Alzheimer's Disease Neuropathology Research Articles

Day-to-day sleep variability with Alzheimer's biomarkers in at-risk elderly.

Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3±5.4; 78males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-β (Aβ)42, and higher plasma p-tau231/Aβ42 were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.

Futuristic Alzheimer's therapy: acoustic-stimulated piezoelectric nanospheres for amyloid reduction.

The degeneration of neurons due to the accumulation of misfolded amyloid aggregates in the central nervous system (CNS) is a fundamental neuropathology of Alzheimer's disease (AD). It is believed that dislodging/clearing these amyloid aggregates from the neuronal tissues could lead to a potential cure for AD. In the present work, we explored biocompatible polydopamine-coated piezoelectric polyvinylidene fluoride (DPVDF) nanospheres as acoustic stimulus-triggered anti-fibrillating and anti-amyloid agents. The nanospheres were tested against two model amyloidogenic peptides, including the reductionist model-based amyloidogenic dipeptide, diphenylalanine, and the amyloid polypeptide, amyloid beta (Aβ42). Our results revealed that DPVDF nanospheres could effectively disassemble the model peptide-derived amyloid fibrils under suitable acoustic stimulation. In vitro studies also showed that the stimulus activated DPVDF nanospheres could efficiently alleviate the neurotoxicity of FF fibrils as exemplified in neuroblastoma, SHSY5Y, cells. Studies carried out in animal models further validated that the nanospheres could dislodge amyloid aggregates in vivo and also help the animals regain their cognitive behavior. Thus, these acoustic stimuli-activated nanospheres could serve as a novel class of disease-modifying nanomaterials for non-invasive electro-chemotherapy of Alzheimer's disease.

Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APPswe/PS1dE9 mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the pathological hallmarks of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. Although there is a hope that anti-amyloid monoclonal antibodies may emerge as a new therapy for AD, the high cost and side effect is a big concern. Non-drug therapy is attracting more attention and may provide a better resolution for the treatment of AD. Given the fact that hypoxia contributes to the pathogenesis of AD, hyperbaric oxygen therapy (HBOT) may be an effective intervention that can alleviate hypoxia and improve AD. However, it remains unclear whether long-term HBOT intervention in the early stage of AD can slow AD progression and ultimately prevent cognitive impairment in this disease. In this study we applied consecutive 3-month HBOT interventions on 3-month-old APPswe/PS1dE9 AD mice which represent the early stage of AD. When the APPswe/PS1dE9 mice at 9-month-old which represent the disease stage we measured cognitive function, 24-h blood oxygen saturation, Aβ and tau pathologies, vascular structure and function, and neuroinflammation in APPswe/PS1dE9 mice. Our results showed that long-term HBOT can attenuate the impairments in cognitive function observed in 9-month-old APPswe/PS1dE9 mice. Most importantly, HBOT effectively reduced the progression of Aβ plaques deposition, hyperphosphorylated tau protein aggregation, and neuronal and synaptic degeneration in the AD mice. Further, long-term HBOT was able to enhance blood oxygen saturation level. Besides, long-term HBOT can improve vascular structure and function, and reduce neuroinflammation in AD mice. This study is the first to demonstrate that long-term HBOT intervention in the early stage of AD can attenuate cognitive impairment and AD-like pathologies. Overall, these findings highlight the potential of long-term HBOT as a disease-modifying approach for AD treatment.

Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer's Disease Neuropathology in a Mouse Model.

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.

Resilience to aging drives personalized intervention strategies for Alzheimer's disease.

There has been little progress in reducing the incidence and mortality of Alzheimer's disease (AD). Prevention of onset, more accurate diagnostic tools, and prediction of health outcomes have all been identified as critical issues, but more and better basic research approaches are needed. The single greatest risk factor associated with AD is aging. It follows that if aging can be delayed, there should be an equivalent delay or even prevention of the onset of AD neuropathology. Therefore, targeting multiple pathways of aging would be a powerful way to enhance resilience to aging and slow or prevent the onset of AD neuropathology and dementia in a personalized manner. More effective and predictive animal models, such as the aging pet cat that spontaneously develops neuropathology similar to human AD patients, are necessary to help validate noninvasive and inexpensive biomarkers for identifying individuals at risk. Resilience to aging and its ability to delay or prevent the onset of age-related diseases should be the focus for preventing brain aging and enhancing resistance to AD.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

Background“Brain-predicted age” estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Advanced Immunolabeling Method for Optical Volumetric Imaging Reveals Dystrophic Neurites of Dopaminergic Neurons in Alzheimer’s Disease Mouse Brain

Optical brain clearing combined with immunolabeling is valuable for analyzing molecular tissue structures, including complex synaptic connectivity. However, the presence of aberrant lipid deposition due to aging and brain disorders poses a challenge for achieving antibody penetration throughout the entire brain volume. Herein, we present an efficient brain-wide immunolabeling method, the immuno-active clearing technique (iACT). The treatment of brain tissues with a zwitterionic detergent, specifically SB3-12, significantly enhanced tissue permeability by effectively mitigating lipid barriers. Notably, Quadrol treatment further refines the methodology by effectively eliminating residual detergents from cleared brain tissues, subsequently amplifying volumetric fluorescence signals. Employing iACT, we uncover disrupted axonal projections within the mesolimbic dopaminergic (DA) circuits in 5xFAD mice. Subsequent characterization of DA neural circuits in 5xFAD mice revealed proximal axonal swelling and misrouting of distal axonal compartments in proximity to amyloid-beta plaques. Importantly, these structural anomalies in DA axons correlate with a marked reduction in DA release within the nucleus accumbens. Collectively, our findings highlight the efficacy of optical volumetric imaging with iACT in resolving intricate structural alterations in deep brain neural circuits. Furthermore, we unveil the compromised integrity of DA pathways, contributing to the underlying neuropathology of Alzheimer’s disease. The iACT technique thus holds significant promise as a valuable asset for advancing our understanding of complex neurodegenerative disorders and may pave the way for targeted therapeutic interventions.Graphical The axonal projection of DA neurons in the septum and the NAc showed dystrophic phenotypes such as growth cone-like enlargement of the axonal terminus and aggregated neurites. Brain-wide imaging of structural defects in the neural circuits was facilitated with brain clearing and antibody penetration assisted with SB3-12 and Quadrol pre-treatment. The whole volumetric imaging process could be completed in a week with the robust iACT method. Created with https://www.biorender.com/.

Mapping enhancer and chromatin accessibility landscapes charts the regulatory network of Alzheimer's disease

BackgroundEnhancers are regulatory elements that target and modulate gene expression and play a role in human health and disease. However, the roles of enhancer regulatory circuit abnormalities driven by epigenetic alterations in Alzheimer's disease (AD) are unclear. MethodsIn this study, a multiomic integrative analysis was performed to map enhancer and chromatin accessibility landscapes and identify regulatory network abnormalities in AD. We identified differentially methylated enhancers and constructed regulatory networks across brain regions using AD brain tissue samples. Through the integration of snATAC-seq and snRNA-seq datasets, we mapped enhancers with DNA methylation alterations (DMA) and chromatin accessibility landscapes. Core regulatory triplets that contributed to AD neuropathology in specific cell types were further prioritized. ResultsWe revealed widespread DNA methylation alterations (DMA) in the enhancers of AD patients across different brain regions. In addition, the genome-wide transcription factor (TF) binding profiles showed that enhancers with DMA are pervasively regulated by TFs. The TF-enhancer-gene regulatory network analysis identified core regulatory triplets that are associated with brain and immune cell proportions and play important roles in AD pathogenesis. Enhancer regulatory circuits with DMA exhibited distinct chromatin accessibility patterns, which were further characterized at single-cell resolutions. ConclusionsOur study comprehensively investigated DNA methylation-mediated regulatory circuit abnormalities and provided novel insights into the potential pathogenesis of AD.

Association between anxiety symptoms and Alzheimer’s disease biomarkers in cognitively healthy adults: A systematic review and meta‐analysis

AbstractBackgroundAnxiety has been identified as both a risk factor and prodromal symptom for Alzheimer’s disease (AD) and related dementias, however, the underlying neurobiological correlates remain unknown. The aim of this systematic review and meta‐analysis was to examine the association between anxiety symptoms and two defining markers of AD neuropathology: amyloid‐beta (Aβ) and tau.MethodSystematic literature searches were conducted across 5 databases. Studies investigating the relationship between anxiety and AD neuropathology (i.e., Aβ and/or tau) in cognitively healthy adults were eligible. Where possible, effect sizes were combined across studies, for Aβ and tau separately, using random‐effects meta‐analyses. Sensitivity analyses were performed to assess whether results differed according to anxiety type (i.e., state and trait) and biomarker assessment modality (i.e., positron emission tomography and cerebrospinal fluid). Between‐study heterogeneity was quantified using I 2 with 95% confidence intervals (CI), publication bias evaluated by examining funnel plots, and risk of bias assessed via the National Heart, Lung, and Blood Institute Quality Assessment Tool.ResultTwenty‐seven studies reporting data from 14 unique cohorts met eligibility criteria (Figure‐1). All studies received a quality rating of either ‘good’ (k = 15) or ‘fair’ (k = 12). Random‐effects meta‐analyses revealed no associations between self‐reported anxiety symptoms and either Aβ (13 studies, N = 5141; Fisher’s z = 0.02, 95% CI ‐0.01–0.05, p = 0.194 [Figure‐2]) or tau (4 studies, N = 1126; Fisher’s z = 0.04, 95% CI ‐0.02–0.09, p = 0.235 [Figure‐3]). There was no evidence of publication bias and heterogeneity was low (I 2 = 0.0%). Results remained substantively unchanged across sensitivity analyses assessing the effects of anxiety type and biomarker assessment modality.ConclusionIn cognitively healthy adults, meta‐analytic syntheses revealed no associations between anxiety symptoms and either Aβ or tau. There is a critical need, however, for larger studies with follow‐up periods to examine the effect of anxiety symptom onset, severity, and chronicity on AD neuropathology. An association between anxiety and dementia‐related neurobiological correlates is also likely complex, underpinned by multiple factors, and not restricted to AD neuropathology. Further research investigating other potential neurobiological correlates is crucial to advance understanding of the relationship between anxiety and dementia.

Clinical Manifestations.

Depression is increasingly recognized as a modulator of dementia risk and course, and is associated with multiple etiologies of cognitive decline. While it has been studied in clinically diagnosed cohorts, which may suffer from diagnostic error, there is less information in neuropathologically-defined subjects. We sought to define the depression prevalence and sex difference at mild cognitive impairment (MCI) and mild dementia in an autopsy-confirmed cohort of Alzheimer's disease (AD) and vascular neuropathology. Retrospective data was gathered from the National Alzheimer's Coordinating Center database on autopsy-confirmed cases of primary Alzheimer's disease (AD) and vascular neuropathology. Prevalence of depression was measured by the Geriatric Depression Scale score > = 5 during any visits at MCI (n = 364 AD cases, n = 51 vascular cases) and mild dementia (n = 557 AD cases, n = 24 vascular cases). We excluded those without pathology report, sex data or GDS results. Groups were compared via the chi-squared test. Depression prevalence was equal in MCI from AD and vascular neuropathology (27% in each, p = 0.9974). At mild dementia, depression was significantly more prevalent in vascular neuropathology compared to AD (37% versus 20%, p = 0.0363). In AD, at MCI there was no sex difference in depression prevalence (male 28% versus female 27%, p = 0.7560) but at mild dementia there was a female predominance (male 16% versus female 25%, p = 0.0075). In contrast, with vascular neuropathology, at MCI there was a trend for female predominance (male 21% versus female 33%, p = 0.3181) and no sex difference at mild dementia (male 38% versus female 36%, p = 0.9158). These results demonstrate that the prevalence of depression in cognitive disorders is driven by etiology, stage, and sex, which promotes further mechanistic studies on the interaction of these factors. Moreover, this illustrates the importance of depression screening in dementia, especially in females and those with suspected vascular etiology.

Examining sex differences in Alzheimer Disease neuropathology in Down Syndrome

AbstractBackgroundPeople with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS.MethodWe examined 35 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men and women.ResultNo significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (R = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (R = 0.93; p = 0.00012) whereas men showed a weaker trend (R = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (R = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (R = ‐0.29; p = 0.41). There was no such trend in the frontal cortex.ConclusionThese results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα.

History of infections is associated with smaller hippocampal volume in older women

AbstractBackgroundAccumulating evidence suggests that infections can play a major role in Alzheimer’s disease (AD), however, mechanism is unclear as multiple pathways may be involved. One possibility is that infections might contribute to AD directly by promoting neuronal death and neurodegeneration.MethodWe investigated the relationship between history of infectious diseases (a potential AD risk factor) and brain hippocampal volume, HV (a biomarker of neurodegeneration and AD neuropathology) in a subsample of the UK Biobank participants with respective information. Infectious disease diagnoses were based on ICD‐10 codes. The left/right HV was measured by the MRI. Analysis of variance (ANOVA) and Welch Two Sample t‐test were used to examine the statistical significance.ResultThe HV was significantly lower in older women (age 65+) with prior history of infections, compared to the same age women without such history (p‐value = 0.014 and 0.029, for the left and right HV, respectively). The effect size increased with age, and this increase was faster for the right vs. left HV. The difference in HV between male subjects with and without history of infections was not statistically significant.ConclusionIn this study, prior infections were significantly associated with the lower left/right HV in women aged 65+, which supports the role of infectious diseases in neurodegeneration and preclinical AD pathology in females. The effect size increased with age, in line with the increase in brain vulnerability to stressors due to aging. The faster increase for the right vs. left HV might indicate that females’ verbal memory declines faster with age compared to visual‐spatial memory, following the exposure to infectious disease, which deserves further investigation. The observed sex differences may reflect a higher vulnerability of the female brain to infection‐related factors, which in turn might contribute to the higher risk of AD in women compared to men.

Neuronal hyperexcitability in AD

AbstractBackgroundBecause neuronal and network deficits are the imperative immediate consequences of pathological changes of disease mechanisms, neurophysiological manifestations associated with Aβ and tau are uniquely positioned to demonstrate the abnormal homeostatic and maladaptive circuit alterations and the dynamic integrated effects of underlying genetics and neuropathological changes in Alzheimer’s disease (AD). Importantly, network dysfunction manifesting as abnormal hyper‐ as well as hypo‐active oscillatory brain rhythms is detectable even during the prodromal phase of disease. Here we leveraged the higher spatial and precise temporal resolution of Magnetoencephalography (MEG) to define frequency‐specific and region‐dependent patterns of oscillatory deficits in AD patients, and to demonstrate the earliest neurophysiological abnormalities associated with AD neuropathology and their mechanistic relationships to network hyperexcitability.MethodWe studied the resting brain oscillations in individuals with AD‐spectrum (n = 88) and age‐matched controls (n = 70) using MEG. In addition, subsets of participants were evaluated with positron emission tomography (PET) with Aβ and tau specific tracers and fluid biomarker including plasma P‐tau181 and Neuro‐Filament‐Light (NFL). We used statistical mixed models to investigate the associations between neural oscillations and pathology. We used a linear Neural‐Mass‐Model (NMM) in combination with empirical MEG spectra to derive the excitatory‐to‐inhibitory activity within neuronal subpopulations in AD patients. Based on standard neurophysiological monitoring we determined clinical evidence of hyperexcitability as AD with and without epileptiform activity (AD‐EPI+; AD‐EPI‐).ResultWhile increase and decrease of oscillatory activity are distinctly associated Aβ and tau, respectively, the characteristic frequency‐specific manifestation in AD was increased spectral signature within delta‐theta (2‐7Hz) and reduced spectral signature within alpha (8‐12Hz). Earliest spectral changes were detected in Aβ+ cognitively unimpaired and the increased spectral signature associated with Aβ was replicated in identical associations with plasma p‐tau181. The presence of APO‐E4 allele strengthened these associations. NMM demonstrated greater excitatory‐inhibitory‐activity in AD‐EPI+ vs. AD‐EPI‐ while these were specifically correlated with the reduced alpha spectrum which was more profound in AD‐EPI+ as well as uniquely associated with increased tau depositions.ConclusionOur results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ, in patients with AD.

Signatures of abnormal deviations in excitation‐inhibition balance for amyloid positive individuals

AbstractBackgroundDysfunctional excitation‐inhibition balance (EIB) is hypothesized to precede cognitive impairment in Alzheimer’s disease (AD); however, overlapping neuropathology (like amyloid plaques) can develop in cognitively normal (CN) and impaired (CI) individuals. We investigate EIB trajectories for individuals with significant amyloid (Aβ+).MethodMultimodal imaging was used to construct hybrid resting‐state structural connectomes (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), computing whole‐brain EIB based on 105 ROIs. This cohort (N = 185, 94 Female) aged 55‐90 (μ FEMALES = 74.9, and μ MALES 73) was limited to Aβ+ individuals with APOE genotyping (ε3/ε3, ε3/ε4, ε4/ε4); grouped further by clinical dementia rating (CDR), with CDR > 0 indicating CI. Imaging, Aβ+ classifications, CDR, and APOE were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.ResultResults presented in Figure 1 suggest whole‐brain EIB in both CN sexes with Aβ+ decreases with increasing age (APOE‐ε4 agnostic). However, sex differences are highlighted with CI; regression analyses produce a marginally significant 4‐way interaction of age, sex, cognitive status, and APOE (P = 0.085, β = ‐0.013). Partial correlation of EIB with age, controlling for sex, APOE and cognitive status is also significant (P = 0.016, r = ‐0.18). Results indicate sex‐mediated EIB differences in individuals with CI, dominated by APOE‐ε4 in women rather than amyloid.ConclusionWe’ve demonstrated EIB deviations in cognitively impaired men and women that may be associated with AD neuropathology. Our findings are consistent with known AD sex differences and suggest novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not. Figure. 1. Whole‐brain excitation‐Inhibition balance (EIB) trajectories for amyloid positive (Aβ+) men and women. The cognitively normal (CN) group (rows A‐B) suggests no sex differences in EIB trajectories with age, while the cognitively impaired (CI) group (rows C‐D) begins to reveal distinct patterns of dysfunction (more significantly in women with APOE‐ε4). Note a value of 0.5 indicates perfect balance.

Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer’s Disease

AbstractBackgroundThe role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer’s disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs’ cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain.MethodThis project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer’s Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05).ResultPrefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden.ConclusionConsistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology.

Phosphorylated tau in the Down syndrome brain: Age related increases and comparison to late‐onset Alzheimer’s Disease

AbstractBackgroundIndividuals with Down Syndrome (DS) have an increased risk of developing Alzheimer’s Disease (AD) with nearly all individuals exhibiting neuropathological changes in the brain by age 40 years, and with a mean diagnosis of dementia by age ∼55 years. The purpose of this postmortem study was to characterize the age‐associated burden of several tau phosphorylation epitopes, including threonine (pT) 181, 217, and 231 by immunohistochemistry in the frontal cortex. We hypothesized that cerebral pT burden would increase with age in DS but not in controls and be higher in DS with AD neuropathology (DSAD) compared to late‐onset AD (LOAD).MethodWe examined 117 brains from: controls (non‐DS n = 53; ages 1‐91), DS without AD (n = 13; ages 1‐48), DSAD (n = 31; age 43‐68), and LOAD (n = 20; ages 63‐96). Serial sections from the frontal cortex were cut at 30µm and immunostained for phosphorylated tau pT181, pT217 and pT231. Whole slide images were digitized and analyzed by Aperio ImageScope software. The % area for each type of tau was quantified using positive pixel counts. Spearman rank correlations on log‐transformed data were used to test for positive age associations and t‐test was used to compare pT between DSAD and LOAD.ResultIn control cases, there was a positive correlation of age with pT181 (r = 0.47 p<0.001) but not with pT217 or pT231. In DS cases across the lifespan (DS and DSAD combined) displayed a positive correlation of age with pT181 (r = 0.70 p<.001), pT217 (r = 0.70 p<.001), and pT231 (r = 0.42 p = 0.005). DSAD cases had significantly higher pT181, pT217 and pT231 (p<.001) than late‐onset AD and control cases.ConclusionThese results suggest that tau phosphorylation for these epitopes is more positively correlated with age in people with DS than people without DS. Although pT181 increased with age in both cohorts, pT217 and pT231 showed a positive correlation with age in people with DS but not controls. Fluid biomarker studies focused on pTau in longitudinal cohorts of people with DS with subsequent brain donation will help reveal the link between peripheral and central pTau levels.

Alterations of Astrocytic Aquaporin 4 expression and distribution in Down Syndrome with Alzheimer’s Disease onset

AbstractBackgroundAstrocytic Aquaporin 4 (AQP4) is a water channel that is typically expressed in astrocytic endfeet, associated with the blood brain barrier (BBB). This association is thought to facilitate the removal of waste products (e.g. beta amyloid (Aβ)) via the ‘glymphatic system’. With Aβ plaque deposition in Alzheimer’s Disease (AD), AQP4 becomes dysregulated observed as a shift in distribution from astrocytic endfeet to astrocytic processes, resulting in inefficient Aβ removal. Here, AQP4 expression and distribution within astrocytes was characterized via immunohistochemistry in human brain tissue from people with Down Syndrome without AD (DS) and with AD (DSAD). We hypothesized that AQP4 protein level would be higher and distributed along astrocytic processes as opposed to the BBB in DSAD relative to DS.MethodAQP4 was evaluated by immunohistochemistry and quantified using QuPath (% loads, positive pixel count) for both frontal (FC) and occipital cortex (OC) in the following groups: DS (n = 17, age range = 0‐51) and DSAD (n = 20, age range = 46‐70). In addition, AQP4 distribution was classified by a blinded observer who annotated distinct AQP4 positive astrocytic morphologies, listed as follows: In WM, ‘Star,’ ‘Webbed,’ and ‘Stippled,’ and in GM, ‘Bushy,’ ‘Branched,’ ‘Globular,’ ‘Endfoot/Vascular Associated.’ResultWe show that AQP4 protein staining was higher in GM DS with AD neuropathology than in DS without AD neuropathology for both FC and OC (FC p = 0.0007; OC p = 0.0034). In addition, we observed a shift from ‘star’ shaped distribution within DS astrocytes to more ‘webbed’ and ‘stippled’ shapes in DSAD; this was not observed in OC. We found a shift in GM morphologies from ‘bushy’ morphology of AQP4 immunostaining in DS to more ‘Branched and Globular’ shapes in DSAD in OC whereas there is a shift from a ‘Bushy’ morphology in DS to more ‘Endfoot/Vascular Associated’ morphologies in the DSAD FC.ConclusionAQP4 expression is higher in DSAD than DS and appears to show a spectrum of astrocyte morphologies with distinct patterns based upon spatial location (FC/OC and GM/WM). Taken together, AQP4 dysfunction and shift to abnormal spatial location may reduce Aβ clearance through the glymphatic system, leading to enhanced plaque formation in DSAD.

Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer’s Disease Neuropathology and Cognitive Decline

AbstractBackgroundWe completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer’s disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane.MethodLeveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit.ResultHigher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/).ConclusionOur results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies.

Glia response on Amyloid plaque microenvironment protects against pathological tau conversion in Alzheimer’s disease resilience

AbstractBackgroundAymptomatic Alzheimer’s disease (AsymAD) subjects have an intrinsic capacity to tolerate the presence of Aβ‐plaques and neurofibrillary tangles (NFTs) without developing cognitive impairment. In contrast to typical demented Alzheimer’s disease (AD) brains, AsymAD brains show distinct neuroinflammatory response and less accumulation of soluble pathological tau species at synaptic levels. The link between these observations and AD neuropathology is not fully understood, but increasing evidence suggests that the local plaque microenvironment plays a key role in the Aβ plaque‐associated tau pathogenesis. In this work we aim to identify the main molecular contributors of resiliency against amyloid and tau aggregation in AsymAD brains.MethodWe conducted a detailed histological and biochemical analysis using postmortem brain cortex samples from age‐matched controls (N = 21), demented AD (N = 22), and AsymAD subjects (N = 30). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the Aβ‐plaque microenvironment in AsymAD versus typical demented AD cases.ResultThere was no difference observed in the overall amyloid plaque burden between AsymAD and demented AD brains. However, immunofluorescence analyses indicates that AsymAD cases have the capability to form a glial barrier surrounding filamentous plaques, thereby avoiding the pathological conversion of tau. This observation is supported by biochemical analysis, which reveals that AsymAD cases have lower levels of high molecular weight tau and less seeding activity in soluble fractions. Using spatial whole transcriptomics to further characterize the plaque niche, we found an enrichment of migration signaling and autophagy in the AsymAD plaque niche, but not in AD. We are currently investigating the significance of these two molecular pathways in the Aβ plaque‐associated tau pathogenesis.ConclusionOur study provides new insights into the mechanism of Alzheimer’s disease resilience focus in the local Aβ plaque‐associated tau pathogenesis and potentials therapeutic approach to cognitive deterioration

Ante‐mortem magnetic resonance imaging grey‐white matter contrast regional signatures of Alzheimer’s disease neuropathology

AbstractBackgroundGrey matter (GM), white matter (WM) contrast (GWC) in T1‐weighted MRI has been shown to decrease with age in healthy populations and cognitive impairment in clinical Alzheimer’s Disease (AD). However, the neuropathological determinants of this signal remain unknown. Here, we aimed to study whether GWC is associated with AD neuropathology and longitudinal hippocampal atrophy.Method157 patients with neuropathological, clinical data and ante‐mortem MRI were selected from the National Alzheimer’s Coordinating Center database. Cortical volume and GWC (WM/GM intensity) in T1/MRI were obtained with Freesurfer 6.0. Hippocampal volume was divided into anterior, intermediate and posterior regions using a lab‐based algorithm. Correlational analysis was conducted for GWC with age, and GWC residuals after linear regression with age for volume, BRAAK stage (neurofibrillary tangles), CERAD score (neuritic plaque density) and Cognitive Dementia Rating Sum‐of‐Boxes (CDR‐SB). APOE genotypes were compared using one‐way‐ANOVA.ResultGWC was negatively correlated with age in widespread brain areas (p < 0.05, FDR), but only the entorhinal cortex showed a positive correlation between volume and GWC. There were no significant correlations between GWC and BRAAK stage, CERAD score, CDR‐SB or differences according to APOE genotype. Entorhinal GWC correlated positively only with the posterior hippocampal volume in BRAAK III‐IV.ConclusionGWC is highly modulated by age, but not by classical AD neuropathology, APOE genotype or dementia severity in this cohort. Entorhinal GWC correlates with entorhinal and posterior hippocampal volume, suggesting it might reflect an early pathophysiological process distinct from classical AD neuropathology.