Cortical Aβ Research Articles

Discovery of Novel Ophthalmic Imaging Biomarkers for Neurodegenerative Disease

AbstractBackgroundThe retina is increasingly investigated as a site of Alzheimer’s Disease (AD) manifestation, with amyloid β (Aβ) plaques being found in the retina of AD and mild cognitively impaired (MCI) patients, however functional changes in the retina are poorly understood. Retinal imaging techniques can be utilized for neurodegenerative biomarkers, since the retina is the only CNS organ available for noninvasive tracking.MethodRetinal imaging techniques were using to compare the retina of wild‐type (WT) or AD transgenic mice containing the APP: Swedish and Indiana mutation expressed under the prion promoter (TgCRND8) at 20 and 30 weeks of age (n = 10 mice per genotype). Optical coherence tomography (OCT) for retinal thickness assessment, Fundus Autofluorescence Imaging (FAF) for aggregate visualization, and electroretinogram (ERG) for retinal neuronal electrical activity were performed. Aβ ELISA was also performed on retina and cortex to evaluate amyloid burden correlation.ResultMean retinal insoluble Aβ 1‐42 was significantly elevated in TgCRND8 mice relative to WT at 23 weeks (35 vs 4.2 pg/mL, P<0.05) and 42 weeks (77.9 vs 7.5 pg/mL, P<0.05), and correlated with insoluble cortical brain Aβ 1‐42 (Pearson’s r = 0.847, P = 0.001). Total retinal thickness was significantly higher in TgCRND8 mice relative to WT (233 µm vs 225 µm, P<0.01). Specifically, the retinal nerve fiber layer (RNFL) was thicker in TgCRND8 mice (28.5 vs 22.9 µm, P<0.01). FAF imaging revealed significant autofluorescent aggregate detection in TgCRND8 mice both in the RNFL (94.3 vs 59.8 spots, P<0.01) and outer plexiform layer (OPL) (87.8 vs 49.3 spots, P<0.01). Lastly ERG revealed reduced b wave amplitude in TgCRND8 mice relative to WT (197.45 vs 457.9 µV, P<0.001) and photopic negative response (PhNR) wave amplitude (8.2 µm vs 25.7 457.9 µV, P<0.001). These values are indicative of dysfunctional bipolar and retinal ganglion cell electrical activity.ConclusionTgCRND8 mice have functional changes in retina thickness, FAF lipofuscin deposition, and ERG, which may prove invaluable as biomarkers for pre‐clinical AD diagnosis, monitoring and drug efficacy trials.

Plasma biomarker and neuroimaging changes in a Chinese community aging cohort: The Greater‐Bay‐Area Healthy Aging Brain Study (GHABS)

AbstractBackgroundTo investigate the alternations of β‐amyloid (Aβ), tau, neurodegeneration, and cognition in different stages of Alzheimer’s disease (AD) in the Chinese community aging population is important for early diagnosis and intervention of AD in China.MethodWe recruited 422 Greater‐Bay‐Area Healthy Aging Brain Study (GHABS) participants from the community and completed cognitive assessments, including 100 cognitively unimpaired (CU), 189 subjective cognitive decline (SCD), 82 mild cognitive impairment (MCI) and 51 AD dementia individuals. Among them, 343 individuals had plasma Aβ42/Aβ40, p‐Tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) data measured by the Simoa platform. Furthermore, 159 and 96 individuals had concurrent MRI and 18F‐D3‐FSP Aβ PET scans, respectively. Generalized linear models were used to compare plasma biomarkers, AD typical cortical FSP Aβ standard uptake value ratio (SUVR), residual hippocampal volume (rHCV), and cognitive scores between different clinical and A/T (A: plasma Aβ42/Aβ40, T: plasma p‐Tau181) groups, controlling for age and sex. Multiple comparison corrections were conducted (Benjamini‐Hochberg, p<0.05). The association of plasma Aβ42/Aβ40 and p‐Tau181 with plasma NfL, GFAP, Aβ PET, rHCV, MoCa, and SCD‐Q were also investigated, including age, sex, and diagnosis as the covariates.ResultSCD individuals had higher plasma p‐Tau181 (standardized β (βstd) = 0.251[95% confidence interval (ci): 0.031, 0.472], p = 0.038) and GFAP (βstd = 0.259[95% ci: 0.035, 0.483], p = 0.023) than the CU individuals (Figure 1). Compared to the A‐/T‐ group, A+/T+ individuals had more (p<0.001) abnormal changes in all the plasma biomarkers, Aβ PET, rHCV, and MoCa, and A‐/T+ individuals had more hippocampal atrophy (p = 0.012) and marginal higher plasma NfL (p = 0.074) (Figure 2). Continuously, lower plasma Aβ42/Aβ40 was only related to higher plasma GFAP (p<0.001), whereas plasma p‐Tau181showed significant association with plasma NfL (p<0.001), plasma GFAP (p = 0.026), Aβ PET (p = 0.028), and MoCA (p = 0.023) (Figure 3).ConclusionThis study summarizes the characteristics of plasma biomarkers and brain imaging of AD and provides novel insights into the alternations of Aβ, tau, neurodegeneration, neuroinflammation, and cognition in different stages of AD in Southern China’s aging population. These findings are critical for using plasma biomarkers and neuroimaging to detect early AD changes in China.

Clinical Phenotypes of Alzheimer’s Disease: Pathological Correlates of Regional Cortical Volume

AbstractBackgroundRecent studies highlight distinct patterns of cortical atrophy in amnestic (typical) and non‐amnestic (atypical – behavioural, dysexecutive and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional phenotypic MRI patterns of cortical atrophy, and their association with Amyloid‐beta (Aβ), phosphorylated Tau (pTau), and axonal degeneration (NfL).MethodPostmortem In‐situ 3DT1 3T‐MRI data were collected for 28 AD (14 typical, 14 atypical) and 10 control brain donors. Images were segmented using QyScore® and regional volumes according to the AAL3 atlas were obtained. At subsequent autopsy, Eight brain regions from the right hemisphere were selected and immunostained for Aβ (4G8), pTau (AT8), and Neurofilament light (NfL), and quantified for area% load. Group comparisons and MRI volume‐pathology associations were analyzed using linear models with covariates age, gender, postmortem delay, and intracranial volume when applicable.ResultsWhen assessing regional cortical volumes, compared to controls, typical AD showed a more parietal‐temporal, while atypical AD showed a more a frontal‐temporal atrophy pattern (fig1).Typical and atypical phenotypes showed different pathological load across all selected regions in both Aβ and NFL (p = 0.032,p = 0.0007, respectively). Subsequent explorative assessment indicates a difference in regional pTau distribution between behavioural, dysexecutive and visuospatial subtypes, specifically in the occipital region (fig2).Addressing MRI‐pathology associations across all selected regions, we observed a positive association between cortical volume and Aβ in typical AD (β = 1.98,p = 0.026), while both pTau and NFL showed a negative association (β = ‐0.26,p = 0.004; β = ‐2.00,p = 0.001, respectively). In atypical AD, only NFL showed a significant negative association (β = ‐2.27,p<0.001) with cortical volume. Regionally (fig3), only NfL associated with MRI volume; with the precuneus in both typical and atypical AD (β = ‐2.81,p = 0.044; β = ‐3.81,p = 0.011, respectively), and with posterior cingulate cortex volume in atypical AD (β = ‐3.24,p = 0.045).ConclusionThis study found varying atrophy patterns in AD phenotypes when compared to controls. Across all selected regions, typical AD showed volume‐pathology associations with Aβ, pTau and axonal damage, while atypical AD only showed associations with axonal damage, indicating a possible difference in volume‐pathology associations between phenotypes. Regionally, cortical volume was predominantly associated with axonal damage, rather than Aβ or pTau protein accumulation, in parietal regions.

Risk architecture for altered hippocampal connectivity in normal aging differ between men and women

AbstractBackgroundFunctional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don’t provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes.MethodOur study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline).ResultThree ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women.ConclusionWe observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies.

Osteopontin exhibits a bidirectional relationship with Alzheimer’s disease pathology in asymptomatic individuals with a parental history of sporadic Alzheimer’s disease

AbstractBackgroundOsteopontin (OPN) is a secreted protein that plays pivotal roles in the recruitment and activation of immune cells, cell survival, and tissue repair following injury. OPN has been demonstrated to be increased in the cerebrospinal fluid (CSF) and brains of individuals with Alzheimer’s disease (AD). However, in order to elucidate the role of OPN in the asymptomatic stage of sporadic AD, we analyzed data from the PREVENT‐AD cohort, which consists of asymptomatic individuals with a parental or multi‐sibling history of AD.MethodThe Olink Proximity Extension Assay was used to measure CSF levels of OPN. CSF levels of amyloid beta (Aβ1‐42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio). Participants were staged as CSF Aβ1‐42 or t‐Tau positive according to specified thresholds of 989 pg/mL and 336 pg/mL, respectively. CSF levels of synaptic proteins, including GAP43, SYT1, SNAP25 and NRGN were measured by immunoprecipitation followed by mass spectrometry. Tau and Aβ positron emission tomography (PET) burdens were measured using 18F‐AV1451 and 18F‐NAV4694.ResultAβ(+)/Tau(‐) individuals displayed a reduction in CSF OPN levels, relative to Aβ(‐)/Tau(‐) individuals (p = 0.001). Furthermore, Aβ(+)/Tau(+) individuals exhibited a significant increase in CSF OPN levels relative to Aβ(+)/Tau(‐) individuals (p < 0.001), and at a trend level, to Aβ(‐)/Tau(‐) individuals (p = 0.069). In addition, CSF OPN levels were positively correlated with synaptic markers in the CSF, including GAP43 (p < 0.001), SYT1 (p = 0.001), SNAP25 (p < 0.001) and NRGN (p = 0.004). Finally, in PET imaging analyses, CSF OPN levels were positively correlated with pTau burden in the entorhinal cortex (p = 0.009), fusiform gyrus (p = 0.030) and lingual gyrus (p = 0.003). However, CSF OPN levels were not correlated with global cortical Aβ burden (p = 0.374).ConclusionOur results suggest that early Aβ pathology dampens OPN levels in asymptomatic individuals with a family history of AD. Furthermore, our data provide compelling evidence that OPN plays a critical role in the compensatory response to neurofibrillary tangle formation, neuronal loss and synaptic dysfunction. Finally, our findings reveal that OPN may be a valuable therapeutic target.

Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population

AbstractBackgroundAlzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.MethodMeasures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐ε4 genotype, β‐amyloid (Aβ) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aβ was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aβ+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aβ levels and cognition covarying for the participant’s age, sex, and years of education where relevant.ResultAs previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aβ (p<0.001). The association between Aβ and history in both parents remained significant when covarying for APOE‐ε4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐ε4 and Aβ. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p<0.001) and in those with only maternal family history (n = 1776, p<0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: β = 0.03, p<0.001 in individuals with maternal history, β = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (βmaternal = 0.02, pmaternal = 0.01; βpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.ConclusionWe confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐ε4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aβ burden among asymptomatic older individuals.

Specific Association of Worry and Amyloid‐β Deposition in Cognitive Unimpaired Older Adults

AbstractBackgroundAnxiety symptoms are common in cognitively unimpaired (CU) older adults prior to the onset of cognitive impairment. Evidence suggests that anxiety symptoms may be sequelae of amyloid‐beta (Aβ) deposition in early Alzheimer’s disease (AD) and/or anxiety may potentiate the pathophysiologic process. Despite this pivotal role, the specific components of anxiety associated with high brain Aβ in CU older adults are relatively unknown. It was previously reported that Aβ deposition is associated with a global anxiety score measured by State‐Trait Anxiety Inventory‐6 (STAI‐6) but not depression measured by Geriatric Depression Scale (GDS) total scores. Here, we examined the specific associations of individual anxiety symptoms with Aβ.MethodOlder adult participants were screened for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study (“A4 study”) and underwent assessments of anxiety (STAI‐6), depression (GDS), cognitive performance (MMSE and Preclinical Alzheimer Cognitive Composite /PACC), subjective cognition (Cognitive Function Instrument/CFI) and cortical Aβ deposition using Florbetapir PET standardized uptake value ratio (SUVR). Linear regression models estimated associations of STAI‐6 items, “calm,” “tense,” “upset,” “relax,” “content,” and “worry,” with Aβ deposition, adjusting for multiple potential confounders.ResultThe sample (n = 4486) were older adults ages 65 ‐ 85 (mean [SD] age, 71.29 [4.67] years, included 2647 women (59%) and 1323 (29.5%) who were classified as Aβ+. STAI‐6 total score ranged from 6 ‐ 24 (Mean 9.9 [3.1]). A significant positive association was found between the anxiety item measuring “worry”, and Aβ, adjusting for age, sex, education, marital status, depression (GDS), objective cognition (MMSE or PACC), and subjective cognition (CFI) [Table 1]. There were other significant (negative) associations between items measuring “calm” and “relax” and Aβ in similar regression models. Only the association of “worry” with Aβ remained significant after further adjustment for global anxiety measured by the total STAI‐6 score.ConclusionIn a large, well‐characterized sample of CU older adults, worry was significantly and most strongly associated with Aβ, independent of psychosocial factors, subjective and objective cognition and global anxiety. These findings suggest that self‐reported worry may have unique explanatory value in the clinical assessment of CU older adults at high risk of AD and cognitive impairment.

Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk.

Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-β [Aβ]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk. Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease. Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits.

Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ). The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits. Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments. Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

The novel visual cognitive assessment test correlates well with plasma oligomeric amyloid beta in patients with mild cognitive impairment

AbstractBackgroundOligomeric Amyloid Beta (OAβ), is representative of a soluble, neurotoxic and pathogenic form of Aβ, which has been found to function as upstream drivers of Alzheimer’s Disease pathology (Tolar et al., 2021). It serves as a contributory factor towards the formation of cortical Aβ plaques and neurofibrillary Tau tangles, and has been found to induce oxidative stress, synaptic toxicity and neuroinflammation (Tolar et al., 2021). The pathology culminates in neuronal dysfunction/death and resultant neurodegeneration which has been found to manifest clinically as symptoms of cognitive decline. OAβ has been found to correlate with the severity of cognitive performance, as well as brain volume reduction (An et al., 2017, Wang et al., 2017, Meng et al., 2019, Youn et al., 2019, Babapour Mofrad et al., 2021). Nevertheless, its effect on language neutral cognitive tests ‐ the novel Visual Cognitive Assessment Test (VCAT) developed and validated by our team of neurologist and neuropsychologists; remains to be evaluated (Kandiah et al., 2016, Lim et al., 2018, Low et al., 2020).MethodsA cross‐sectional pilot study was conducted in a cohort of 63 patients, clinically diagnosed with mild cognitive impairment (MCI). The patients underwent cognitive evaluation tests, Multimer Detection System (MDS) based plasma OAβ analysis and MRI based cortical grey matter evaluations (Wang et al., 2017, Youn et al., 2019, Pyun et al., 2021, Vipin et al., 2021). Pearson’s correlation evaluated associations between plasma OAβ, cognitive scores [Mini‐Mental State Examination (MMSE), VCAT] and brain volume measures [Grey Matter Volume (GMV) / Intracranial Volume (ICV)].ResultsIncreasing plasma OAβ expression associated with decreasing, VCAT scores (r = ‐0.291, 95% CI = ‐0.504 to ‐0.044, p = 0.022) and MMSE scores (r = ‐0.272, 95% CI = ‐0.489 to ‐0.024, p = 0.032), in MCI patients (Figure 1A, B). Additionally increasing plasma OAβ expression also associated with decreasing and GMV/ ICV ratio (r = ‐0.264, 95% CI = ‐0.489 to ‐0.007, p = 0.045), in MCI patients (Figure 1C).ConclusionFindings from this study, emphasise on the promising clinical utility of plasma OAβ as a biomarker. Future longitudinal studies will validate these associations across the Alzheimer’s disease spectrum.

BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides

BackgroundAbnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer’s disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions.MethodsWe conducted unbiased single cell RNA-seq (scRNA-seq) using purified astrocytes from Bace1 KO mice and wild type control littermates. Similar scRNA-seq was also conducted using AD mice with conditional deletion of Bace1 in the adult stage (5xFAD;Bace1fl/fl;UBC-creER compared to 5xFAD;Bace1fl/fl controls). We compared the transcriptomes of astrocyte and reactive astrocyte clusters and identified several differentially expressed genes, which were further validated using Bace1 KO astrocyte cultures. Mice with astrocyte-specific Bace1 knockout in 5xFAD background were used to compare amyloid deposition. Mechanistic studies using cultured astrocytes were used to identify BACE1 substrates for changes in gene expression and signaling activity. ResultsAmong altered genes, Clusterin (Clu) and Cxcl14 were significantly upregulated and validated by measuring protein levels. Moreover, BACE1 deficiency enhanced both astrocytic Aβ uptake and degradation, and this effect was significantly attenuated by siRNA knockdown of Clu. Mechanistic study suggests that BACE1 deficiency abolishes cleavage of astrocytic insulin receptors (IR), and this may enhance expression of Clu and Cxcl14. Acutely isolated astrocytes from astrocyte-specific knockout of Bace1 mice (Bace1 fl/fl;Gfap-cre) show similar increases in CLU and IR. Furthermore, astrocyte-specific knockout of Bace1 in a 5xFAD background resulted in a significant attenuation in cortical Aβ plaque load through enhanced clearance.ConclusionTogether, our study suggests that BACE1 in astrocytes regulates expression of Clu and Cxcl14, likely via the control of insulin receptor pathway, and inhibition of astrocytic BACE1 is a potential alternative strategy for enhancing Aβ clearance.

MicroRNAs in tear fluids predict underlying molecular changes associated with Alzheimer's disease.

Extracellular circulating microRNAs (miRNAs) have been discussed as potential biomarkers for Alzheimer's disease (AD) diagnosis. As the retina is a part of the CNS, we hypothesize that miRNAs expression levels in the brain, particularly neocortex-hippocampus, eye tissues, and tear fluids are similar at different stages of AD progression. Ten miRNA candidates were systematically investigated in transgenic APP-PS1 mice, noncarrier siblings, and C57BL/6J wild-type controls at young and old ages. Relative expression levels of tested miRNAs revealed a similar pattern in both APP-PS1 mice and noncarrier siblings when compared with age- and sex-matched wild-type controls. However, the differences seen in expression levels between APP-PS1 mice and noncarrier siblings could possibly have resulted from underlying molecular etiology of AD. Importantly, miRNAs associated with amyloid beta (Aβ) production (-101a, -15a, and -342) and proinflammation (-125b, -146a, and -34a) showed significant up-regulations in the tear fluids with disease progression, as tracked by cortical Aβ load and reactive astrogliosis. Overall, for the first time, the translational potential of up-regulated tear fluid miRNAs associated with AD pathogenesis was comprehensively demonstrated.

Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation

The neuroendocrine peptide somatostatin (SST) has long been thought of as influencing the deposition of the amyloid β peptide (Aβ) in Alzheimer’s disease (AD). Missing have been in vivo data in a relevant Aβ amyloidosis model. Here we crossed AppNL-F/NL-F mice with Sst-deficient mice to assess if and how the presence of Sst influences pathological hallmarks of Aβ amyloidosis. We found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. Sst-deficiency led to a subtle but significant increase in the density of cortical Aβ amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of Aβ assembly that manifest in the appearance of SDS-stable smears of 55–150 kDa in Sst null brain samples. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting Aβ amyloid plaque formation through direct interference with Aβ aggregation rather than through its effects on neprilysin expression.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Molecular imaging of the association between serotonin degeneration and beta-amyloid deposition in mild cognitive impairment

BackgroundDegeneration of the serotonin system has been observed in Alzheimer’s disease (AD) and in mild cognitive impairment (MCI). In transgenic amyloid mouse models, serotonin degeneration is detected prior to widespread cortical beta-amyloid (Aβ) deposition, also suggesting that serotonin degeneration may be observed in preclinical AD. MethodsThe differences in the distribution of serotonin degeneration (reflected by the loss of the serotonin transporter, 5-HTT) relative to Aβ deposition was measured with positron emission tomography in a group of individuals with MCI and a group of healthy older adults. A multi-modal partial least squares (mmPLS) algorithm was applied to identify the spatial covariance pattern between 5-HTT availability and Aβ deposition. ResultsForty-five individuals with MCI and 35 healthy older adults were studied, 22 and 27 of whom were included in the analyses who were “amyloid positive” and “amyloid negative”, respectively. A pattern of lower cortical, subcortical and limbic 5-HTT availability and higher cortical Aβ deposition distinguished the MCI from the healthy older control participants. Greater expression of this pattern was correlated with greater deficits in memory and executive function in the MCI group, not in the control group. ConclusionA spatial covariance pattern of lower 5-HTT availability and Aβ deposition was observed to a greater extent in an MCI group relative to a control group and was associated with cognitive impairment in the MCI group. The results support the application of mmPLS to understand the neurochemical changes associated with Aβ deposition in the course of preclinical AD.

Associations between cortical β-amyloid burden, fornix microstructure and cognitive processing of faces, places, bodies and other visual objects in early Alzheimer's disease.

Using two imaging modalities, that is, Pittsburgh compound B (PiB) positron emission tomography (PET) and diffusion tensor imaging (DTI) the present study tested associations between cortical amyloid-beta (Aβ) burden and fornix microstructural changes with cognitive deficits in early Alzheimer's disease (AD), namely deficits in working memory (1-back) processing of visual object categories (faces, places, objects, bodies and verbal material). Second, we examined cortical Aβ associations with fornix microstructure. Seventeen early AD patients and 17 healthy-matched controls were included. Constrained spherical deconvolution-based tractography was used to segment the fornix and a control tract the central branch of the superior longitudinal fasciculus (CB-SLF) previously implicated in working memory processes. Standard uptake value ratios (SUVR) of Aβ were extracted from 45 cortical/subcortical regions from the AAL atlas and subject to principal component analysis for data reduction. Patients exhibited (i) impairments in cognitive performance (ii) reductions in fornix fractional anisotropy (FA) and (iii) increases in a component that loaded highly on cortical Aβ. There were no group differences in CB-SLF FA and in a component loading highly on subcortical Aβ. Partial correlation analysis in the patient group showed (i) positive associations between fornix FA and performance for all the visual object categories and (ii) a negative association between the cortical Aβ component and performance for the object categories but not for the remaining classes of visual stimuli. A subsequent analysis showed a positive association between overall cognition (performance across distinct 1-back task conditions) with fornix FA but no association with cortical Aβ burden, in keeping with influential accounts on early onset AD. This indicates that the fornix degenerates early in AD and contributes to deficits in working memory processing of visual object categories; though it is also important to acknowledge the importance of prospective longitudinal studies with larger samples. Overall, the effect sizes of fornical degeneration on visual working memory appeared stronger than the ones related to amyloid burden.

Neuroinflammation is independently associated with brain network dysfunction in Alzheimer’s disease

Brain network dysfunction is increasingly recognised in Alzheimer’s disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. 42 participants (12 Aβ-positive MCI, 14 Aβ-positive AD and 16 Aβ-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aβ deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aβ-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised β = −0.375, p = 0.037) and network local efficiency (standardised β = −0.468, p < 0.001), independent of cortical thickness and Aβ deposition, while Aβ was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aβ and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer’s disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.

Role of astrogliosis in the relationship between cerebrovascular burden and Alzheimer’s disease pathology

AbstractBackgroundCerebrovascular disease represents a common co‐pathology of Alzheimer's disease (AD) contributing to cognitive decline. While both vascular injury and AD pathology were previously linked to reactive astrocytes (astrogliosis), the interrelationship between these biomarkers remains unclear in AD. Here, we investigated potential effects of plasma glial fibrillary acidic protein (GFAP), an assumed marker of astrogliosis, on the relationship between vascular burden and AD pathology.MethodWe enrolled 210 participants across the AD continuum, including 111 cognitively normal amyloid‐negative (CN Aβ‐), 37 CN Aβ+, and 62 MCI/AD Aβ+ (TRIAD). Amyloid‐β pathology was quantified through 18F‐NAV4694‐PET standardized uptake value ratio (SUVR) in the AD‐signature regions, while tau pathology was quantified through 18F‐MK6240‐PET SUVR in regions corresponding to Braak stages. Vascular burden was quantified as the log‐transform of white matter hyperintensity volume by intracranial volume (WMH). GFAP levels were log‐transformed. At baseline, we employed linear regression models to investigate the effects of WMH and GFAP on tau pathology. Longitudinally, we performed linear mixed effect modeling to investigate the effects of baseline WMH and GFAP on tau accumulation over time (613±252 days). All analyses were adjusted for baseline age, sex, APOE‐ε4, and cortical Aβ. Last, we investigated a potential mediating effect of GFAP in the relationship between WMH and tau accumulation over time, using bias‐corrected bootstrapping with 5,000 replications.ResultAt baseline, GFAP (P=0.001), but not WMH, was positively associated with tau in the lower Braak I‐II regions. Conversely, both GFAP and WMH were positively associated with tau in the higher Braak regions (P&lt;0.001), as was their interaction (WMH*GFAP; Braak III‐IV β=0.14±0.06, P=0.014; Braak V‐VI β=0.19±0.06, P=0.001). Longitudinally, baseline Aβ but not WMH or GFAP predicted tau accumulation (P&lt;0.001). Serial mediation analysis revealed a significant indirect effect of WMH→GFAP→cortical Aβ→Tau increases [95%CI 0.03,0.29].ConclusionWe observed an interaction effect between higher WMH volumes and plasma GFAP levels on tau pathology across the AD continuum. Furthermore, we observed an indirect effect of WMH volumes on tau accumulation over time through amyloidosis and plasma GFAP. These results may indicate that reactive astrogliosis, potentially secondary to vascular injury, may be a factor contributing to AD progression.

Ex vivo quantitative amyloid and perivascular space measurements in white and gray matter on immunohistological microscopy in AD, MCI, and cognitively intact individuals

AbstractBackgroundAmyloid (Aβ) clearance is disturbed in late‐onset Alzheimer’s disease (AD), and a local relationship between Aβ clearance and gray (GM) and white matter (WM) perivascular spaces (PVS) is presumed. Most in vivo primate work has focused on MRI‐visible PVS in WM, described as pathological and enlarged, while nearly all in vivo mechanistic work in animals interrogates “normal” GM PVS. This disparity describes a critical knowledge gap in the morphology, location and relevance of PVS to Aβ clearance.Method: Ex vivo samples from four locations in 22 NIA‐Layton Oregon Alzheimer’s Disease Research Center participants (mean age at death=92y). Pre mortem diagnoses were cognitively intact (“C”, N=9), mild cognitive impairment (“MCI”, N=5), and AD (N=8, confirmed post mortem). Samples were sliced, stained and digitized (3.52µm/pixel). GM masks and morphometrics of vessels&gt;6200µm2 in WM (n=1403) and GM (n=237) were derived from trichrome stain (Fig. 2H,C, and D). Aβ coverage (% positive 4G8 pixels in GM pixels within 1.76mm of the nearest GM pixel to the vessel center‐of‐mass) and normalized PVS size were used as dependent variables (Fig. 2D&amp;F).ResultThere were significant main effects of group for Aβ burden in GM nearest to WM vessels (C&lt;MCI&lt;AD). Main group effects for Aβ around GM vessels were ordered differently (C&gt;AD&gt;MCI) (Fig. 3D). There were significant main effects of group for PVS size in GM (AD&gt;MCI and C) but not WM (Fig. 3C). There were no vessel‐by‐vessel associations between PVSnorm and nearby cortical amyloid within group. (Fig. 3E)ConclusionIn MCI, relatively smaller PVS and high cortical Aβ near GM vessels may reflect a functional waste clearance system in those for whom Aβ burden is not yet advanced. In AD, large GM PVS and an absence of a relationship with cortical Aβ may describe a clearance system overwhelmed by Aβ deposition. Absence of group‐wise differences of relative PVS size in WM vessels, along with no vessel‐by‐vessel association of PVS size with nearby GM Aβ suggests that WM PVS size may not be relevant to Aβ clearance at this scale in individuals of advanced age.

Independent and interactive effects of APOEε4 and β‐amyloid on cortical thickness in Alzheimer’s disease

AbstractBackgroundThe apolipoprotein (APOE) ε4 allele is a major risk factor for Alzheimer’s disease (AD) and potentiates β‐amyloid (Aβ) accumulation. Both APOEε4 and Aβ individually contribute to neurodegeneration in the aging brain. Here, we investigate the independent and interactive effects of APOEε4 and global Aβ load on cortical thickness and disease severity across the AD continuum.MethodWe used FreeSurfer v7.1.1 to derive brain morphometry measures from regions‐of‐interest (ROIs) in 796 subjects (N=475 controls (CN), N=77 participants with mild cognitive impairment (MCI), N=244 with dementia; Table 1) to analyze associations between cortical thickness, APOEε4, and Aβ using available T1‐weighted MRI scans from ADNI phases 2 and 3. Multiple linear regression models were run, covarying for age and sex, to examine the effects of APOEε4 status, global Aβ, and their interaction on morphometric measures from ROIs known to be vulnerable to Aβ deposition in aging and disease (Figure 1‐ adapted from La Joie et al.).ResultIn the MCI and dementia groups, higher global Aβ was associated with lower cortical thickness in middle temporal, fusiform, and parietal regions (p&lt;0.05), but was not associated with cortical thickness in controls. In the dementia group, there was a significant effect of Aβ (p&lt;0.001) and an APOEε4 by Aβ interaction (p=0.01) in the inferior parietal gyrus (Figure 2). The interaction effect requires replication due to the multiple hypothesis testing.ConclusionUnlike in healthy aging, as disease severity increases, the interactive effect of Aβ and APOEε4 status significantly affects cortical thickness in regions associated with Aβ deposition. This suggests that APOEε4 differentially affects cortical thinning during different stages of disease severity.