Early Stages Of Alzheimer's Disease Research Articles

Brain gray matter volume mediated the relationship between plasma p‐tau and cognition of early Alzheimer’s disease

AbstractBackgroundCognitive deterioration and atrophy of the brain gray matter volume (GMV) are the main symptoms of Alzheimer’s disease (AD). Accumulated pieces of evidence have shown that plasma concentrations of phosphorylated‐tau (p‐tau) performed better in early diagnosing, differentiating, and monitoring the progression of AD. However, the relationship between plasma p‐tau concentrations, the GMV of brain regions, and cognitive function remains poorly understood. Previous studies indicate that brain GMV may mediate the relationship between biomarkers and cognitive function, and in this study, we aimed to investigate whether GMV plays a mediating role in the association between plasma p‐tau concentrations and cognition.Method99 participants in total, including 47 patients with a diagnosis of early AD and 52 cognitively unimpaired (CU) individuals, were enrolled in this study. All participants completed laboratory tests, magnetic resonance imaging scans, and neuropsychological assessments. Plasma p‐tau217 and p‐tau181 concentrations were measured using an enzyme‐linked immunosorbent assay kit. Voxel‐based morphometry was performed to assess brain GMV. Partial correlations and mediation analyses were performed in the AD group.ResultConcentrations of both plasma p‐tau217 and p‐tau181 were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p‐tau217 concentrations, GMV, and Mini‐Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p‐tau217 concentrations and MMSE scores. We did not find a significant correlation between plasma p‐tau181 concentrations and MMSE scores.ConclusionThe findings indicate that p‐tau217 was a promising biomarker for central processes affecting brain GMV and cognitive function. It may provide potential targets for future intervention and treatment of tau‐targeting therapies at the early stage of AD.

High cholesterol levels promotes TNF‐α‐dependent necroptosis in Alzheimer’s disease

AbstractBackgroundNecroptosis has been reported in post‐mortem Alzheimer’s disease (AD) brains, but still, the events that trigger or regulate this type of inflammatory cell death in AD are not fully known. Oxidative stress may be determinant as to whether a cell initiates necroptosis; Therefore, it is, likely that mitochondrial dysfunction, observed in the early stages of AD, might favor cells to undergo necroptosis. Previous studies from our group have shown that high intracellular cholesterol levels deplete the mitochondrial pool of GSH, thus sensitizing neurons against amyloid‐beta (Ab)‐induced mitochondrial oxidative stress. The present study is aimed to evaluate whether cholesterol can regulate the necroptotic pathway using both APP‐PSEN1 mice that overexpress the cholesterol‐related transcription factor SREBF2 and cholesterol‐enriched SH‐SY5Y cells.MethodCholesterol enrichment was assessed by incubating the cells with soluble cholesterol:methyl‐cyclodextrin complex (50 mg/ml) for 1 h followed by 4 h recovery. To induce necroptosis, cells were treated with TLQ [TNFa (10 ng/ml) plus the SMAC mimetic (LCL‐161, 10 mM) and the pan‐caspase inhibitor qVD‐OPH (10 mM)] for 24 h.ResultsBrains from APP‐PSEN1‐SREBF2 mice show up‐regulated expression of the necroptosis‐related proteins RIPK3 and MLKL, which together with RIPK1 accumulated in the urea‐soluble protein fraction, indicative of necrosome assembly. Moreover, western blot analyses of brain extracts from triple transgenic mice also showed high levels of c‐FLIP, the natural inhibitor of caspase‐8, further pointing to a cholesterol‐regulated engagement of the necroptotic pathway. In SH‐SY5Y cells, cholesterol enrichment resulted in enhanced cell death after exposure to TLQ, which was prevented by RIPK1 and RIPK3 inhibitors (Necrostatin and GSK’872, respectively). Similar protection against TLQ‐induced necroptosis was achieved when mitochondrial GSH levels were recovered by GSH ethyl ester. Intriguingly, cholesterol also regulated the intracellular localization of RIPK3 and MLKL. Confocal microscopy showed an increased presence of nuclear RIPK3 and MLKL in cholesterol‐enriched cells, recently described as a requirement for the subsequent necrosome formation in the cytosol.ConclusionOverall, these findings indicate that high intracellular cholesterol levels compromise neuronal viability, promoting oxidative stress and subsequent necroptosis, a pro‐inflammatory type of cell death, which ultimately may contribute to chronic neuroinflammation in AD.

Longitudinal morphometry of medial temporal lobe subregions in earlyAlzheimer’s disease

AbstractBackgroundStructural MRI is frequently used to track Alzheimer’s disease (AD) progression in clinic, research, and pharmacological trials. It has been shown that established MRI‐derived measures lack diagnostic sensitivity particularly in early stages of AD. Here, we investigate if the utility of structural MRI for tracking early AD progression can be increased when focusing on subregions of the medial temporal lobe (MTL) which are known to exhibit earliest AD‐related neuropathological change.MethodWe used data from N = 143 participants enrolled in the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE). This included cognitively unimpaired participants who were either Aβ‐negative (CU Aβ‐; n = 67) or Aβ‐positive (CU Aβ+; n = 20), Aβ+ participants with subjective cognitive decline (SCD Aβ+; n = 38), and Aβ+ participants with MCI (MCI Aβ+; n = 18).Participants underwent annual assessments up to three years after baseline, including MRI (2.19 ± 0.86 follow‐ups) and a neuropsychological testing (2.18 ± 0.83 follow‐ups). Segmentations of MTL subregions were generated using a longiudinal, template‐based implementation of the Automated Segmentation of Hippocampal Subfields (ASHS; Yushkevich et al., 2015, Hum Brain Mapp.) algorithm (Figure 1). Linear mixed models were fitted to derive volumetric slopes and to test their relationship with longitudinal changes in Preclinical Alzheimer Cognitive Composite (PACC‐5) scores.ResultWe observed significant volume losses across diagnostic groups with the MCI Aβ+ group exhibiting the fastest rates. Compared with the CU Aβ‐ group, there were accelerated volume losses in the subiculum and dentate gyrus in the SCD Aβ+ group and, additionally, in the entorhinal cortex and Brodmann areas 35 and 36 in the MCI Aβ+ group. There was also a trend towards faster volume losses in the entorhinal cortex in the CU Aβ+ group. Higher rates of MTL subregional volume losses, particularly in the cornu ammonis 1 subfield, were related to a faster decline on the PACC‐5 in the MCI Aβ+ group. This effect remained significant when controlling for baseline volumes.ConclusionOur findings highlight the viability of subregional MTL morphometry for tracking earliest neurodegeneration and related cognitive decline due to AD.

Decay in Entorhinal White Matter/Gray Matter contrast in Alzheimer’s Disease Patients is reduced by 40Hz sensory stimulation

AbstractBackgroundPrevious research has shown that white matter (WM) and gray matter (GM) tissues exhibit regionally selective pathological changes in Alzheimer’s disease (AD). The contrast between WM and GM signal intensities (WM/GM contrast) measured by magnetic resonance imaging (MRI) has previously been proposed as a method for quantifying these changes. It has been shown that WM/GM contrast can provide sensitive, independent, and distinct information about pathologies compared with traditional MRI measures. Studies have also shown, including entorhinal WM/GM contrast to traditional MRI measures resulted in better discrimination between AD and controls. We previously demonstrated that 40Hz auditory‐visual stimulation therapy reduced WM atrophy and myelin loss in AD patients. The present study quantified the effects of the therapy on the WM/GM contrast in the entorhinal region.MethodThis study used neuroimaging data from Overture, a phase I/II randomized, placebo‐controlled feasibility study (NCT03556280) in patients on the AD spectrum. Treatment group received 40Hz gamma sensory stimulation daily at home for six months, whereas placebo group received sham stimulation. Structural MRI was obtained at baseline, month 3 and month 6 visits using 1.5 Tesla scanner. FreeSurfer was used to process T1 MRI including entorhinal parcellation and cortical reconstructions for 38 participants (66% Treatment, 34% Placebo). For each vertex, WM signal intensity (WMI) is sampled at 1mm below, and GM signal intensity (GMI) is sampled at 30% of cortical thickness above the WM/GM border. WM/GM contrast was calculated as 100*(WMI–GMI)/(0.5*(WMI+GMI)) %. Bayesian linear mixed effects modeling was used to model changes in WM/GM contrast in the entorhinal region.ResultFollowing 6 months of treatment, we observed that the treatment group demonstrated 0.06±0.99% decrease and the placebo group demonstrated 1.26±1.04% decrease in WM/GM contrast (p<0.022).ConclusionWe found that six months of 40Hz gamma sensory therapy reduced the decline in WM/GM contrast in the entorhinal region. Since WM/GM contrast is associated with AD severity, and the entorhinal region is of particular interest in the early stages of AD, early intervention of the therapy may result in enhanced tissue preservation and reduced neurological damage.

A multicenter validation study on the diagnostic and prognostic value of CSF Neurogranin and BACE1

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). Currently, AD is still mostly diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Disease‐modifying treatments should be most effective in the earliest stages, before amyloid plaques and neurodegeneration become prevalent. Thus, further identification of biomarkers is required that can detect AD in the predementia stage. This study aimed to assess the clinical utility of synaptic proteins neurogranin and beta‐secretase 1 (BACE1) in the diagnosis and prognosis of AD.MethodWe enrolled 530 participants from DELCODE, a multicenter prospective cohort study, including healthy controls (HC), subjective cognitive decline (SCD) subjects, mild cognitive impairment (MCI) subjects, mild AD dementia and first‐degree relatives of AD patients. Based on amyloid and tau status, we divided the participants into four groups: A−T−; A−T+; A+T−; A+T+. Neurogranin and BACE1 levels across groups were assessed by ANCOVA after adjusted for age and sex. To test the correlation of the biomarkers to cognitive performance, we used linear mixed models to model baseline biomarker levels and 7 years longitudinal MMSE and PACC5 scores.ResultRegardless of amyloid status, CSF neurogranin and BACE1 levels were significantly higher in T+ group compared with T‐ (all p < 0.0001). Furthermore, for participants with negative tau status, neurogranin and BACE1 levels were lower in A+ group compared with A‐ (both p < 0.0001). After adjusting for covariates (Age, Sex, Education, APOEε4), linear mixed‐effect models indicated that higher neurogranin predicts faster decline in MMSE (β = ‐0.14, p < 0.01) and PACC5 (β = ‐0.03, p < 0.05) over 7 years.ConclusionThis study reveals that neurogranin and BACE1 could offer insight into identifying patients at early stages of AD and improve prediction of cognitive decline.

Plasma biomarkers across the Alzheimer’s disease continuum in the New Zealand‐Dementia Prevention Research Clinics

AbstractBackgroundAdvances in ultra‐sensitive immunoassay methods, like Single molecule array (Simoa) technology, show that Alzheimer’s disease (AD) neuropathology can be detected in blood at the earliest stages of AD. This study compared cross‐sectional biomarker profiles for participants from the New Zealand‐Dementia Prevention Research Clinics (NZ‐DPRCs) who spanned the continuum from healthy older adults to a clinical diagnosis of AD.MethodBlood plasma samples were obtained from 253 NZ‐DPRC participants (aged 55 to 87) from their baseline assessment. Participants were classified as cognitively normal adults (CN, n = 34), subjective cognitive decline (SCD, n = 64), non‐amnestic mild cognitive impairment (single and multi‐domain, non‐aMCI, n = 23), amnestic MCI (single and multi‐domain, aMCI, n = 105), and AD (n = 27). Six plasma biomarkers were selected for quantification by the HD‐X Simoa analyser (Quanterix, Billerica, MA; University of Gothenburg, Sweden): AD biomarkers amyloid‐beta peptides (Aß1‐40; Aß1‐42) and phosphorylated tau species (p‐tau181; p‐tau231); neurofilament light (NfL), for general neuronal damage; and glial fibrillary acidic protein (GFAP), for astrocyte activation. Clinical, imaging and genetic demographic data were assessed in relation to the plasma biomarkers.ResultPlasma biomarkers across the five groups (figure 1) were assessed by linear regression adjusted for age and sex. P‐tau181, p‐tau231, GFAP and NfL were natural log‐transformed to approximate normality and improve homogeneity of variance. Biomarkers p‐tau181, p‐tau231, GFAP, NfL, Aß1‐42/Aß1‐40 ratio and Aß1‐42, all showed group effects (P < 0.05; Aß1‐40, p<0.08). Tukey’s HSD post‐hoc test for pairwise group comparisons showed significant differences in GFAP for AD vs CN, SCD, non‐aMCI as well as SCD vs MCI (P < 0.05); p‐tau181 for AD vs CN and SCD (P < 0.05); p‐tau231 for AD vs non‐aMCI (P < 0.05); Aß1‐42 for aMCI vs CN and SCD (P < 0.05); Aß1‐42/Aß1‐40 ratio for SCD vs aMCI (P < 0.05). ROC analysis will be reported for the diagnostic accuracy of these blood analytes.ConclusionSimoa‐quantitated blood biomarkers in the NZ‐DPRC cohort differentiates clinical groups spanning the AD continuum cross‐sectionally.

A short‐hybrid scale for detecting anosognosia from the prodromal stage of Alzheimer’s disease

AbstractBackgroundWhile not originally developed for this purpose, evidence suggests that the Healthy Aging Brain Care Monitor questionnaire (HABC‐M; Monahan et al, 2012, 2014) may be a valuable instrument for assessing unawareness of cognitive decline (i.e., anosognosia) from preclinical stages of Alzheimer’s disease (AD) (Cacciamani et al, 2017). This is relevant because anosognosia may delay AD diagnosis and therapeutic interventions, with adverse consequences for patients and caregivers. However, several open questions remain: What is the actual effectiveness of this instrument across the AD spectrum? How do the cognitive, functional, and psychological subscales of the HABC‐M differ in their sensitivity to anosognosia in AD? Does the caregiver burden subscale provide additional information about AD patient’s anosognosia? The present study aimed to address these specific questions.MethodsThe HABC‐M was administered to 60 participants (30 AD patients and 30 healthy controls) and their partners (caregivers/informants). A measure of self‐awareness was then estimated by computing the discrepancy scores between the participants and their partners for the different subscales of HABC‐M (with the exception of the caregiver burden subscale, which is a caregiver‐exclusive questionnaire). To evaluate whether these measures can discriminate between patients at different stages of AD and controls, we fit linear models adjusted for age, sex, and education, and computed receiver operating characteristic curves.ResultsAll HABC‐M discrepancy scores, as well as the caregiver burden score, were able to discriminate controls from patients in distinct AD stages. For best performance, the area‐under‐curve for the HABC‐M cognitive subscale discriminated prodromal AD versus controls with a value 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden score raised it to 0.94 [0.86;0.99].ConclusionThe HABC‐M cognitive subscale (six items) can detect anosognosia from the earliest stages of AD. Separately, the caregiver burden subscale (four items) may corroborate the suspicion of anosognosia. A short‐hybrid scale combining these 10 items, instead of the 31 items of the total HABC‐M questionnaire, could provide a practical and efficient instrument for detection of anosognosia in the clinical setting. Importantly, such an instrument could further contribute to a timely AD diagnosis.

Remote assessment of functional impairment in Alzheimer’s disease: results of the RADAR‐AD study

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer’s disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer’s disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia.MethodFour study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida’s research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams.ResultCompliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p<0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity).ConclusionThe RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

Microbial infection and associated inflammasome in the retina of Alzheimer’s disease patients

AbstractBackgroundRecent advances in Alzheimer’s disease (AD) research revealed that AD pathology is not confined to the brain but also occur in the neurosensory retina. Data have further suggested parallels between retinal and brain AD biomarkers. While the exact etiology of AD pathogenesis is undefined, an emerging theory has linked AD with microbial infection as a plausible cause for AD progression. The presence of several microbes including Chlamydia pneumoniae (Cp), Borrelia burgdorferi, Porphyromonas gingivalis, and Toxoplasma gondii have been reported in the post‐mortem brain of AD patients and murine models. However, the existence and role of microbial infection in AD retina has never been studied.MethodWe employed a range of histological, biochemical, and genetic techniques to detect bacterial infection and other associated biomarkers in postmortem retinas of patients with mild cognitive impairment (MCI) or AD dementia, compared to retinas from age‐matched individuals who displayed normal cognition (NC). We assessed the presence and burden of Cp and correlated with gliosis, inflammasome, and apoptosis markers.ResultWe discovered the presence of Cp inclusions in postmortem retinas of patients with MCI and AD as compared to age‐ and sex‐matched NC individuals. Our experimental evidence revealed Cp‐infected retinal neuronal cells in AD patients, with no increase in retinal Cp infection in MCI versus CN and a significant 4‐fold increase in of Cp immunoreactivity in retinas of AD patients versus MCI and CN subjects. These data possibly indicate that Cp infection mainly occur during the dementia phase of AD and is less observable at the early functional impairment stages of AD. Retinal microglia were found to aggregate around and engulf Cp‐infected cells. Alongside Cp infection, retinal tissues from MCI and AD patients exhibited increased NLRP3 inflammasome and gliosis. Our data suggest Cp‐triggered inflammasome activation, that can lead to neuronal degeneration. We further found a relationship between the severity of retinal Cp infection and brain pathology; retinal Cp burden was associated with brain neurofibrillary tangles, neuropil threads, Braak stage.ConclusionCp‐triggered chronic inflammation could be a detrimental process leading to retinal degeneration in AD, suggesting potential new therapeutic avenues involving early antibiotic treatment or inflammasome attenuation.

APNmAb005, an anti‐tau antibody targeting synaptic tau oligomers, in Phase 1 for treatment of Alzheimer’s Disease and primary tauopathies

AbstractBackgroundAccumulation of tau oligomers at the synapses in Alzheimer’s disease (AD) disrupts neuronal activities and leads to neurodegeneration. Tau immunotherapy has been actively pursued as a treatment for tauopathies in the past decade. Despite several failed Phase 2 trials of N‐terminus binding antibodies a variety of tau epitopes are being investigated at different stages of clinical trials. APNmAb005 is a humanized monoclonal antibody designed to block synaptic toxicity elicited by tau oligomers.MethodAPNmAb005 was selected as a clinical candidate from APRINOIA’s antibody discovery platform based on its unique binding properties to pathological tau in vitro immunoassays as well in vivo efficacy studies in rTg4510 mice. Humanized APNmAb005 is in IgG4 backbone and the production was scaled up successfully with good stability and solubility to support preclinical and clinical development. GLP safety study was conducted in cynomolgus monkeys. A Phase 1a randomized, double‐blind, placebo‐controlled study of APNmAb005 in healthy subjects is underway.ResultEpitope‐mapping study reveals that APNmAb005 binds to a conformation‐dependent epitope in the mid‐region, which results in a preferable recognition of pathological tau in early Braak stage (III‐IV) AD brains as well as tau aggregates in astrocytes and oligodendrocytes in brains from progressive supranuclear palsy (PSP) patients but not monomeric tau in normal brains. APNmAb005 blocks in vitro tau seeding at nanomolar concentrations and rescues neuronal loss in rTG4510 mice. Four‐week repeat dosing toxicology study shows no observed adverse effects.ConclusionAPNmAb005 is a conformation selective antibody that binds to tau oligomers and aggregates preferentiually in synapses in pathological brain tissues and inhibits tau spreading. The mid‐region conformation dependent epitope is distinct from all other tau antibodies currently in clinical development. APNmAb005 offers a unique tau immunotherapy for neurodegenerative disorders and is currently in Phase 1 to evaluate its safety and tolerability.

Alzheimer’s Disease mechanistic pathways were discovered through in silico experiments in causal AI based digital twins

AbstractBackgroundBeyond a single‐gene‐based approach, pathway‐based approaches have become important in drug development paradigm. Several pathways are known for the pathogenesis of Alzheimer’s disease (AD), but these may be from animal studies or observational human subject studies. Here, we focus on identification of gene pathways with direct causal relationships to AD through Gemini Digital Twins of AD patients.MethodTwo independent and complementary AD Digital Twins were built using an A.I. platform REFSTM [aitiabio.com], based on Bayesian network models of ADNI and ANMerge consortium data which reverse‐engineered the connectivity of ∼59K and ∼35K multi‐modal variables and a wide range of AD‐related outcomes (cognitive, imaging and biomarker) profiled from 317 subjects (Control:MCI:Dementia = 97:191:29) and 199 subjects (Control:MCI:Dementia = 65:63:71), respectively [Fig1]. The average causal effect of each gene (at the blood gene expression level) on each outcome was estimated through in silico counterfactual experiments. Pathway enrichment analyses were performed on metascape.org.ResultWe identified a total of 573 and 300 AD‐driver‐genes from ADNI‐ and ANMerge‐based Digital Twins, of which 41 overlapped (significance‐of‐overlap = 6e‐15). These 41 robustly validated genes, of which 61% were identified by the network as causal mediators of APOE4 genotype, were enriched in several biological processes known for AD such as ‘regulation of RNA splicing’ and ‘macrophage activation’ [Fig2]. The AD‐driver‐genes were also enriched in other interesting pathways in both Digital Twins, such as ‘immune response’ and ‘oxidative stress’. Furthermore, the ADNI‐specific AD‐driver‐genes, representing a sample population with a higher proportion of MCI patients, were related to additional processes such as ‘mitochondrial respiration’ and ‘ribosomal sub‐complexes pathways’, previously known to be involved specifically in early stage AD.ConclusionWe prioritized several AD‐related pathways for potential drug development identified from causal driver genes discovered and validated in two independent Digital Twins. Some of these pathways are more related to proteopathic biochemical phase of AD, rather than cellular phase, suggesting an area of a potential early intervention. Investigating causal genes from two complementary consortium studies with a different proportion of early vs. late stage AD patients may be a promising approach to identify disease‐stage‐specific and disease‐stage‐common signatures in the pathway‐based drug discovery efforts.

Plasma neurofilament light chain predicts Alzheimer’s disease in patients with subjective cognitive decline and mild cognitive impairment: a longitudinal study

AbstractBackgroundSubjective cognitive decline (SCD) and mild cognitive impairment (MCI) represent a target population for early detection of Alzheimer’s Disease (AD). Nevertheless, both MCI and SCD are common and heterogeneous conditions. We aim to evaluate the accuracy of plasma neurofilament light chain (NfL) in predicting AD and the progression of cognitive decline in patients with SCD and MCI.Method140 patients (45 SCD, 73 MCI, and 22 AD dementia [AD‐D]) underwent plasma NfL and CSF biomarker measurement at baseline. A subgroup of patients also underwent amyloid‐PET and 18F‐FDG‐PET brain scans. They were rated according to the A/T/N system and followed up for a mean time of 2.72±0.95 years. Forty‐eight (19 SCD, 29 MCI) had plasma NfL measurement also after two years from baseline.ResultNfL levels were higher in AD‐D than MCI and in MCI than SCD. In each group, patients with ATN profiles consistent with AD (A+/T+/N+ or A+/T+/N‐ [defined as ATN+]) had higher NfL levels (F[5,103] = 13.50, p<0.001, η2 = 0.396) than patients classified as ATN‐ (including patients with normal AD biomarkers, isolate Aβ pathology [A+] and non‐AD pathologic changes). NfL can distinguish ATN‐ and ATN+ patients with high accuracy (AUC = 0.82) and cut‐off values of 19.45 pg/mL in SCD and 20.45 pg/mL in MCI provide the highest Youden’s index. During the follow‐up, nine (30%) SCD patients progressed to MCI (p‐SCD) and 14 (29.79%) MCI patients developed AD‐D (p‐MCI). The previously defined cut‐off values identified p‐SCD with an 80.00% [95%C.I. = 65.69:94.31] accuracy. The rate of NfL change per year was higher in p‐MCI (3.52±4.06 pg/mL) as compared to np‐SCD (0.81±1.25 pg/mL) and np‐MCI (‐0.13±3.24 pg/mL) and np‐MCI (‐0.13±3.24 pg/mL) patients and in ATN+ (1.53±3.60 pg/mL) as compared to patients in the A+ group (‐0.97±1.66 pg/mL). A rate of change lower than 1.64 pg/mL can exclude progression to AD with a 92.86% (95%C.I. = 83.32:100) accuracy.ConclusionNfL concentration and change over time are increased in SCD and MCI patients with a biological demonstration of AD and can predict the progression of cognitive decline. Despite being considered a non‐specific neurodegeneration biomarker, if applied to selected populations, NfL may be a reliable, non‐invasive tool to detect the early stages of AD.

PP125 Why Understanding The Burden Of The Population Is Fundamental

IntroductionDespite intense efforts in development of new treatments over the last two decades, symptomatic treatments remain the only option for the vast majority patients diagnosed with dementia due to Alzheimer’s disease (AD). There remains a significant unmet need for disease modifying therapies (DMTs) to slow or stop AD progression. DMTs in development are targeting early stages of AD (pre-clinical, mild cognitive impairment and mild dementia stages), thereby creating an entirely new treatment paradigm for patients, clinicians, and payers. A key challenge will be in identifying the appropriate patient for treatment in a very heterogenous population. We have performed a literature review to better understand and define the AD population, with a view to enabling more targeted treatment in future.MethodsEmbase, MEDLINE and the Cochrane Library were searched to identify publications between 2010-2021 on observational studies reporting evidence on prevalence and subgroup identification, including clinical feasibility of identification. The search was restricted to English language.ResultsWe identified 45 studies, mostly from Europe, USA and Asia. Populations were primarily grouped based on generic demographic factors (e.g., age, sex, gender), AD staging, comorbidities or biomarkers. Prevalence data was available for six subpopulations: pre-dementia stage, mild dementia, age, Apolipoprotein E (APOE) genotype, comorbid obesity and hypertension. Across these, data on prevalence were heterogenous depending on study design and country of origin, and ranging between 66 million to 102 million for people with mild AD dementia, or as another example, ranging between 46 million to 92 million for APOE genotype carriers worldwide.ConclusionsThe heterogeneity and the uncertainty in prevalence of the AD population represent big challenges to clinicians and payers. Future discussions on target patient identification for new treatments should be aligned and integrated with current clinical practice e.g. leveraging validated biomarkers as diagnostic tools. Additional research on an integrated approach to identify patients who would benefit the most from DMTs will be needed.

Plasma p‐tau212 is an early biomarker to identify Alzheimer’s Disease pathology in Down Syndrome

AbstractBackgroundThe life‐time risk of Alzheimer´s disease (AD) in people with Down Syndrome (DS) is above 95% by the seventh decade of life. Understanding the strong biological relation between those conditions is important to accelerate progress in diagnostics and treatment. Tau phosphorylation at threonine‐212 (p‐tau212) is very sensitive to Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A), which is encoded in chromosome 21. Published results showed that p‐tau212 was significantly increased in AD‐DS male brains. This suggests a possible involvement of p‐tau212 in early progression to AD in individuals with DS. Here, we assessed the potential of these biomarker in DS and sporadic AD.MethodUsing SIMOA technology, we tested in‐house developed p‐tau212 immunoassay (n = 245 for plasma, n = 329 for CSF and n = 115 paired samples) and p‐tau181 (n = 459 for plasma, n = 357 for CSF and n = 245 for p‐tau212 paired plasma samples). A subset of participants had amyloid‐PET data. We used AUC‐ROC to examine diagnostic potential and DeLong test for comparison. Spearman correlations were used to establish associations. Age‐related changes of p‐tau212 and p‐tau181 were examined in relation to amyloid positivity in CSF and Amyloid‐PET.ResultPlasma/CSF p‐tau212 and p‐tau181 showed excellent analytical performances. Plasma p‐tau212 started increasing around 20 years before people were diagnosed as prodromal AD‐DS (pDS) and CSF p‐tau212 approximately 27 years. Paired plasma and CSF p‐tau212 measurements correlated strongly (r = 0.71;p<0.001). Both plasma biomarkers were successful in differentiating asymptomatic DS (aDS) from dementia‐DS (dDS) with an AUC = 91% for p‐tau212 and AUC = 88% for p‐tau181. Plasma p‐tau212 had greater than p‐tau181 magnitude of change in early stages of AD performing 3.4 vs 2‐fold change for pDS and 3 vs 2.1 for vs mild cognitive impairment (MCI‐AD). Pattern remained the same for dDS, AD and CSF measurements. Moreover, plasma p‐tau212 was 2.4‐fold increased in aDS people, when compared to CN. Aside of great discrimination in DS, plasma p‐tau212 had significantly better performance than p‐tau181 for differentiating CN from MCI‐AD (AUC = 84%‐91%;p = 0.026) and CN from MCI‐AD+AD (AUC = 86%‐93%;p = 0.026).ConclusionPlasma p‐tau212 is useful for early DS and AD differentiation. Blood‐based p‐tau212 will be a cost‐effective and simple‐to‐implement alternative to in vivo and autopsy‐based evaluations for AD changes in DS and sporadic cases.

Potential neural substrates underlying circadian and olfactory disruptions in preclinical Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers.

Alzheimer disease biomarkers are associated with decline in subjective memory, attention, and spatial navigation ability in clinically normal adults.

Subtle changes in memory, attention, and spatial navigation abilities have been associated with preclinical Alzheimer disease (AD). The current study examined whether baseline AD biomarkers are associated with self- and informant-reported decline in memory, attention, and spatial navigation. Clinically normal (Clinical Dementia Rating Scale (CDR®) = 0) adults aged 56-93 (N = 320) and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog) annually for an average of 4 years. Biomarker data was collected within (±) 2 years of baseline (i.e., cerebrospinal fluid (CSF) p-tau181/Aβ42 ratio and hippocampal volume). Clinical progression was defined as CDR > 0 at time of final available ECog. Self- and informant-reported memory, attention, and spatial navigation significantly declined over time (ps < .001). Baseline AD biomarkers were significantly associated with self- and informant-reported decline in cognitive ability (ps < .030), with the exception of p-tau181/Aβ42 ratio and self-reported attention (p = .364). Clinical progression did not significantly moderate the relationship between AD biomarkers and decline in self- or informant-reported cognitive ability (ps > .062). Post-hoc analyses indicated that biomarker burden was also associated with self- and informant-reported decline in total ECog (ps < .002), and again clinical progression did not significantly moderate these relationships (ps > .299). AD biomarkers at baseline may indicate risk of decline in self- and informant-reported change in memory, attention, and spatial navigation ability. As such, subjectively reported decline in these domains may have clinical utility in tracking the subtle cognitive changes associated with the earliest stages of AD.

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

BackgroundSynaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.MethodsHippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.ResultscircRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.ConclusionsIn conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

AMSF: attention-based multi-view slice fusion for early diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a high prevalence in the elderly population over 65 years of age. Intervention in the early stages of AD is of great significance to alleviate the symptoms. Recent advances in deep learning have shown extreme advantages in computer-aided diagnosis of AD. However, most studies only focus on extracting features from slices in specific directions or whole brain images, ignoring the complementarity between features from different angles. To overcome the above problem, attention-based multi-view slice fusion (AMSF) is proposed for accurate early diagnosis of AD. It adopts the fusion of three-dimensional (3D) global features with multi-view 2D slice features by using an attention mechanism to guide the fusion of slice features for each view, to generate a comprehensive representation of the MRI images for classification. The experiments on the public dataset demonstrate that AMSF achieves 94.3% accuracy with 1.6-7.1% higher than other previous promising methods. It indicates that the better solution for AD early diagnosis depends not only on the large scale of the dataset but also on the organic combination of feature construction strategy and deep neural networks.

Linking Social Cognition, Parvalbumin Interneurons, and Oxytocin in Alzheimer's Disease: An Update.

Finding a cure for Alzheimer's disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.

Cerebrospinal Fluid Complement 4 Levels Were Associated with Alzheimer's Disease Pathology and Cognition in Non-Demented Elderly.

Numerous studies have shown that the complement system plays an important role in Alzheimer's disease (AD). However, whether complement 4 (C4) protein in cerebrospinal fluid (CSF) was associated with AD pathology, especially in the early stage of AD, is still unclear. We aimed to explore the association of CSF C4 with AD pathology and cognition in the preclinical AD. The study included a total of 287 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Based on the A/T scheme, they were divided into four groups to access the changes of CSF C4 in the preclinical AD. Linear regression models were used to test the associations between CSF C4 and AD core biomarkers, namely Aβ42, P-tau, and T-tau. The level of CSF C4 decreased in the A + T- group compared with the A-T- group (p = 0.04) and it increased in the A-T+ group compared to the A + T- group (p = 0.01). In pooled samples, C4 was significantly associated with AD core biomarkers (all p < 0.05), but only in the A + group after stratification according to the A/T scheme. Furthermore, CSF C4 levels at baseline were associated with longitudinal cognitive changes. Our results showed that CSF C4 levels changed dynamically in the preclinical AD, and that the responses of CSF C4 to brain Aβ pathology, tau pathology and neurodegeneration were found only in the presence of amyloid plaques, both of which indicates the complex link between C4 and AD.