AD Prevention Research Articles

Excessive daytime sleepiness and napping in cognitively normal adults: associations with subsequent amyloid deposition measured by PiB PET.

Study objectives To determine the association of excessive daytime sleepiness (EDS) and napping with subsequent brain β-amyloid (Aβ) deposition in cognitively normal persons. Methods We studied 124 community-dwelling participants in the Baltimore Longitudinal Study of Aging Neuroimaging Substudy who completed self-report measures of EDS and napping at our study baseline and underwent [11C] Pittsburgh compound B positron emission tomography (PiB PET) scans of the brain, an average ±standard deviation of 15.7 ± 3.4 years later (range 6.9 to 24.6). Scans with a cortical distribution volume ratio of >1.06 were considered Aβ-positive. Results Participants were aged 60.1 ± 9.8 years (range 36.2 to 82.7) at study baseline; 24.4% had EDS and 28.5% napped. In unadjusted analyses, compared with participants without EDS, those with EDS had more than 3 times the odds of being Aβ+ at follow-up (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.44, 7.90, p = 0.005), and 2.75 times the odds after adjustment for age, age2, sex, education, and body mass index (OR = 2.75, 95% CI: 1.09, 6.95, p = 0.033). There was a trend-level unadjusted association between napping and Aβ status (OR = 2.01, 95% CI: 0.90, 4.50, p = 0.091) that became nonsignificant after adjustment (OR = 1.86, 95% CI: 0.73, 4.75, p = 0.194). Conclusions EDS is associated with more than 2.5 times the odds of Aβ deposition an average of 15.7 years later. If common EDS causes (e.g., sleep-disordered breathing, insufficient sleep) are associated with temporally distal AD biomarkers, this could have important implications for AD prevention.

Excessive daytime sleepiness and napping in cognitively normal adults: associations with subsequent amyloid deposition measured by PiB PET.

To determine the association of excessive daytime sleepiness (EDS) and napping with subsequent brain β-amyloid (Aβ) deposition in cognitively normal persons. We studied 124 community-dwelling participants in the Baltimore Longitudinal Study of Aging Neuroimaging Substudy who completed self-report measures of EDS and napping at our study baseline and underwent [11C] Pittsburgh compound B positron emission tomography (PiB PET) scans of the brain, an average ±standard deviation of 15.7 ± 3.4 years later (range 6.9 to 24.6). Scans with a cortical distribution volume ratio of >1.06 were considered Aβ-positive. Participants were aged 60.1 ± 9.8 years (range 36.2 to 82.7) at study baseline; 24.4% had EDS and 28.5% napped. In unadjusted analyses, compared with participants without EDS, those with EDS had more than 3 times the odds of being Aβ+ at follow-up (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.44, 7.90, p = 0.005), and 2.75 times the odds after adjustment for age, age2, sex, education, and body mass index (OR = 2.75, 95% CI: 1.09, 6.95, p = 0.033). There was a trend-level unadjusted association between napping and Aβ status (OR = 2.01, 95% CI: 0.90, 4.50, p = 0.091) that became nonsignificant after adjustment (OR = 1.86, 95% CI: 0.73, 4.75, p = 0.194). EDS is associated with more than 2.5 times the odds of Aβ deposition an average of 15.7 years later. If common EDS causes (e.g., sleep-disordered breathing, insufficient sleep) are associated with temporally distal AD biomarkers, this could have important implications for AD prevention.

Synergistic interaction between APOE and family history of Alzheimer\u2019s disease on cerebral amyloid deposition and glucose metabolism

BackgroundRecently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer’s disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks—the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)—on AD-related brain changes in cognitively normal (CN) middle-aged and older adults.Methods[11C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [18F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses.ResultsA significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aβ) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions.ConclusionsStrong synergistic effects of APOE4 and FH on Aβ deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aβ. Other unspecified risk factors—genes and/or environmental—that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.

Cognitive and emotional alterations in App knock-in mouse models of A\u03b2 amyloidosis

BackgroundAlzheimer’s disease (AD), the most common cause of dementia, is characterized by the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Mouse models of Aβ amyloidosis generated by knock-in (KI) of a humanized Aβ sequence provide distinct advantages over traditional transgenic models that rely on overexpression of amyloid precursor protein (APP). In App-KI mice, three familial AD-associated mutations were introduced into the endogenous mouse App locus to recapitulate Aβ pathology observed in AD: the Swedish (NL) mutation, which elevates total Aβ production; the Beyreuther/Iberian (F) mutation, which increases the Aβ42/Aβ40 ratio; and the Arctic (G) mutation, which promotes Aβ aggregation. AppNL-G-F mice harbor all three mutations and develop progressive Aβ amyloidosis and neuroinflammatory response in broader brain areas, whereas AppNL mice carrying only the Swedish mutation exhibit no overt AD-related pathological changes. To identify behavioral alterations associated with Aβ pathology, we assessed emotional and cognitive domains of AppNL-G-F and AppNL mice at different time points, using the elevated plus maze, contextual fear conditioning, and Barnes maze tasks.ResultsAssessments of emotional domains revealed that, in comparison with wild-type (WT) C57BL/6J mice, AppNL-G-F/NL-G-F mice exhibited anxiolytic-like behavior that was detectable from 6 months of age. By contrast, AppNL/NL mice exhibited anxiogenic-like behavior from 15 months of age. In the contextual fear conditioning task, both AppNL/NL and AppNL-G-F/NL-G-F mice exhibited intact learning and memory up to 15–18 months of age, whereas AppNL-G-F/NL-G-F mice exhibited hyper-reactivity to painful stimuli. In the Barnes maze task, AppNL-G-F/NL-G-F mice exhibited a subtle decline in spatial learning ability at 8 months of age, but retained normal memory functions.ConclusionAppNL/NL and AppNL-G-F/NL-G-F mice exhibit behavioral changes associated with non-cognitive, emotional domains before the onset of definitive cognitive deficits. Our observations consistently indicate that AppNL-G-F/NL-G-F mice represent a model for preclinical AD. These mice are useful for the study of AD prevention rather than treatment after neurodegeneration.

ABVAC40 TREATMENT IN DOGS INDUCES SPECIFIC ANTIBODY RESPONSE AND INCREMENT OF Aβ40 LEVELS IN PLASMA

Canines may suffer a syndrome of cognitive dysfunction associated with aging that is considered a natural (non-transgenic) model of Alzheimer's Disease which has been used to test several amyloid targeting therapies. Here we present the results of a randomised, double-blind, placebo-controlled, parallel group study of ABvac40 in dogs to assess immunogenicity and changes in plasma Aβ biomarkers. ABvac40 is an active vaccine against Aβ40 which has shown favourable results in Phase I. A Phase II clinical trial on ABvac40 is currently ongoing in France, Italy, Spain and Sweden. Twelve young dogs were subcutaneously injected with either ABvac40 (N=8) or placebo (n=4) in days D0, D14 and D28. Blood samples were collected on days D0 (before vaccination), and D7, D21, D35, D42 and D56. Levels of specific anti-Aβ40 antibodies were assessed by titration ELISAs. Free in plasma (FP) and total in plasma (TP) levels of Aβ40 and Aβ42 were quantified using ABtest (Araclon Biotech, Zaragoza, Spain). In the context of this immunization experiment, the TP level of Aβ in plasma is the amount of peptide bound to plasma components, with the exclusion of those bound to the specific anti-Aβ40 antibodies which probably escape detection by ABtest, plus the peptide found free in plasma. At each visit, the increment in antibody titers and peptide levels from baseline in the ABvac40 and placebo groups were compared by Mann-Whitney test. All the dogs receiving ABvac40 developed specific anti-Aβ40 antibodies. At D21, levels of FP40 experienced a substantial but transient increase, returning to pre-immune levels at D35. Levels of TP40 were also dramatically increased at D21 but, interestingly, they remained elevated until D42, longer than FP40 levels. In addition, the FP40/TP40 ratio was significantly reduced from D21 onwards, compared to the pre-immune levels. Neither specific anti-Aβ40 antibodies nor changes in the Aβ plasma levels were observed in the placebo group. Treatment of dogs with ABvac40 elicits the production of anti-Aβ40 specific antibodies and increase the plasma levels of Aβ40 suggesting a positive action on its target molecule, which makes our vaccine ABvac40 a promising candidate for AD prevention and early treatment.

The Role of Fluoxetine in Activating Wnt/β-Catenin Signaling and Repressing β-Amyloid Production in an Alzheimer Mouse Model.

Fluoxetine (FLX) is one of the selective serotonin reuptake inhibitors (SSRIs) antidepressants, which could be used to relieve depression and anxiety among AD patients. This study was designed to search for new mechanisms by which fluoxetine could activate Wnt/β-catenin signaling pathway and reduce amyloidosis in AD brain. Fluoxetine was administered via intragastric injection to APP/tau/PS1 mouse model of Alzheimer’s disease (3×Tg-AD) mice for 4 months. In the hippocampus of AD mouse model, there could be observed neuronal apoptosis, as well as an increase in Aβ (amyloid-β) production. Moreover, there is a strong association between down-regulation of Wnt/β-catenin signaling and the alteration of AD pathology. The activity of protein phosphatases of type 2A (PP2A) could be significantly enhanced by the treatment of fluoxetine. The activation of PP2A, caused by fluoxetine, could then play a positive role in raising the level of active β-catenin, and deliver a negative impact in GSK3β activity in the hippocampal tissue. Both the changes mentioned above would lead to the activation of Wnt/β-catenin signaling. Meanwhile, fluoxetine treatment would reduce APP cleavage and Aβ generation. It could also prevent apoptosis in 3×Tg-AD primary neuronal cell, and have protective effects on neuron synapse. These findings imply that Wnt/β-catenin signaling could be a potential target outcome for AD prevention, and fluoxetine has the potential to be a promising drug in both AD prevention and treatment.

Amyloid-associated increases in longitudinal report of subjective cognitive complaints

IntroductionTo investigate whether baseline subjective cognitive complaints (SCCs) predict longitudinal decline on neuropsychological testing and whether SCC increases longitudinally, in the setting of high levels of amyloid burden. MethodsTwo hundred seventy-nine clinically normal older participants (mean age = 73.7 ± 6.1 years) from the Harvard Aging Brain Study, a cohort of community-dwelling individuals, were followed longitudinally (4.27 ± 1.35 years) with annual subjective memory questionnaires and neuropsychological assessment. 11C Pittsburgh compound-B positron emission tomography was used to measure cortical amyloid and to classify status (Aβ+/Aβ−) at baseline. ResultsHigher baseline SCC predicted more rapid cognitive decline on neuropsychological measures among those with elevated amyloid (t = −2.18, P < .0001). In addition, longitudinal report of SCC significantly increased over time, with SCC progression most pronounced among Aβ+ individuals (t = 2.24, P = .0005). DiscussionSCC may inform risk for future cognitive decline and track progression of self-perceived decline, particularly in those along the AD trajectory, providing potentially important indicators of clinical meaningfulness in AD prevention trials.

Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3β pathway in cells and in APP/PS1 transgenic mice

Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment.

COMPARING CLINICALLY BASED VERSUS ALGORITHM-GENERATED INTERVENTIONS IN THE CONTEXT OF ALZHEIMER’S DISEASE (AD) PREVENTION

The Alzheimer's Prevention Clinic (APC) at Weill Cornell Medicine utilizes precision medicine interventions to reduce individual risk towards developing AD. The APC provides direct clinical care to people who undergo a comprehensive assessment and receive evidence-based, individualized interventions applying principles of pharmacogenomics and nutrigenomics, with the goal of stabilizing or improving cognition and blood biomarkers. Muses Labs follows a similar paradigm in the absence of an in-person clinical visit, using an informatics platform that receives and processes multi-sourced data to provide a targeted intervention plan known as the AD1 Protocol. In this pilot study, five subjects (ages 51–65) from the APC prospective cohort (n=377) were recruited to submit their clinical data to Muses Labs. Recommendations given by the APC neurologist were compared to artificial-intelligence generated recommendations from AD1. For each APC subject, an average of 334 data points (e.g., clinical history, labs, biometrics, cognition) were assessed compared with 1,029 data points assessed by Muses Labs for interpretation (sourced from genome, medical history – including comorbidities, medications, allergies, and vaccines – labs, and cognitive testing). The APC analyzed 58 blood biomarkers and 4 genetic risk factors, while Muses Labs processed an average of 107 blood biomarkers and ∼1,000 single nucleotide polymorphisms (SNPs). APC recommendations averaged 3.8 supplements/vitamins, 13.6 dietary modifications, and 8.4 lifestyle changes per subject, while AD1 averaged 16.8 supplements/vitamins, 5.2 potential supplements/vitamins, 9.2 dietary modifications, 5.8 lifestyle changes, and 4.4 additional diagnostic tests. AD1 reports averaged 7,504.2 words per person, while APC interventions averaged 1,272.8 words, both excluding laboratory results. Given the complexity of emerging precision medicine interventions for AD prevention, novel and collaborative efforts using both clinical informatics and physician-based approaches may offer a more comprehensive set of potential therapeutic recommendations for those seeking to reduce risk. Using consistent software-based decision trees that utilize emerging evidence could facilitate the application of precision medicine in the clinic, expand the number of potential interventions, and make complex protocols readily accessible to a large number of physicians and patients worldwide. Further study is warranted to evaluate the longitudinal effectiveness of these augmented preventative approaches.

Evaluation of a DNA A\u03b242 vaccine in adult rhesus monkeys (Macaca mulatta): antibody kinetics and immune profile after intradermal immunization with full-length DNA A\u03b242 trimer

BackgroundAggregated amyloid-β peptide 1–42 (Aβ42), derived from the cellular amyloid precursor protein, is one of the pathological hallmarks of Alzheimer’s disease (AD). Although active immunization against Aβ42 peptide was successful in AD mouse models and led to removal of plaques and improved memory, a similar clinical trial in humans (Aβ42 peptide immunization with QS-21 adjuvant) was stopped in phase II, when 6% of the treated patients developed encephalitis. Currently ongoing passive immunizations with the injection of preformed monoclonal antibodies against different epitopes within the Aβ1–42 peptide, which do not lead to activation of the immune system, have shown some effects in slowing AD pathology. Active DNA Aβ42 immunizations administered with the gene gun into the skin are noninflammatory because they activate a different T-cell population (Th2) with different cytokine responses eliciting a different humoral immune response. We present our findings in rhesus macaques that underwent the DNA Aβ42 immunization via gene gun delivery into the skin.MethodsSix rhesus monkeys received two different doses of a DNA Aβ42 trimer vaccine. The humoral immune response was analyzed from blood throughout the study, and cellular immune responses were determined in peripheral blood mononuclear cells (PBMCs) after three and six immunizations.ResultsDNA Aβ42 trimer immunization led to high titer antibody responses in the nonhuman primate (NHP) model. Antibodies generated in the rhesus monkeys following DNA Aβ42 immunization detected amyloid plaques consisting of human Aβ42 peptide in the brain of the triple-transgenic AD mouse model. T-cell responses showed no interferon (IFN)-γ- and interleukin (IL)-17-producing cells from PBMCs in Enzyme-Linked ImmunoSpot assays after three immunization time points. At six immunization time points, IFN-γ- and IL-17-producing cells were found in immunized animals as well as in control animals and were thus considered nonspecific and not due to the immunization regimen. IFN-γ and IL-17 secretion in response to Aβ42 peptide restimulation became undetectable after a 3-month rest period.ConclusionsIntradermal DNA Aβ42 immunization delivered with the gene gun produces a high antibody response in NHPs and is highly likely to be effective and safe in a clinical AD prevention trial in patients.

Otophylloside B Protects Against A\u03b2 Toxicity in Caenorhabditis elegans Models of Alzheimer\u2019s Disease

Alzheimer’s disease (AD) is a major public health concern worldwide and the few drugs currently available only treat the symptoms. Hence, there is a strong need to find more effective anti-AD agents. Cynanchum otophyllum is a traditional Chinese medicine for treating epilepsy, and otophylloside B (Ot B), isolated from C. otophyllum, is the essential active component. Having previously identified anti-aging effects of Ot B, we evaluated Ot B for AD prevention in C. elegans models of AD and found that Ot B extended lifespan, increased heat stress-resistance, delayed body paralysis, and increased the chemotaxis response. Collectively, these results indicated that Ot B protects against Aβ toxicity. Further mechanistic studies revealed that Ot B decreased Aβ deposition by decreasing the expression of Aβ at the mRNA level. Genetic analyses showed that Ot B mediated its effects by increasing the activity of heat shock transcription factor (HSF) by upregulating the expression of hsf-1 and its target genes, hsp-12.6, hsp-16.2 and hsp-70. Ot B also increased the expression of sod-3 by partially activating DAF-16, while SKN-1 was not essential in Ot B-mediated protection against Aβ toxicity.Graphical

Alzheimer’s Disease: An Epidemiologic Disaster From Nutritional Perspective

For both prevention and treatment the major objective of this article is to summarize the non-modifiable and some modifiable risk factors of AD, including nutrition and diet, and to discuss different aspects of AD prevention.

A survey of knowledge and views concerning genetic and amyloid positron emission tomography status disclosure

IntroductionThis survey characterizes viewpoints of cognitively intact at-risk participants in an Alzheimer Prevention Registry if given the opportunity to learn their genetic and amyloid positron emission tomography (PET) status. MethodsA total of 207 participants were offered a 25-item survey. They were asked if they wished to know their apolipoprotein E (APOE) and amyloid PET status and if so, reasons for wanting to know, or not, and the effects of such information on life plans. ResultsOne hundred sixty-four (79.2%) of the registrants completed the survey. Among those who were unaware of their APOE or amyloid PET results, 80% desired to know this information. The most common reasons for wanting disclosure were to participate in research, arrange personal affairs, prepare family for illness, and move life plans closer into the future. When asked if disclosure would help with making plans to end one's life when starting to lose their memory, 12.7% versus 11.5% responded yes for APOE and amyloid PET disclosures, respectively. Disclosure of these test results, if required for participation in a clinical trial, would make 15% of the people less likely to participate. Likelihood of participation in prevention research and the desire to know test results were not related to scores on brief tests of knowledge about the tests. DiscussionThese results suggest that stakeholders in AD prevention research generally wish to know biological test information about their risk for developing AD to assist in making life plans.

How can we really improve screening methods for AD prevention trials?

How can we really improve screening methods for AD prevention trials?

Potential Roles of Selenium and Selenoproteins in the Prevention of Alzheimer's Disease.

Alzheimer's disease is a devastating and invariably fatal neurodegenerative brain disorder with no cure. AD is characterized by two pathological protein deposits, the senile plaques composed mainly of amyloid-β (Aβ) peptide and the neurofibrillary tangles which are bundles of paired helical filaments (PHF) of protein tau. In addition, oxidative stress, disorders in signal transduction and metal ions dyshomeostasis also play significant roles in the development of AD. A large body of studies suggests that selenium (Se), either as Se-containing compounds or as selenoproteins, may be beneficial in reducing Alzheimer's pathology. Se is involved in most of the molecular pathways that are important in the progression of AD. We reviewed the literature regarding Se and AD and discussed the roles and mechanisms of Se in AD, as well as the potential of Se in AD prevention.

Differential Influence of Carotid Stenosis and White Matter Disease on Motor and Cognitive Activation.

Cognitive and motor performance can be supported, especially in older subjects, by different types of brain activations, which can be accurately studied by functional magnetic resonance imaging (fMRI). Vascular risk factors (VRFs) are extremely important in the development of cognitive impairment, but few studies have focused on the fMRI cortical activation characteristics of healthy subjects with and without silent cerebrovascular disease including white matter hyperintensities (WMH) and carotid stenosis (CS) performing cognitive tasks. Thirty-five volunteers with and without asymptomatic unilateral carotid stenosis above 70% and variable degrees of WMH underwent performance of a simple motor and cognitive task during an fMRI session. While the performance of the motor task resulted in a cortical activation dependent of age but not of WMH and carotid stenosis, performance of the cognitive task was accompanied by a significantly increased activation independently correlated with age, presence of WMH as well as of carotid stenosis. in this study, cognitive domains regulating attention and working memory appear to be activated with a pattern influenced by the presence of carotid stenosis as well as by white matter hyperintensities. The impairment of these cognitive abilities is of high relevance in Alzheimer's disease pathology. The fMRI pattern shown in patients with asymptomatic but significant carotid stenosis might be related to chronic cerebrovascular hypoperfusion, a critical pathophysiological mechanisms in AD. In these patients, carotid endoarterectomy should be considered also for AD prevention and might be recommended.

Identifying cost-effective predictive rules of amyloid-β level by integrating neuropsychological tests and plasma-based markers.

Detecting participants who are positive for amyloid-β (Aβ) pathology is germane in designing prevention trials by enriching for those cases that are more likely to be amyloid positive. Existing brain amyloid measurement techniques, such as the Pittsburgh Compound B-positron emission tomography and cerebrospinal fluid, are not reasonable first-line approaches limited by either feasibility or cost. We aimed to identify simple and cost-effective rules that can predict brain Aβ level by integrating both neuropsychological measurements and blood-based markers. Several decision tree models were built for extracting the predictive rules based on the Alzheimer's Disease Neuroimaging Initiative cohort. We successfully extracted predictive rules of Aβ level. For cognitive function variables, cases above the 45th percentile in total cognitive score (TOTALMOD), above the 52nd percentile of delayed word recall, and above the 70th percentile in orientation resulted in a group that was highly enriched for amyloid negative cases. Conversely scoring below the 15th percentile of TOTALMOD resulted in a group highly enriched for amyloid positive cases. For blood protein markers, scoring below the 57th percentile for apolipoprotein E (ApoE) levels (irrespective of genotype) enriched two fold for the risk of being amyloid positive. In the high ApoE cases, scoring above the 60th percentile for transthyretin resulted in a group that was >90% amyloid negative. A third decision tree using both cognitive and blood-marker data slightly improved the classification of cases. Our study demonstrated that the integration of the neuropsychological measurements and blood-based markers significantly improved prediction accuracy. The prediction model has led to several simple rules, which have a great potential of being naturally translated into clinical settings such as enrichment screening for AD prevention trials of anti-amyloid treatments.

The How and Why Behind the Newest AD Prevention Trial

The How and Why Behind the Newest AD Prevention Trial

Neural and cell‐cell junction autoantibodies in megacity children: the neurodegenerative impact (835.2)

Millions of children in the USA, Mexico and around the world are chronically exposed to concentrations of air pollutants, including fine particulate matter, above safety standards. Mexico City children exposed to high concentrations of particulate matter (PM) exhibit a breakdown of the nasal, olfactory, and brain‐blood‐barriers (BBB), along a brain gene imbalance in oxidative stress, inflammation, innate and adaptive immune responses, and the accumulation of misfolded proteins observed in the early stages of Alzheimer (AD) and Parkinson’s diseases.We measure serum autoantibodies associated with epithelial and endothelial barriers, and neural proteins in 95 Mexican children age 11.02 ±3.6 years, with exposures to megacity severe air pollution versus clean air controls. MC children had significantly increased IgG high affinity antibodies for cell‐cell junction and neural proteins including: occludin‐zonulin, actin, S‐100, myelin oligodendrocyte glycoprotein, and myelin basic protein (p&lt;0.001). The major factor determining the impact of brain autoantibodies is the integrity of the BBB, thus, cell‐cell junction and brain autoantibodies might contribute to the white matter integrity alterations, structural/volumetric brain changes and the selective impairment in subscales tapping on attention, short term memory and learning abilities present in highly exposed children. Increasing research supports dysregulated immune responses in the pathophysiology of AD. Early neurodegeneration‐related dysregulated immune responses might indicate pathways that can be targeted for childhood interventions aiming at AD prevention. AD affects 5.2 million Americans today. By 2050, 13.8 million will be affected. Early identification of subjects at risk and effective prevention strategies are urgently needed.

The neglected targets in AD prevention and treatment

The neglected targets in AD prevention and treatment