two evaluated cerebrospinal fluid (CSF) (table 1). One of the serum studies (Namekawa) included two subgroups, one with subjects that besides depression after 60 years old also had a history of depression before age 60, and one with participants with a first episode of major depressive disorder after 60 years old. Both subgroups were analyzed separately in the meta‐analysis. The meta‐analysis of plasma and serum studies showed that individuals with LLD had lower levels of Aβ42 (estimate ‐0.344, p<0.001) (Fig. 1) and higher levels of Aβ40/42 ratio (estimate 0.428, p<0.001) compared to controls (Fig. 2). The results remained significant when plasma and serum were analyzed independently.ConclusionIn this systematic review and meta‐analysis, we found significantly lower levels of Aβ42 and higher levels of Aβ40/42 ratio in cognitively unimpaired older adults with LLD compared to controls. These findings support the idea that LLD is associated with AD pathology. This is a relevant area of research for increasing the understanding of AD’s clinical presentation that could potentially impact access to early diagnosis and treatment.

Association of precuneus Aβ burden with default mode network function.

It remains unclear whether the local amyloid-beta (Aβ) burden in key regions within the default mode network (DMN) affects network and cognitive functions. Participants included 1002 individuals from the Chinese Preclinical Alzheimer's Disease Study cohort who underwent 18F-florbetapir positron emission tomography resting-state functional magnetic resonance imaging scanning and neuropsychological tests. The correlations between precuneus (PRC) Aβ burden, DMN function, and cognitive function were investigated. In individuals with high PRC Aβ burden, there is a bidirectional relationship between DMN local function or functional connectivity and PRC Aβ deposition across various cognitive states, which is also linked to cognitive function. Even below thePRC Aβ threshold, DMN function remains related to PRC Aβ deposition and cognitive performance. The findings reveal the critical role of PRC Aβ deposition in disrupting neural networks associated with cognitive decline and the necessity of early detection and monitoring of PRC Aβ deposition. Precuneus (PRC) Aβ burden impacts DMN function in different cognitive stages. High PRC Aβ burden is linked to early neural compensation and subsequent dysfunction. Low PRC Aβ burden correlates with neural changes before significant Aβ accumulation. Changes in DMN function and connectivity provide insights into AD progression. Early detection of regional Aβ burden can help monitor the risk of cognitive decline.

Elevated cerebral blood flow proxy with increased beta-amyloid burden in Alzheimer’s disease preclinical phase evaluated by dual-phase 18F-florbetaben positron emission tomography

This study investigated the earliest change of cerebral blood flow (CBF) and its relationship with β-amyloid (Aβ) burden in preclinical Alzheimer’s disease (AD) employing dual-phase 18F-florbetaben (FBB) PET. Seventy-one cognitively normal (NC) individuals were classified as Aβ negative (Aβ−NC) or positive (Aβ+NC) based on two different cutoff values: an SUVR of > 1.08 and a Centiloid scale of > 20. The PET scans were acquired in two phases: an early phase (0–10 min, eFBB) and a delayed phase (90–110 min, dFBB), which were averaged to generate single-frame images for each phase. Furthermore, an R1 parametric map was generated from the early phase data using a simplified reference tissue model. We conducted regional and voxel-based analyses to compare the eFBB, dFBB, and R1 images between the Aβ positive and negative groups. In addition, the correlations between the CBF proxy R1 and the dFBB SUVR were analyzed. The Aβ+NC group showed significantly higher dFBB SUVR in both the global cerebral cortex and target regions compared to the Aβ−NC group, while no significant differences were observed in eFBB SUVR between the two groups. Furthermore, the Aβ+NC group exhibited significantly higher R1 values, a proxy for cerebral perfusion, in both the global cerebral cortex and target regions compared to the Aβ−NC group. Significant positive correlations were observed between R1 and dFBB SUVR in both the global cerebral cortex and target regions, which remained significant after controlling for demographics and cognitive profiles, except for the medial temporal and occipital cortices. The findings reveal increased CBF in preclinical AD and a positive correlation between CBF and amyloid pathology. The positive correlation between R1 and amyloid burden may indicate a compensatory mechanism in the preclinical stage of Alzheimer’s disease, but to elucidate this hypothesis, further longitudinal observational studies are necessary.

Impaired glymphatic function as a biomarker for subjective cognitive decline: An exploratory dual cohort study.

Subjective cognitive decline (SCD) has been recognized as a potential risk stage for progression to Alzheimer's disease (AD), while glymphatic dysfunction is considered an important characteristic of AD. We hypothesize that glymphatic dysfunction occurs during the SCD stage, aiming to discover potential biomarkers for SCD. Participants from two independent studies, Sino Longitudinal Study on Cognitive Decline (SILCODE, n=654) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=650), representing different ethnicities and disease stages, were included to assess glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Abnormal glymphatic function occurs during the SCD stage, with the ALPS index demonstrating excellent classification performance for SCD and normal controls (area under the receiver operating characteristic curve [AUC]SILCODE=0.816, AUCADNI=0.797). Lower ALPS index indicates higher risk of cognitive progression, which is negatively correlated with Subjective Cognitive Decline Questionnaire 9 scores and amyloid positron emission tomography burden. Our study suggests the ALPS index has the potential to serve as a biomarker for SCD. Glymphatic function characterized by the analysis along the perivascular space (ALPS) index becomes abnormal in subjective cognitive decline (SCD), the earliest symptomatic manifestation and preclinical stage of Alzheimer's disease (AD). The ALPS index demonstrates excellent classification performance for SCD and normal controls in the East Asian and Western cohorts. Participants with a lower ALPS index show a higher risk of clinical progression. The ALPS index is closely associated with serval cognitive scales and amyloid beta burden.

Integrated Genome-Wide Analysis of DNA Methylation and Gene Expression in the Hippocampi of 5xFAD Alzheimer's Disease Mouse Model.

DNA methylation forms 5-methylcytosine and its regulation in the hippocampus is critical for learning and memory. Indeed, dysregulation of DNA methylation is associated with neurological diseases. Alzheimer's disease (AD) is the predominant of dementia and a neurodegenerative disorder. We examined the learning and memory function in 3- and 9-month-old wild-type and 5xfamiliar Alzheimer's disease (5xFAD) transgenic mice by performing the object recognition memory and Y-maze tests, and identified the hippocampal amyloid beta burden. To investigate the epigenetically regulated genes involved in the development or neuropathology of AD, we performed genome-wide DNA methylation sequencing and RNA sequencing analyses in the hippocampus of 9-month-old wild-type and 5xFAD tg mice. To validate the genes inversely regulated by epigenetics, we confirmed their methylation status and mRNA levels. At 9 months of age, 5xFAD tg mice showed significant cognitive impairment and amyloid-beta plaques in the hippocampus. DNA methylation sequencing identified a total of 13,777 differentially methylated regions, including 4484 of hyper- and 9293 of hypomethylated regions, that are associated with several gene ontology (GO) terms including 'nervous system development' and 'axon guidance'. In RNA sequencing analysis, we confirmed a total of 101 differentially expressed genes, including 52 up- and 49 downregulated genes, associated with GO functions such as 'positive regulation of synaptic transmission, glutamatergic' and 'actin filament organization'. Through further integrated analysis of DNA methylation and RNA sequencing, three epigenetically regulated genes were selected: thymus cell antigen 1, theta (Thy1), myosin VI (Myo6), and filamin A-interacting protein 1-like (Filip1l). The methylation level of Thy1 decreased and its mRNA levels increased, whereas that of Myo6 and Filip1l increased and their mRNA levels decreased. The common functions of these three genes may be associated with the neural cytoskeleton and synaptic plasticity. We suggest that the candidate genes epigenetically play a role in AD-associated neuropathology (i.e., amyloid-beta plaques) and memory deficit by influencing neural structure and synaptic plasticity. Furthermore, counteracting dysregulated epigenetic changes may delay or ameliorate AD onset or symptoms.

Lower Locus Coeruleus Integrity Signals Elevated Entorhinal Tau and Clinical Progression in Asymptomatic Older Individuals.

Elevated entorhinal cortex (EC) tau in low beta-amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)-derived locus coeruleus integrity, neocortical beta-amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta-amyloid PET-negative. We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T-MRI of the locus coeruleus, Pittsburgh compound-B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB- sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR-sum-of-boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB- sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden-index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut-off, lower locus coeruleus integrity was associated with a two-fold increase in clinical progression, including mild cognitive impairment. Locus coeruleus integrity has promise as a low-cost, non-invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta-amyloid individuals. ANN NEUROL 2024;96:650-661.

Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology.

To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT308AKT1/total AKT1, but not with pS307IRS-1/total IRS-1 or the density of cells stained positive for pS616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.

Association of whole-person eigen-polygenic risk scores with Alzheimer's disease.

Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.

Gray matter gamma-hydroxy-butyric acid and glutamate reflect beta-amyloid burden at old age.

Gray matter-specific metabolic imaging with high-resolution atlas-based MRSI at 7 Tesla.Higher GABA and glutamate relate to ß-amyloid burden, in an APOE4-dependent manner.Gray matter GABA and glutamate identify older adults with high risk of future AD.GABA and glutamate might reflect altered synaptic and neuronal activity at early AD.

Alterations in Gut Microbiota and Their Correlation with Brain Beta-Amyloid Burden Measured by 18F-Florbetaben PET in Mild Cognitive Impairment Due to Alzheimer's Disease.

(1) Background: This study investigated changes in the gut microbial composition of individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and their relationship with positron emission tomography (PET) amyloid accumulation. (2) Methods: In total, 17 cognitively normal individuals without amyloid-beta (Aβ) accumulation (Aβ-NC) and 24 with Aβ-positive mild cognitive impairment (Aβ+MCI) who underwent 18F-florbetaben PET and fecal bacterial 16S ribosomal RNA gene sequencing were enrolled. The taxonomic compositions of the Aβ-NC and Aβ+MCI groups were compared. The abundance of taxa was correlated with the standardized uptake value ratio (SUVR), using generalized linear models. (3) Results: There were significant differences in microbiome richness (ACE, p = 0.034 and Chao1, p = 0.024), alpha diversity (Shannon, p = 0.039), and beta diversity (Bray-Curtis, p = 0.018 and Generalized UniFrac, p = 0.034) between the Aβ-NC and Aβ+MCI groups. The global SUVR was positively correlated with the genus Intestinibacter (q = 0.006) and negatively correlated with the genera Roseburia (q = 0.008) and Agathobaculum (q = 0.029). (4) Conclusions: In this study, we identified significant changes in the gut microbiota composition that occur in individuals with MCI due to AD. In particular, the correlation analysis results between PET amyloid burden and gut microbial abundance showed that amyloid deposition is associated with a reduction in specific taxa involved in butyrate production.

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer's disease.

JOURNAL/nrgr/04.03/01300535-202419110-00027/figure1/v/2024-03-08T184507Z/r/image-tiff Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer's disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson's and Huntington's diseases, however, the effect of Citri Reticulatae Semen on Alzheimer's disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer's disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer's disease via its neuroprotective autophagic effects.

Maternal fish-oil supplementation reduces presenilin 1 level and the amyloid-beta burden in adult 5xFAD offspring without major changes in brain fatty acids

Omega-3 fatty acid interventions show potential benefits in Alzheimer?s disease (AD) when initiated during its early stages. This study investigated whether maternal diet supplemented with omega-3-rich fish oil (FO) could delay or reduce amyloid beta (A?) formation, a key feature of AD, in 5xFAD transgenic offspring. Dams received FO during mating, pregnancy, and lactation. Brain tissues from female offspring were collected at 2 and 6 months of age. The findings indicated a shift in amyloid precursor protein processing, evidenced by increased soluble amyloid precursor protein ? (sAPP?) levels, suggesting a transition from amyloidogenic to non-amyloidogenic pathway. FO influenced the expression of presenilin 1 and 2 but did not impact A? levels in 2-month-old mice. However, FO reduced the A? burden in the brains of 6-month-old animals. Lipidomic analysis revealed that 5xFAD mice have unimpaired omega-3 acquisition during gestation and lactation in comparison to non-transgenic littermates. However, a response to FO supplementation was found in non-transgenic offspring only, indicating that alterations in brain lipids are not the primary mechanism of FO-induced A? decline in 5xFAD. In conclusion, FO did not prevent or delay amyloid pathology in genetically predisposed animals but did mitigate its progression, suggesting mechanisms that warrant further investigation.

Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's disease.

Microglial endolysosomal (dys)function is strongly implicated in neurodegenerative disease. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer's disease (AD) models and human AD brain, and that the emergence of this state is emphasised in females. Cst7 (encoding cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-/-AppNL-G-F microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aβ) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-/-AppNL-G-F microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aβ burden. Overall, our study reveals functional roles for one of the most commonly upregulated genes in microglia across disease models, and the sex-specific profiles of Cst7-/--altered microglial disease phenotypes. More broadly, the findings raise important implications for AD including crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

Effect of white matter hyperintensities and amyloid on neurodegenerative change and cognitive trajectory in cognitively unimpaired older adults

AbstractBackgroundOverwhelming evidence of association between amyloidosis and neurodegeneration, particularly in the hippocampus, has been reported. However, the recognition of cerebrovascular disease (CVD), the most common comorbidity in elderly patients with dementia2, as a contributor to neurodegeneration process has remained modest. The objective of this study is to investigate the contributions of amyloidosis, as measured by amyloid PET, and CVD, as reflected by white matter hyperintensity (WMH), on neurodegenerative change and how their combination impacts cognitive trajectory in cognitively unimpaired (CU) individuals.Method139 CU participants from the University of California, Davis Alzheimer’s Disease Research Center diversity cohort received at least two cognitive assessments and underwent a PET exam at baseline, and baseline and follow‐up MRI imaging (Table 1). Z‐score measures of DVR19 and SUVR20 values were used as measure of baseline amyloid beta (Aβ) burden. Baseline WMH volume was log‐transformed and regressed against intracranial volume (TCV). Four markers of neurodegeneration were used, including hippocampal volume (regressed against TCV), mean cortical GM thickness and two cognitive‐related signature region of interest (sROI), including episodic memory and executive function. We used structural equation modeling (SEM) analyses (Figure 1) to investigate associations between cognitive performance trajectories (∼6 years), including episodic memory and executive function, and baseline Aβ, baseline WMH and change in the four neurodegeneration markers.ResultSEM analysis revealed significant effects of increased baseline Aβ and greater baseline WMH on accelerated decrease in neurodegeneration marker measures in all models (Figure 2). Increased baseline amyloid and WMH, but not neurodegenerative change measures, were also associated with accelerated decline in episodic memory performance (pvalues<0.05, Figure 2, panels A‐C‐E). Finally, increased baseline Aβ and accelerated decreased in cortical GM and sROI thickness were found to be associated with accelerated decline in executive function (pvalues<0.05, Figure 2, panels B‐D‐F).ConclusionOur findings suggest that both CVD and amyloidosis simultaneously impact neurodegenerative change and that these pathologies are associated with cognitive trajectories, but the dynamics of these trajectory are different for executive and memory, suggesting different early path of vulnerability for these domains and emphasizing the need to thoroughly understand the interaction between amyloidosis, CVD, and neurodegeneration.

Examining the diagnostic value of the mnemonic discrimination task for classification of cognitive status and amyloid-beta burden

Alzheimer's disease (AD) is the most common type of dementia, characterized by early memory impairments and gradual worsening of daily functions. AD-related pathology, such as amyloid-beta (Aβ) plaques, begins to accumulate many years before the onset of clinical symptoms. Predicting risk for AD via related pathology is critical as the preclinical stage could serve as a therapeutic time window, allowing for early management of the disease and reducing health and economic costs. Current methods for detecting AD pathology, however, are often expensive and invasive, limiting wide and easy access to a clinical setting. A non-invasive, cost-efficient platform, such as computerized cognitive tests, could be potentially useful to identify at-risk individuals as early as possible. In this study, we examined the diagnostic value of an episodic memory task, the mnemonic discrimination task (MDT), for predicting risk of cognitive impairment or Aβ burden. We constructed a random forest classification algorithm, utilizing MDT performance metrics and various neuropsychological test scores as input features, and assessed model performance using area under the curve (AUC). Models based on MDT performance metrics achieved classification results with an AUC of 0.83 for cognitive status and an AUC of 0.64 for Aβ status. Our findings suggest that mnemonic discrimination function may be a useful predictor of progression to prodromal AD or increased risk of Aβ load, which could be a cost-efficient, noninvasive cognitive testing solution for potentially wide-scale assessment of AD pathological and cognitive risk.

6 Posterior cerebral artery-defined white matter hyperintensities are associated with object domain memory and transentorhinal volume independently of global beta-amyloid burden

Objective:White matter hyperintensities (WMH) are a radiological marker of small vessel cerebrovascular disease that are related to cognition and memory decline in aging and Alzheimer’s disease (AD). However, the mechanisms that link WMH to memory impairment and whether they interact with or act independently of AD pathophysiology are unclear. The transentorhinal cortex (BA35) is among the earliest anatomical regions to show tau deposition and subsequent atrophy, and baseline posterior WMH is related to longitudinal cortical thinning of the entorhinal cortex. However, it is unclear whether regional WMH are related to BA35 volume specifically, and whether this relationship is influenced by amyloid-β (Aβ) burden. We hypothesized that WMH in the vascular territory of the posterior cerebral artery (PCA), which perfuses both posterior and medial temporal lobe regions, would be associated with reduced BA35 volume and with lower memory in older adults independently of Aβ.Participants and Methods:114 older adults without dementia, aged 60 to 98 years (mean (SD) = 78.31 (11.02), 71 (62.8%) women), were included. Regional WMH volumes were derived from T2-FLAIR images using ANTs, a vascular territory atlas and manual editing. Global Aβ was assessed with 18F-florbetapir PET, using SUVR of a cortical composite region (FBP mean SUVR) with a cerebellar reference region. Total transentorhinal (BA35) volume was derived using T1 and T2-weighted images using ASHS. To assess hippocampal pattern separation ability, an index of episodic memory, participants completed both object (MDT-O) and spatial (MDT-S) versions of a mnemonic discrimination task, with the lure discrimination index as the outcome. Using linear regressions, we first tested for associations among PCA-defined WMH, Aβ, BA35 volume, and MDT-S and MDT-O scores. We then tested whether the relationship between PCA-defined WMH and MDT-O performance was mediated by BA35 volume and whether this mediation was moderated by Aβ. All models adjusted for age, sex, and education.Results:PCA-defined WMH were related to higher FBP mean SUVR (b=0.287, p=0.042) and lower BA35 volume (b=-0.222, p=0.038). PCA-defined WMH were also negatively related to MDT-O performance (b=-0.229, p=0.044), but not to MDT-S (b=-0.171, p=0.118). FBP mean SUVR was not related to BA35 volume (b=-0.131, p=0.344) or MDT performance (MDT-S: b=-0.138, p=0.348; MDT-O: b=0.059, p=0.690). Furthermore, FBP mean SUVR did not interact with PCA-defined WMH to predict memory performance (interaction b=-0.039, p=0.973), nor BA35 volume (interaction b=-0.140, p=0.894). The association of PCA-defined WMH to MDT-O was fully mediated by BA35 volume (indirect effect b=-0.0005, 95% CI (-0.0014, -0.0003)). This mediation was not moderated by FBP mean SUVR (indirect effect b=-0.00001, 95% CI (-0.001, 0.001)).Conclusions:We found that PCA-defined WMH were related to memory performance in older adults, and this association is fully mediated by transentorhinal volume. While PCA-defined WMH are related to higher global Aβ burden, there is no interaction between PCA-defined WMH and Aβ on BA35 volume. These findings point to an amyloid-independent vascular pathway towards memory decline in aging and AD. Future work should examine whether the pathway linking PCA-defined WMH to transentorhinal cortex atrophy and subsequent memory decline is mediated by regional tau pathology.

An autonomic mode of brain activity.

The relevance of interactions between autonomic and central nervous systems remains unclear for human brain function and health, particularly when both systems are challenged under sleep deprivation (SD). We measured brain activity (with fMRI), pulse and respiratory signals, and baseline brain amyloid beta burden (with PET) in healthy participants. We found that SD relative to rested wakefulness (RW) resulted in a significant increase in synchronized low frequency (LF, < 0.1Hz) activity in an autonomically-related network (AN), including dorsal attention, visual, and sensorimotor regions, which we previously found to have consistent temporal coupling with LF pulse signal changes (regulated by sympathetic tone). SD resulted in a significant phase coherence between the LF component of the pulse signal and a medial network with peak effects in the midbrain reticular formation, and between LF component of the respiratory variations (regulated by respiratory motor output) and a cerebellar network. The LF power of AN during SD was significantly and independently correlated with pulse-medial network and respiratory-cerebellar network phase coherences (total adjusted R2 = 0.78). Higher LF power of AN during SD (but not RW) was associated with lower amyloid beta burden (Cohen's d = 0.8). In sum, SD triggered an autonomic mode of synchronized brain activity that was associated with distinct autonomic-central interactions. Findings highlight the direct relevance of global cortical synchronization to brain clearance mechanisms.