Underlying Alzheimer's Disease Pathology Research Articles

The Association Between Plasma Amyloid-β 42/40 and Percentage of Semantic Intrusion Errors in Mild Cognitive Impairment.

Semantic intrusion errors (SIEs) are both sensitive and specific to PET amyloid-β (Aβ) burden in older adults with amnestic mild cognitive impairment (aMCI). Plasma Aβ biomarkers including the Aβ42/40 ratio using mass spectrometry are expected to become increasingly valuable in clinical settings. Plasma biomarkers are more clinically informative if linked to cognitive deficits that are salient to Alzheimer's disease (AD). This study included 119 older adults enrolled in the 1Florida Alzheimer's Disease Research Center (ADRC), 45 aMCI participants scored below the established Aβ42/40 ratio cut-off of 0.160 using the Quest AD-Detect™ assay indicating Aβ positivity (Aβ+), while 50 aMCI participants scored above this cut-off indicating Aβ negative status (Aβ-). Additionally, 24 cognitively unimpaired (CU) persons scored above the cut-off of 0.160 (Aβ-). The aMCI plasma Aβ+ group evidenced the greatest percentage of SIEs, followed by the aMCI Aβ-. The CU Aβ- group exhibited the lowest percentage of SIEs. After adjustment for global cognitive impairment, aMCI plasma Aβ+ continued to demonstrate greater SIEs on tests tapping the failure to recover from proactive semantic interference (frPSI) as compared to the aMCI Aβ-group. Using pre-established cut-offs for frPSI impairment, 8.3% of CU Aβ- participants evidenced deficits, compared to 37.8% of aMCI Aβ-, and 74.0% of aMCI Aβ+. SIEs reflecting frPSI were associated with aMCI Aβ+ status based on the Aβ42/40 ratio. Results suggest the importance of SIEs as salient cognitive markers that map onto underlying AD pathology in the blood.

Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology: a cohort study

BackgroundAutopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.MethodsA total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.ResultsAcross the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.ConclusionsOur findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Future perspective and clinical applicability of the combined use of plasma phosphorylated tau 181 and neurofilament light chain in Subjective Cognitive Decline and Mild Cognitive Impairment

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer’s Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1–40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP−) when they were A−, A+/T−/N−, or A+/T−/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP− patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn’s k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.

Proteome Analysis in Plasma and Brain Reveals a Novel Plasma Biomarker Linked to Antemortem Cognitive Impairment and Postmortem Neuropathological Traits for Alzheimer Disease

AbstractBackgroundIdentification of blood‐based biomarkers that are indicative of Alzheimer’s disease (AD) pathology may help with early detection.MethodsWe generated proteome data for ∼7,000 proteins in both antemortem plasma and postmortem brain tissue from 103 participants of the Boston University Alzheimer’s Disease Research Center. All participants completed comprehensive neuropsychological evaluations and dementia severity was measured by global cognitive dementia rating (CDR) scores. A pathological AD diagnosis was established using NIA Reagan criteria. We conducted association tests with dementia (i.e., CDR ≥1 for dementia, CDR &lt;1 for control) and autopsy‐confirmed AD status as binary outcomes. Plasma proteins significantly associated with clinical or pathological AD (P&lt;0.05) were tested for association with quantitative cognitive tests and AD‐related neuropathological traits in which outcomes were rank‐transformed after adjusting for sex and either age at last antemortem exam or death.ResultsOf the 103 brain donors, 43 were diagnosed with dementia and 55 had autopsy‐confirmed AD. Five proteins (ACES, AURKB, CBARP, G45IP, and MMP‐8) measured in plasma were significantly associated with both pathological AD and dementia, while 252 plasma proteins were associated with either diagnosis (P&lt;0.05). MMP‐8 was the only protein that was significantly associated in both plasma and brain with autopsy‐confirmed AD (Pplasma = 0.005, Pbrain = 0.001) and dementia (Pplasma = 0.01, Pbrain = 9×10−5). ACES and AURKB levels in plasma and brain were significantly associated with dementia (P&lt;0.05). Levels of these. Increased MMP‐8 level in plasma was associated with decreased animals (P = 0.03) and scores (P = 0.04), which both assess verbal fluency. Dementia and pathologically confirmed AD were associated with lower AURKB and elevated ACES levels in plasma. Decreased plasma ACES level was associated with executive function (TrailsB: P = 0.01) and language (Boston Naming Test: P = 0.02) impairment, and the reduced plasma AURKB level was associated with memory impairment (Logical Memory Immediate Recall score: P = 0.03).ConclusionMMP‐8, a neutrophil collagenase and member of the matrix metalloproteinase family, is a potential blood‐based biomarker for dementia and underlying AD pathology and is associated predominantly with impaired verbal fluency.

Domain‐specific subtle cognitive decline associations with cerebrospinal fluid and plasma β‐amyloid and p‐tau Alzheimer’s disease biomarkers in cognitively unimpaired individuals

AbstractBackgroundPresence of Alzheimer’s disease (AD) core pathology, β‐amyloid (Aβ) and p‐tau, has been proven to impact cognitive function even in cognitively unimpaired (CU) individuals. Although the Aβ and p‐tau (AT) effect has been mainly associated with memory function, recent evidence (Tideman, P., 2022. Neurology) suggested that Aβ levels were associated independently of p‐tau with the cross‐sectional performance in executive functioning. The aim of the present study was to explore specific associations of cerebrospinal fluid (CSF) and plasma Aβ and p‐tau baseline levels with the longitudinal change in several cognitive domains in a sample of CU individuals at increased risk of AD.MethodWe analyzed the associations of baseline CSF Aβ42/40, and p‐tau181 as well as plasma Aβ42/40, and p‐tau231 levels, with domain‐specific cognitive changes 3 years after baseline in 337 CU participants from the ALFA+ study. We defined AT groups (A‐T‐, A+T‐, and A+T+) using CSF levels, and the A‐T‐ group’s baseline performance served as reference to compute z‐scores for Visual Processing, Semantic Fluency, Executive Functioning, Episodic Memory, and Attentional Processing. Delta scores were computed by subtracting baseline from follow‐up scores and then compared among AT groups by means of ANCOVAs. Multiple linear regressions were performed on the whole sample using CSF Aβ42/40, p‐tau181 and plasma Aβ42/40, p‐tau231 as predictors of change in cognitive function.ResultA+T+ individuals showed a significant decline in Executive Function (p = 0.005, Cohen’s d = 0.716), and Attentional Processing (p = 0.032, Cohen’s d = 0.563), but not in Episodic Memory (p = 0.334) when compared with A‐T‐ individuals. In the whole sample, CSF Aβ42/40 was associated independently of p‐tau181 with a decline in Semantic Fluency (β = 6.284, p = 0.013), Attentional Processing (β = 3.828, p = 0.020), and Episodic Memory (β = 3.513, p = 0.004). Plasma p‐tau231 levels were associated with a decline in Semantic Fluency (β = ‐0.413, p = 0.045). CSF p‐tau181 and plasma Aβ42/40 were not associated with cognitive changes.ConclusionExecutive Function and Attentional Processing were more sensitive than Episodic Memory in capturing the early subtle cognitive changes in CU individuals with underlying AD pathology. Attentional Processing was the only cognitive domain associated both with the status of AD biomarkers and with the effect of CSF Aβ levels independently of p‐tau.

ABCA7 Mutations Can Present as Behavioral Variant Frontotemporal Dementia Without Amyloid Pathology

AbstractBackground ABCA7 was identified as an Alzheimer’s disease (AD) risk gene in 2011 through GWAS studies and subsequently its role in pathogenesis was confirmed via in‐vivo studies demonstrating loss of ABCA7 was sufficient to the trigger amyloid cascade. The most common presentation of ABCA7 loss of function mutations is an amnestic syndrome, however it less commonly can present with behavioral or motor symptoms. While the described clinical presentation can vary, almost all cases have been associated with AD pathology. Here we present three cases of bvFTD clinical syndromes in ABCA7 mutations carriers without evidence of AD pathology.MethodPatients underwent a comprehensive clinical assessment including neurological history, examination, neuropsychological testing, MR brain imaging, and lumbar puncture. AD biomarkers were assessed through CSF testing. Genetic testing was obtained through CLIA certified whole genome sequencing.ResultWe identified three individuals with mutations in ABCA7. Two of these individuals harbor the p.I1878M mutation and one with the p.W1214* mutation on genetic testing. They presented with behavioral variant frontotemporal dementia with no evidence of amyloid pathology on CSF biomarker testing.ConclusionWe present three cases of symptomatic ABCA7 mutation carriers without evidence of underlying AD pathology. The exact function of ABCA7 is unknown, however its purported involvement in lipid transport and immune responses are common pathways in neurodegenerative disease and raises the possibility of converging disease cascades.

Longitudinal white matter hyperintensities in Down’s syndrome

AbstractBackgroundDown’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD). Typically not complicated by systemic vascular risk factors, the DS population represents a unique opportunity to unravel the complex relationship between AD and cerebrovascular disease. Here, we aim at studying the evolution over time of white matter hyperintensities (WMHs), a key hallmark of cerebrovascular disease frequently found in AD, and to assess their topographical progression and associations with AD biomarkers in adults with DS.MethodThis longitudinal study included 43 DS adults (age = 39.8±10.4y; females = 41.9%; n = 37 asymptomatic AD, n = 6 symptomatic AD) and 81 euploid controls (age = 53.7±6.2y; females = 67.3%) from the Down‐Alzheimer Barcelona Neuroimaging Initiative, with at least 2 MRI visits with T1 and FLAIR acquisitions (time delay = 3.4±1.6y). WMHs were segmented using the Lesion Prediction Algorithm implemented in the Lesion Segmentation Toolbox (SPM12). WMH volumes were extracted in 36 regions of interest and used to compute total and regional annual volume changes. Non‐parametric statistical tests were performed to assess the effect of disease severity on WMH volume changes over time and define associations between longitudinal WMHs and baseline demographic and genetic data, and fluid biomarkers.ResultTotal annual WMH volume change increased in symptomatic DS compared to both asymptomatic DS and controls (Figure 1A). Regionally, WMH load increased in regions showing WMH at baseline in all groups (Figure 2). These changes were greater and more distributed, involving layers more distant from the ventricles (especially in occipito‐parietal regions) in symptomatic DS. Age, but not sex, intellectual disability, or APOEε4 status, was associated with longitudinal WMH in DS (Figure 1B‐F): the annual WMH volume changes in DS differed from controls at age ∼45y. Finally, WMH volume changes were negatively related to CSF‐Aβ42/40 and positively related to plasma and CSF ptau‐181 and neurofilament light (Figure 3).ConclusionPathological increases in WMH volume start ∼10 years before the mean age at onset for AD (53.8y) in DS and relate to underlying AD pathology and neurodegeneration. Regional analyses suggest that WMH volume changes increase with disease progression and progressively involve deeper white matter areas. Together, these results support that WMHs are tightly related to AD pathogenesis.

Plasma p-tau181 as a promising non-invasive biomarker of Alzheimer's Disease pathology in Subjective Cognitive Decline and Mild Cognitive Impairment

IntroductionThe aim of this study is to investigate the role of plasma phosphorylated tau (p-tau) 181 as a potential biomarker for Alzheimer's Disease (AD) pathology in the early stages of the disease, as a valuable marker for tauopathy. Materials and methodsThirty-three Subjective Cognitive Decline (SCD), 32 Mild Cognitive Impairment (MCI) and 14 AD demented (AD-d) patients underwent plasma p-tau181 analysis with SiMoA assay. Twenty-six SCD, 32 MCI and 14 AD-d patients also underwent CSF biomarkers analysis (Aβ1–42, Aβ1–42/1–40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) when A+ was associated with T+ (regardless of N), or non-carriers (AP-) when they were A- (regardless of T and N), or A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. ResultsPlasma p-tau181 levels were higher in SCD AP+ than in SCD AP- (2.85 ± 0.53 vs 1.73 ± 0.64, p < 0.001), and in MCI AP+ than in MCI AP- (4.03 ± 1.07 vs 2.04 ± 0.87, p < 0.001). In a multivariate linear regression analysis, AP status was the only variable that influenced plasma p-tau181 (B = 1.670 [95% CI 1.097:2.244], p < 0.001). Plasma p-tau181 was highly accurate for discriminating between AP+ and AP- patients (AUC = 0.910). We identified a cut-off level of 2.69 pg/mL to distinguish between AP+ and AP- (sensibility 0.86, specificity 0.82, PPV 75.00% NPV 90.32%). ConclusionsPlasma p-tau181 levels were influenced by the presence of underlying AD pathology, independently from the cognitive status and were highly accurate in differentiating SCD-MCI patients who were carriers of AD pathology from non-carriers. Plasma p-tau181 might be a promising non-invasive biomarker of AD pathology at a very early stage.

MicroRNA-125a-3p Modulate Amyloid β-Protein through the MAPK Pathway in Alzheimer's Disease.

MicroRNA (miR)-125a-3p is reported to play an important role in some central nervous system diseases, such as Alzheimer's disease (AD). However, a study has not been conducted on the mechanism of miR-125a-3p in the pathological process of AD. First, we assessed the expression of miR-125a-3p in AD cohort. Subsequently, we altered the expressions of miR-125a-3p to assess its role in cell viability, cell apoptosis, amyloid-β (Aβ) metabolism, and synaptic activity. Finally, we identified its potential mechanism underlying AD pathology. This study unveiled the potential function of miR-125a-3p through modulating amyloid precursor protein processing. Additionally, miR-125a-3p influenced cell survival and activated synaptic expression through the modulation of Aβ metabolism in the mitogen-activated protein kinase (MAPK) pathway via fibroblast growth factor receptor 2. Our study indicates that targeting miR-125a-3p may be an applicable therapy for AD in the future. However, more in vitro and in vivo studies with more samples are needed to confirm these results.

Seizure Rates Across Pathologically-Confirmed Dementia Subtypes (P3-6.005)

<h3>Objective:</h3> Taking advantage of a large autopsy series of uniformly pathologically-characterized persons with dementia (PWD), our goal was to determine the seizure occurrence rate for different types of pathologically confirmed dementia subtypes. <h3>Background:</h3> The incidence of seizures in PWD is higher than in persons without dementia. However, evidence of this is based on studies that included clinically-diagnosed all-cause dementia, pathologically-diagnosed Alzheimer’s Disease (AD), or clinically-diagnosed subtypes of dementia without pathological confirmation. <h3>Design/Methods:</h3> Retrospective review of clinical and autopsy records among all veterans who died while in a VA-based Special Dementia Care Unit and whose families consented to brain autopsy was conducted. <h3>Results:</h3> Of the 335 veterans, the majority (n = 327, 97.61%) were male with an average age of 78 years at death (SD=7.62). The average age at first reported symptom was 71 (SD=8.28). Overall, 57 (17%) veterans had evidence of new-onset seizures after the date of their dementia diagnosis and were thus considered to have dementia-related seizures. Of those with AD-only neuropathology (n=121), 26 (21.5%) had developed seizures and accounted for 45.6% of all the dementia-related seizure cases. In addition, most of the remaining cases of dementia-related seizures (n=26, 45.6%) showed evidence of AD pathology and in addition to another comorbid pathology. The remaining five (8.8%) were diagnosed with Frontotemporal Dementia and/or Traumatic Brain Injury. <h3>Conclusions:</h3> Dementia-related seizures are common and are associated with AD pathology. Even among pathologically mixed dementias, seizure prevalence was driven by AD pathology. Diagnosis of seizures in patients with dementia may reflect underlying AD pathology, regardless of clinical presentation. The development of dementia-related seizures should raise the possibility of underlying AD pathology and thus could have implications for treatment response. <b>Disclosure:</b> An immediate family member of Dr. Moo has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Taylor and Francis. Dr. Moo has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Smith Mirabella Blake. Dr. Moo has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cambridge Medical Experts. The institution of Dr. Moo has received research support from VA HSR&amp;D. The institution of Dr. Moo has received research support from VA Office of Rural Health. Prof. Shirk has received personal compensation for serving as an employee of Hologic. The institution of Prof. Shirk has received research support from Alzheimer’s Association. The institution of Prof. Shirk has received research support from VA. The institution of Prof. Shirk has received research support from NIA. Dr. Baumann has nothing to disclose. Dr. Sullivan has nothing to disclose.

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood-brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome

Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. While AD is primarily a neurological disease of the brain, individuals with AD often experience intestinal disorders, and gut abnormalities have been implicated as a major risk factor in the development of AD and relevant dementia. However, the mechanisms that mediate gut injury and contribute to the vicious cycle between gut abnormalities and brain injury in AD remain unknown. In the present study, a bioinformatics analysis was performed on the proteomics data of variously aged AD mouse colon tissues. We found that levels of integrin β3 and β-galactosidase (β-gal), two markers of cellular senescence, increased with age in the colonic tissue of mice with AD. The advanced artificial intelligence (AI)-based prediction of AD risk also demonstrated the association between integrin β3 and β-gal and AD phenotypes. Moreover, we showed that elevated integrin β3 levels were accompanied by senescence phenotypes and immune cell accumulation in AD mouse colonic tissue. Further, integrin β3 genetic downregulation abolished upregulated senescence markers and inflammatory responses in colonic epithelial cells in conditions associated with AD. We provide a new understanding of the molecular actions underpinning inflammatory responses during AD and suggest integrin β3 may function as novel target mediating gut abnormalities in this disease.

Underlying clusters of NIA‐AA Research Framework stage 2 criteria and their relationship with AD biomarkers in the DELCODE study

AbstractBackgroundAs part of the updated NIA‐AA Research Framework for Alzheimer’s disease (AD), a numeric clinical staging scheme, applicable only to individuals in the Alzheimer’s continuum, has been introduced. “Stage 2” is defined as a transitional stage, characterized by subtle or subjective decline in cognition or neuropsychiatric symptoms (NPS) that might reflect underlying AD pathology (Jack et al., Alzheimers Dement. 2018). Here, we aimed to cluster a sample of cognitively healthy participants based on stage 2 criteria and compare the emerging clusters with regard to differences in CSF biomarker status.MethodFor this analysis, we included baseline data of N = 349 cognitively healthy participants with available CSF biomarker information from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. A two‐step cluster analysis (TSCA) was applied based on CSF Aß42/40 status and stage 2 criteria, which included a) subtle objective cognitive impairment (&lt;0.5SD) in any of five factor scores from DELCODE’s neuropsychological test battery, b) subjective cognitive decline (SCD) with concern in any of the five SCD‐Interview domains and c) the presence of agitation, depression, anxiety, disinhibition, irritability or sleep disturbances on the Neuropsychiatric Inventory Questionnaire [NPI‐Q]. The TSCA identifies the optimal number of clusters by grouping cases into preclusters first and then clustering those using a hierarchical algorithm.ResultThe TSCA yielded three clusters. Cluster 1 (n = 114) was characterized by subtle cognitive impairment in memory, language, executive function and working memory as well as SCD in the memory and language domain. In contrast, cluster 2 (n = 104) was predominantly formed by participants that reported SCD and NPS without subtle objective impairment. In cluster 3 (n = 121), none of the stage 2 criteria were prominent. In comparison to clusters 2 and 3, participants in cluster 1 had lower levels of Aß42/40 (H(2) = 11.58, p = .003) and Aß42/ptau‐181 (H(2) = 12.06, p = .002). We observed no significant differences between clusters 2 and 3.ConclusionOur analysis resulted in three distinct clusters of cognitively healthy participants with different distributions of stage 2 criteria. The criteria prominent in participants of cluster 1 seem most promising to identify individuals at risk of progression due to underlying AD pathology.

Longitudinal Blood Biomarker Trajectories in Preclinical Alzheimer’s Disease

AbstractBackgroundBlood‐biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross‐sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood‐biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood‐biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET.MethodWe included a subset of 126 cognitively unimpaired older adults from the Prevent‐AD cohort. Blood was drawn from baseline up to four‐year follow‐up visits. We measured Aβ42/Aβ40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ (18F‐NAV4694) and tau (18F‐flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ‐PET retention (SUVR cut‐off = 1.29), and tau‐PET positivity by entorhinal cortex flortaucipir binding (SUVR cut‐off = 1.23). Using these thresholds, 82 subjects were classified as A‐T‐, 29 as A+T‐, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups.ResultAmyloid‐PET‐positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ42/40 when compared with amyloid‐PET‐negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A‐T‐ group (p = 0.01; Figure 1). Overall, the A+T‐ and A+T+ groups had lower levels of plasma Aβ42/40 compared with the A‐T‐ group (p = 0.05, p = 0.0189; Figure 2), and the A+T‐ group had higher pTau231 compared with A‐T‐ participants (p = 0.0006; Figure 3). Longitudinal rate of change in Aβ42/40 and pTau231 did not differ between the groups.ConclusionWe observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.

Diagnosing Alzheimer Disease: Which Dementia Screening Tool to Use in Elderly Puerto Ricans with Mild Cognitive Impairment and Early Alzheimer Disease?

AbstractBackgroundMost of the time, Alzheimer Disease (AD)’s diagnosis is not made at its earliest periods and prodromal stages, for instance at Mild Cognitive Impairment (MCI) and Early Alzheimer Disease (E‐AD) stage. Commonly, AD’s diagnosis is made when significant impairment interferes with the habitual daily activities (1). Our pilot study, serves to demonstrate a correlation between the screening tools, including the Mini‐mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating Scale (CDR), and the biological biomarkers in the cerebral spinal fluid (CSF) (Amyloid Beta 1‐42 (Aβ42 pg/mL), Tau proteins (tTau (pg/mL) and tTau/Aβ42 ratio in Puerto Ricans &gt; 55 years old with MCI and E‐AD. To our knowledge, this is the first study trying to create a correlation between memory tests scores and underlying AD pathology to improve early detection in elderly Puerto Ricans.MethodThirty participants were evaluated including, demographics, clinical characteristics, memory scales and CSF biomarkers. CSF biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) were determined using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MOCA, MMSE, CDR) and CSF markers were performed using Spearman’s rho correlation.ResultOur study revealed statistical association in favor of a direct relationship between MMSE and tTau/Aβ42 ratio in CSF (p= .022, 95.00% CI = [‐.69, ‐.07] (Figure 1). We found a trend towards significance with an inverse relationship with MMSE and Aβ42 (p=.069) (Figure 2) and a direct relationship with MMSE and tTau (p= .098) (Figure 3). Besides, MoCA and tTau/Aβ42 ratio had a statistically significant direct relationship (p = 0.035) (Figure 4). There was no significant statistical association between CDR test with CSF biomarkers in elderly Puerto Ricans.ConclusionMMSE was the dementia screening test consistently identifying a statistically significant or a‐trend‐towards a significant association with the CSF Alzheimer Disease’ s biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) in elderly Puerto Ricans with MCI and E‐AD. Clinically, &gt; 55 y/o Puerto Rican patients with MCI and E‐AD should be screened with MMSE for a higher likelihood of earlier detection and, thus, initiation of disease‐modifying treatment.

Longitudinal Blood Biomarker Trajectories in Preclinical Alzheimer’s Disease

AbstractBackgroundBlood‐biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross‐sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood‐biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood‐biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET.MethodWe included a subset of 126 cognitively unimpaired older adults from the Prevent‐AD cohort. Blood was drawn from baseline up to four‐year follow‐up visits. We measured Aβ42/Aβ40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ (18F‐NAV4694) and tau (18F‐flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ‐PET retention (SUVR cut‐off = 1.29), and tau‐PET positivity by entorhinal cortex flortaucipir binding (SUVR cut‐off = 1.23). Using these thresholds, 82 subjects were classified as A‐T‐, 29 as A+T‐, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups.ResultAmyloid‐PET‐positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ42/40 when compared with amyloid‐PET‐negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A‐T‐ group (p = 0.01; Figure 1). Overall, the A+T‐ and A+T+ groups had lower levels of plasma Aβ42/40 compared with the A‐T‐ group (p = 0.05, p = 0.0189; Figure 2), and the A+T‐ group had higher pTau231 compared with A‐T‐ participants (p = 0.0006; Figure 3). Longitudinal rate of change in Aβ42/40 and pTau231 did not differ between the groups.ConclusionWe observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.

Characterization of Altered Molecular Pathways in the Entorhinal Cortex of Alzheimer's Disease Patients and In Silico Prediction of Potential Repurposable Drugs.

Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-β plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first brain area associated with pathologic changes in AD, even preceding atrophy of the hippocampus. In the current study, we have performed a meta-analysis of publicly available expression data sets of the entorhinal cortex (EC) in order to identify potential pathways underlying AD pathology. The meta-analysis identified 1915 differentially expressed genes (DEGs) between the EC from normal and AD patients. Among the downregulated DEGs, we found a significant enrichment of biological processes pertaining to the “neuronal system” (R-HSA-112316) and the “synaptic signaling” (GO:0099536), while the “regulation of protein catabolic process” (GO:00042176) and “transport of small molecules” (R-HSA-382551) resulted in enrichment among both the upregulated and downregulated DEGs. Finally, by means of an in silico pharmacology approach, we have prioritized drugs and molecules potentially able to revert the transcriptional changes associated with AD pathology. The drugs with a mostly anti-correlated signature were: efavirenz, an anti-retroviral drug; tacrolimus, a calcineurin inhibitor; and sirolimus, an mTOR inhibitor. Among the predicted drugs, those potentially able to cross the blood-brain barrier have also been identified. Overall, our study found a disease-specific set of dysfunctional biological pathways characterizing the EC in AD patients and identified a set of drugs that could in the future be exploited as potential therapeutic strategies. The approach used in the current study has some limitations, as it does not account for possible post-transcriptional events regulating the cellular phenotype, and also, much clinical information about the samples included in the meta-analysis was not available. However, despite these limitations, our study sets the basis for future investigations on the pathogenetic processes occurring in AD and proposes the repurposing of currently used drugs for the treatment of AD patients.

Dopamine transporter SPECT imaging in corticobasal syndrome: A peak into the underlying pathology?

Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer's disease (AD). Dopamine transporter density imaging with Ioflupane 123 I SPECT (DaTscan) may be normal in CBS. No studies to date have examined the relationship between DaTscan status and underlying pathology in CBS. The main objective of the study was to test whether a normal DaTscan in CBS patients is indicative of an underlying AD pathology, as determined by cerebrospinal fluid (CSF) biomarkers. Eighteen CBS patients were included. They were divided into patients with an AD and a non-AD disease pathology, based on their cerebrospinal fluid biochemical profile. A typical AD CSF profile was defined as an increase in total and phosphorylated at threonine 181 tau protein in addition to a decrease in amyloid-beta with 42 amino acids. DaTscan data were compared in these two groups. Eight of the 18 CBS patients (44%) had a normal DaTscan. Seven of the 18 CBS patients (39%) had an AD cerebrospinal fluid biochemical profile. Two of seven CBS patients with AD biomarker profile had abnormal DaTscans. Three of 11 CBS patients with a non-AD biomarker profile had normal DaTscans. A normal DaTscan was indicative of AD pathology with suboptimal (~70%) sensitivity and specificity. Semi-quantitative DaTscan analysis did not differentiate between AD from non-AD CSF biomarker profile in CBS. A normal DaTscan is indicative of AD in CBS, but the sensitivity and specificity of DaTscan as an in vivo marker of AD pathology is suboptimal.

Brain oxygen extraction and neural tissue susceptibility are associated with cognitive impairment in older individuals.

We investigated the effects of aging, white matter hyperintensities (WMH), and cognitive impairment on brain iron levels and cerebral oxygen metabolism, known to be altered in Alzheimer's disease (AD), using quantitative susceptibility mapping and MR-based cerebral oxygen extraction fraction (OEF). In 100 individuals over the age of 50 (68/32 cognitively impaired/intact), OEF and neural tissue susceptibility (χn ) were computed retrospectively from MRI multi-echo gradient echo data, obtained on a 3 Tesla MRI scanner. The effects of age and WMH on OEF and χn were assessed within groups, and OEF and χn were assessed between groups, using multivariate regression analyses. Cognitively impaired subjects were found to have 19% higher OEF and 34% higher χn than cognitively intact subjects in the cortical gray matter and several frontal, temporal, and parietal regions (p<.05). Increased WMH burden was significantly associated with decreased OEF in the cognitively impaired, but not in the cognitively intact. Older age had a stronger association with decreased OEF in the cognitively intact group. Both older age and increased WMH burden were significantly associated with increased χn in temporoparietal regions in the cognitively impaired. Higher brain OEF and χn in cognitively impaired older individuals may reflect altered oxygen metabolism and iron in areas with underlying AD pathology. Both age and WMH have associations with OEF and χn but are modified by the presence of cognitive impairment.