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Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several nonmutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo. [ABSTRACT FROM AUTHOR]

Alzheimer’s Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

Background: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzymelinked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/β-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin+/BrdU+ and NeuN+/BrdU+ cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also upregulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3β and β-catenin protein while increased CyclinD1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/ß-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

BackgroundAn increasing prevalence of cognitive disorders warrants comprehensive systematic reviews on the effect of diet on cognitive health. Studies have suggested that the Mediterranean (MeDi) diet has protective effects against metabolic diseases. However, comprehensive systematic reviews on the effect of the MeDi diet on the cognitive decline are limited. We investigated whether adherence to the MeDi diet could lower the risk of the cognitive disorder or improve cognitive function in older adults.MethodsIn this systematic review and meta-analysis, PubMed, Web of Science, PsycINFO, Scopus, and Cochrane databases were searched from inception to June 2021. Cohort studies and randomized controlled trials (RCTs) were included. The effect sizes were estimated as log risk ratios and standard mean differences (SMDs) with 95% confidence intervals (CIs). The Newcastle–Ottawa score and Cochrane Collaboration’s tool were used to assess the risk of bias in cohort studies and RCTs, respectively.ResultsOf the 1,687 screened studies, 31 cohort studies and five RCTs met the eligibility criteria for qualitative analysis; 26 cohort studies and two RCTs were included in the meta-analysis. In the cohort studies, high adherence to the MeDi diet was associated with lower risk of mild cognitive impairment (MCI) [risk ratio (RR) = 0.75 (0.66–0.86)], and Alzheimer’s disease (AD) [RR = 0.71 (0.56–0.89)]. In the RCTs, high adherence to the MeDi diet was associated with better episodic [SMD = 0.20 (0.09–0.30)] and working memories [SMD = 0.17 (0.01–0.32)] than lowest group.ConclusionAdherence to the MeDi diet may reduce the risk of MCI and AD. However, other associations with cognitive outcomes (global cognition, working memory, and episodic memory) remain open to interpretation. Overall, the MeDi diet is recommended to prevent or delay cognitive disorders and improve cognitive function. Further, long-term RCTs are warranted to strengthen the evidence.Systematic review registration[https://www.crd.york.ac.uk], identifier [CRD42021276801].

Background: Dementia is a global challenge with 10 million individuals being diagnosed every year. Currently, there are no established disease-modifying treatments for dementia. Impaired nutrient sensing has been implicated in the pathogenesis of dementia. Compounds that inhibit the glycogen synthase kinase-3 (GSK3) pathway have been investigated as a possible treatment to attenuate the progression of the disease, particularly the suppression of the hyper-phosphorylation process of the tau protein.Aims: Systematically summarizing compounds which have been tested to inhibit the GSK3 pathway to treat cognitive impairment and dementia.Methods: PubMed, Embase and Web of Science databases were searched from inception until 28 July 2021 for articles published in English. Interventional animal studies inhibiting the GSK3 pathway in Alzheimer’s disease (AD), Parkinson’s dementia, Lewy body dementia, vascular dementia, mild cognitive impairment (MCI) and normal cognitive ageing investigating the change in cognition as the outcome were included. The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias tool for animal studies was applied.Results: Out of 4,154 articles, 29 described compounds inhibiting the GSK3 pathway. All studies were based on animal models of MCI, AD or normal cognitive ageing. Thirteen out of 21 natural compounds and five out of nine synthetic compounds tested in MCI and dementia animal models showed an overall positive effect on cognition. No articles reported human studies. The risk of bias was largely unclear.Conclusion: Novel therapeutics involved in the modulation of the GSK3 nutrient sensing pathway have the potential to improve cognitive function. Overall, there is a clear lack of translation from animal models to humans.

Epidemiological studies suggest that heavy alcohol use early in life is associated with increased risk for Alzheimer's disease (AD). However, mechanisms connecting AD with alcohol use have not been identified. Both heavy alcohol use and AD feature increased proinflammatory signaling. Therefore, we hypothesized that adolescent binge ethanol would increase AD molecular and behavioral pathology in adulthood through proinflammatory signaling. The 3xTg-AD mouse model (APPSwe, tauP301, Psen1tm1Mpm) which features amyloid (Aβ) and tau pathology beginning at 6–12 months underwent adolescent intermittent ethanol (AIE, 5 g/kg/d, i.g., P25-55) with assessment of AD pathologic mediators at P200. A second group of mice received AIE +/− minocycline (30 mg/kg/d, IP) followed by behavioral testing in adulthood. Behavioral testing and age of testing included: locomotor activity and exploration (27–28 weeks), novel object recognition (NORT, 28-30 weeks), 3-chamber sociability and social memory (29–31 weeks), prepulse inhibition (PPI, 30–32 weeks), Morris Water Maze with reversal (MWM, 31–35 weeks), and Piezo sleep monitoring (35–37 weeks). We found that AIE increased levels of neurotoxic Aβ1–42 in adult female hippocampus as well as intraneuronal Aβ1–42 in amygdala and entorhinal cortex. Phosphorylated tau at residue Thr181 (p-tau-181) was also increased in female hippocampus by AIE. Several proinflammatory genes were persistently increased by AIE in the female hippocampus, including IL-1β, MCP-1, IL-6, and IFNα. Expression of these genes was strongly correlated with the levels of Aβ1–42 and p-tau-181 in hippocampus. AIE caused persistent decreases in locomotor activity (open-field and NORT habituation) and increased anxiety-like behavior (thigmotaxis) while reducing memory retention. Treatment with the anti-inflammatory compound minocycline during AIE blocked persistent increases in Aβ1–42 in amygdala and p-tau-181 in hippocampus, and prevented AIE-induced thigmotaxis and memory loss. Together, these data find that adolescent binge ethanol enhances AD molecular and behavioral pathology in adulthood through proinflammatory signaling. Blockade of proinflammatory signaling during ethanol exposure prevents ethanol-induced effects on pathologic accumulation of AD-associated proteins and persistent behavior changes relevant to human AD. [ABSTRACT FROM AUTHOR]

Early detection of Alzheimer's disease (AD), such as predicting development from mild cognitive impairment (MCI) to AD, is critical for slowing disease progression and increasing quality of life. Although deep learning is a promising technique for structural MRI-based diagnosis, the paucity of training samples limits its power, especially for three-dimensional (3D) models. To this end, we propose a two-stage model combining both transfer learning and contrastive learning that can achieve high accuracy of MRI-based early AD diagnosis even when the sample numbers are restricted. Specifically, a 3D CNN model was pretrained using publicly available medical image data to learn common medical features, and contrastive learning was further utilized to learn more specific features of MCI images. The two-stage model outperformed each benchmark method. Compared with the previous studies, we show that our model achieves superior performance in progressive MCI patients with an accuracy of 0.82 and AUC of 0.84. We further enhance the interpretability of the model by using 3D Grad-CAM, which highlights brain regions with high-predictive weights. Brain regions, including the hippocampus, temporal, and precuneus, are associated with the classification of MCI, which is supported by the various types of literature. Our model provides a novel model to avoid overfitting because of a lack of medical data and enable the early detection of AD. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that heavy alcohol use early in life is associated with increased risk for Alzheimer’s disease (AD). However, mechanisms connecting AD with alcohol use have not been identified. Both heavy alcohol use and AD feature increased proinflammatory signaling. Therefore, we hypothesized that adolescent binge ethanol would increase AD molecular and behavioral pathology in adulthood through proinflammatory signaling. The 3xTg-AD mouse model (APPSwe, tauP301, Psen1tm1Mpm) which features amyloid (Aβ) and tau pathology beginning at 6–12 months underwent adolescent intermittent ethanol (AIE, 5 g/kg/d, i.g., P25-55) with assessment of AD pathologic mediators at P200. A second group of mice received AIE +/− minocycline (30 mg/kg/d, IP) followed by behavioral testing in adulthood. Behavioral testing and age of testing included: locomotor activity and exploration (27–28 weeks), novel object recognition (NORT, 28-30 weeks), 3-chamber sociability and social memory (29–31 weeks), prepulse inhibition (PPI, 30–32 weeks), Morris Water Maze with reversal (MWM, 31–35 weeks), and Piezo sleep monitoring (35–37 weeks). We found that AIE increased levels of neurotoxic Aβ1–42 in adult female hippocampus as well as intraneuronal Aβ1–42 in amygdala and entorhinal cortex. Phosphorylated tau at residue Thr181 (p-tau-181) was also increased in female hippocampus by AIE. Several proinflammatory genes were persistently increased by AIE in the female hippocampus, including IL-1β, MCP-1, IL-6, and IFNα. Expression of these genes was strongly correlated with the levels of Aβ1–42 and p-tau-181 in hippocampus. AIE caused persistent decreases in locomotor activity (open-field and NORT habituation) and increased anxiety-like behavior (thigmotaxis) while reducing memory retention. Treatment with the anti-inflammatory compound minocycline during AIE blocked persistent increases in Aβ1–42 in amygdala and p-tau-181 in hippocampus, and prevented AIE-induced thigmotaxis and memory loss. Together, these data find that adolescent binge ethanol enhances AD molecular and behavioral pathology in adulthood through proinflammatory signaling. Blockade of proinflammatory signaling during ethanol exposure prevents ethanol-induced effects on pathologic accumulation of AD-associated proteins and persistent behavior changes relevant to human AD.

Early detection of Alzheimer’s disease (AD), such as predicting development from mild cognitive impairment (MCI) to AD, is critical for slowing disease progression and increasing quality of life. Although deep learning is a promising technique for structural MRI-based diagnosis, the paucity of training samples limits its power, especially for three-dimensional (3D) models. To this end, we propose a two-stage model combining both transfer learning and contrastive learning that can achieve high accuracy of MRI-based early AD diagnosis even when the sample numbers are restricted. Specifically, a 3D CNN model was pretrained using publicly available medical image data to learn common medical features, and contrastive learning was further utilized to learn more specific features of MCI images. The two-stage model outperformed each benchmark method. Compared with the previous studies, we show that our model achieves superior performance in progressive MCI patients with an accuracy of 0.82 and AUC of 0.84. We further enhance the interpretability of the model by using 3D Grad-CAM, which highlights brain regions with high-predictive weights. Brain regions, including the hippocampus, temporal, and precuneus, are associated with the classification of MCI, which is supported by the various types of literature. Our model provides a novel model to avoid overfitting because of a lack of medical data and enable the early detection of AD.

Alzheimer's Disease (AD) is a progressive neurologic disease and the most common form of dementia. While the causes of AD are not completely understood, genetics plays a key role in the etiology of AD, and thus finding genetic factors holds the potential to uncover novel AD mechanisms. For this study, we focus on copy number variation (CNV) detection and burden analysis. Leveraging whole-genome sequence (WGS) data released by Alzheimer's Disease Sequencing Project (ADSP), we developed a scalable bioinformatics pipeline to identify CNVs. This pipeline was applied to 1,737 AD cases and 2,063 cognitively normal controls. As a result, we observed 237,306 and 42,767 deletions and duplications, respectively, with an average of 2,255 deletions and 1,820 duplications per subject. The burden tests show that Non-Hispanic-White cases on average have 16 more duplications than controls do (p -value 2e-6), and Hispanic cases have larger deletions than controls do (p -value 6.8e-5). [ABSTRACT FROM AUTHOR]

Alzheimer’s Disease (AD) is a progressive neurologic disease and the most common form of dementia. While the causes of AD are not completely understood, genetics plays a key role in the etiology of AD, and thus finding genetic factors holds the potential to uncover novel AD mechanisms. For this study, we focus on copy number variation (CNV) detection and burden analysis. Leveraging whole-genome sequence (WGS) data released by Alzheimer’s Disease Sequencing Project (ADSP), we developed a scalable bioinformatics pipeline to identify CNVs. This pipeline was applied to 1,737 AD cases and 2,063 cognitively normal controls. As a result, we observed 237,306 and 42,767 deletions and duplications, respectively, with an average of 2,255 deletions and 1,820 duplications per subject. The burden tests show that Non-Hispanic-White cases on average have 16 more duplications than controls do (p-value 2e-6), and Hispanic cases have larger deletions than controls do (p-value 6.8e-5).

Background: While the lockdown strategies taken by many countries effectively limited the spread of COVID-19, those were thought to have a negative impact on older people. This study aimed to investigate the impact of lockdown on cognitive function and neuropsychiatric symptoms over a 1-year follow-up period in patients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and dementia with Lewy bodies (DLB).Methods: We enrolled consecutive patients with MCI, probable AD or DLB who were receiving outpatient memory care before the COVID-19 pandemic and followed-up with them after 1 year by face-to-face during the COVID-19 pandemic to assess changes in physical activity, social contact, cognitive function and neuropsychiatric symptoms (NPS).Results: Total 105 probable AD, 50 MCI and 22 probable DLB patients were included and completed the 1-year follow-up between October 31 and November 30, 2020. Among the respondents, 42% of MCI, 54.3% of AD and 72.7% of DLB patients had a decline in MMSE scores and 54.4% of DLB patients had worsening Neuropsychiatric inventory (NPI) scores. Patients with DLB showed a more rapid decline of MMSE than those with AD. Diminished physical activity and social contact might have hastened the deterioration of cognition and the worsening of NPS.Conclusion: Social isolation and physical inactivity even after strict lockdown for at least 6 months were correlated with accelerated decline of cognitive function and NPS in patients with AD and DLB.

Alzheimer’s disease (AD) is a neurodegenerative disorder which spans several years from preclinical manifestations to dementia. In recent years, interest in the application of machine learning (ML) algorithms to personalized medicine has grown considerably, and a major challenge that such models face is the transferability from the research settings to clinical practice. The objective of this work was to demonstrate the transferability of the Subtype and Stage Inference (SuStaIn) model from well-characterized research data set, employed as training set, to independent less-structured and heterogeneous test sets representative of the clinical setting. The training set was composed of MRI data of 1043 subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI), and the test set was composed of data from 767 subjects from OASIS, Pharma-Cog, and ViTA clinical datasets. Both sets included subjects covering the entire spectrum of AD, and for both sets volumes of relevant brain regions were derived from T1-3D MRI scans processed with Freesurfer v5.3 cross-sectional stream. In order to assess the predictive value of the model, subpopulations of subjects with stable mild cognitive impairment (MCI) and MCIs that progressed to AD dementia (pMCI) were identified in both sets. SuStaIn identified three disease subtypes, of which the most prevalent corresponded to the typical atrophy pattern of AD. The other SuStaIn subtypes exhibited similarities with the previously defined hippocampal sparing and limbic predominant atrophy patterns of AD. Subject subtyping proved to be consistent in time for all cohorts and the staging provided by the model was correlated with cognitive performance. Classification of subjects on the basis of a combination of SuStaIn subtype and stage, mini mental state examination and amyloid-β1-42 cerebrospinal fluid concentration was proven to predict conversion from MCI to AD dementia on par with other novel statistical algorithms, with ROC curves that were not statistically different for the training and test sets and with area under curve respectively equal to 0.77 and 0.76. This study proves the transferability of a SuStaIn model for AD from research data to less-structured clinical cohorts, and indicates transferability to the clinical setting.

Background: While the lockdown strategies taken by many countries effectively limited the spread of COVID-19, those were thought to have a negative impact on older people. This study aimed to investigate the impact of lockdown on cognitive function and neuropsychiatric symptoms over a 1-year follow-up period in patients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Methods: We enrolled consecutive patients with MCI, probable AD or DLB who were receiving outpatient memory care before the COVID-19 pandemic and followed-up with them after 1 year by face-to-face during the COVID-19 pandemic to assess changes in physical activity, social contact, cognitive function and neuropsychiatric symptoms (NPS). Results: Total 105 probable AD, 50 MCI and 22 probable DLB patients were included and completed the 1-year follow-up between October 31 and November 30, 2020. Among the respondents, 42% of MCI, 54.3% of AD and 72.7% of DLB patients had a decline in MMSE scores and 54.4% of DLB patients had worsening Neuropsychiatric inventory (NPI) scores. Patients with DLB showed a more rapid decline of MMSE than those with AD. Diminished physical activity and social contact might have hastened the deterioration of cognition and the worsening of NPS. Conclusion: Social isolation and physical inactivity even after strict lockdown for at least 6 months were correlated with accelerated decline of cognitive function and NPS in patients with AD and DLB. [ABSTRACT FROM AUTHOR]

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking.Methods: We developed and evaluated a rapid language test for PPA (“PARIS”) assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia (“LAST”, “ART”).Results: The application duration of the “PARIS” was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the “PARIS” reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the “LAST” and “ART,” the “PARIS” also had the highest sensitivity for detecting language decline.Conclusions: The “PARIS” is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing.

Pauses, disfluencies and language problems in Alzheimer’s disease can be naturally modeled by fine-tuning Transformer-based pre-trained language models such as BERT and ERNIE. Using this method with pause-encoded transcripts, we achieved 89.6% accuracy on the test set of the ADReSS (Alzheimer’s Dementia Recognition through Spontaneous Speech) Challenge. The best accuracy was obtained with ERNIE, plus an encoding of pauses. Robustness is a challenge for large models and small training sets. Ensemble over many runs of BERT/ERNIE fine-tuning reduced variance and improved accuracy. We found that um was used much less frequently in Alzheimer’s speech, compared to uh. We discussed this interesting finding from linguistic and cognitive perspectives.

Alzheimer’s disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ1–42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ1–42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ1–42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ1–42-injected mice compared with controls. These molecular changes in Aβ1–42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ1–42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits.

Objective: This review summarizes recent findings on the epigenetics of Alzheimer's disease (AD) and provides therapeutic strategies for AD.Methods: We searched the following keywords: “genetics,” “epigenetics,” “Alzheimer's disease,” “DNA methylation,” “DNA hydroxymethylation,” “histone modifications,” “non-coding RNAs,” and “therapeutic strategies” in PubMed.Results: In this review, we summarizes recent studies of epigenetics in AD, including DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs. There are no consistent results of global DNA methylation/hydroxymethylation in AD. Epigenetic genome-wide association studies show that many differentially methylated sites exist in AD. Several studies investigate the role of histone modifications in AD; for example, histone acetylation decreases, whereas H3 phosphorylation increases significantly in AD. In addition, non-coding RNAs, such as microRNA-16 and BACE1-antisense transcript (BACE1-AS), are associated with the pathology of AD. These epigenetic changes provide us with novel insights into the pathogenesis of AD and may be potential therapeutic strategies for AD.Conclusion: Epigenetics is associated with the pathogenesis of AD, including DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs, which provide potential therapeutic strategies for AD.

The sense of smell has been shown to deteriorate in patients with some neurodegenerative disorders. In Parkinson’s disease (PD) and Alzheimer’s disease (AD), decreased ability to smell is associated with early disease stages. Thus, olfactory neurons in the nose and olfactory bulb (OB) may provide a window into brain physiology and pathophysiology to address the pathogenesis of neurodegenerative diseases. Because nasal olfactory receptor neurons regenerate throughout life, the olfactory system offers a broad variety of cellular mechanisms that could be altered in AD, including odorant receptor expression, neurogenesis and neurodegeneration in the olfactory epithelium, axonal targeting to the OB, and synaptogenesis and neurogenesis in the OB. This review focuses on pathophysiological changes in the periphery of the olfactory system during the progression of AD in mice, highlighting how the olfactory epithelium and the OB are particularly sensitive to changes in proteins and enzymes involved in AD pathogenesis. Evidence reviewed here in the context of the emergence of other typical pathological changes in AD suggests that olfactory impairments could be used to understand the molecular mechanisms involved in the early phases of the pathology.

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking. Methods: We developed and evaluated a rapid language test for PPA ("PARIS") assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia ("LAST", "ART"). Results: The application duration of the "PARIS" was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the "PARIS" reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the "LAST" and "ART," the "PARIS" also had the highest sensitivity for detecting language decline. Conclusions: The "PARIS" is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing. [ABSTRACT FROM AUTHOR]

Aging is associated with subjective memory complaints. Approximately half of those with subjective memory complaints have objective cognitive impairment. Previous studies have provided evidence of an association between genetic risk for Alzheimer's disease (AD) and dementia progression. Also, aging is a significant risk factor for vascular pathology that may underlie at least some of the cognitive changes. This study investigates the relative contribution of subjective cognitive complaints (SCC), vascular function, and genetic risk for dementia in predicting objective cognitive performance. Multiple regression and relative importance analysis were used to investigate the relative contribution of vascular function, self-reported SCC, and dementia genetic risk, in predicting objective cognition in a sample of 238 healthy community-dwelling older adults. Age, sex, premorbid cognitive abilities, subjective verbal memory complaints, higher cerebrovascular blood flow during submaximal exercise, and certain dementia risk alleles were significant predictors of worse objective verbal memory performance (p < 0.001, R 2 = 35.2–36.4%). Using relative importance analysis, subjective verbal memory complaints, and certain dementia risk alleles contributed more variance than cerebrovascular measures. These results suggest that age-related changes in memory in healthy older adults can be predicted by subjective memory complaints, genetic risk, and to a lesser extent, cerebrovascular function. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ1–42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ1–42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ1–42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ1–42-injected mice compared with controls. These molecular changes in Aβ1–42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ1–42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits. [ABSTRACT FROM AUTHOR]

Objective: This review summarizes recent findings on the epigenetics of Alzheimer's disease (AD) and provides therapeutic strategies for AD. Methods: We searched the following keywords: "genetics," "epigenetics," "Alzheimer's disease," "DNA methylation," "DNA hydroxymethylation," "histone modifications," "non-coding RNAs," and "therapeutic strategies" in PubMed. Results: In this review, we summarizes recent studies of epigenetics in AD, including DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs. There are no consistent results of global DNA methylation/hydroxymethylation in AD. Epigenetic genome-wide association studies show that many differentially methylated sites exist in AD. Several studies investigate the role of histone modifications in AD; for example, histone acetylation decreases, whereas H3 phosphorylation increases significantly in AD. In addition, non-coding RNAs, such as microRNA-16 and BACE1-antisense transcript (BACE1-AS), are associated with the pathology of AD. These epigenetic changes provide us with novel insights into the pathogenesis of AD and may be potential therapeutic strategies for AD. Conclusion: Epigenetics is associated with the pathogenesis of AD, including DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs, which provide potential therapeutic strategies for AD. [ABSTRACT FROM AUTHOR]

The sense of smell has been shown to deteriorate in patients with some neurodegenerative disorders. In Parkinson's disease (PD) and Alzheimer's disease (AD), decreased ability to smell is associated with early disease stages. Thus, olfactory neurons in the nose and olfactory bulb (OB) may provide a window into brain physiology and pathophysiology to address the pathogenesis of neurodegenerative diseases. Because nasal olfactory receptor neurons regenerate throughout life, the olfactory system offers a broad variety of cellular mechanisms that could be altered in AD, including odorant receptor expression, neurogenesis and neurodegeneration in the olfactory epithelium, axonal targeting to the OB, and synaptogenesis and neurogenesis in the OB. This review focuses on pathophysiological changes in the periphery of the olfactory system during the progression of AD in mice, highlighting how the olfactory epithelium and the OB are particularly sensitive to changes in proteins and enzymes involved in AD pathogenesis. Evidence reviewed here in the context of the emergence of other typical pathological changes in AD suggests that olfactory impairments could be used to understand the molecular mechanisms involved in the early phases of the pathology. [ABSTRACT FROM AUTHOR]

Ganoderma lucidum, a mushroom long used in the East for a broad range of disorders, contains numerous pharmacologically active compounds. Very important of them are highly oxygenated anti-inflammatory triterpenes, which are the aim of this mini-review.

Background: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/β-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin + /BrdU + and NeuN + /BrdU + cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3β and β-catenin protein while increased CyclinD 1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/β-catenin signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yan, Huang, Xiong, Song, Li, Yang, Sun, Zhang and Ji.)

Background: Dementia is a global challenge with 10 million individuals being diagnosed every year. Currently, there are no established disease-modifying treatments for dementia. Impaired nutrient sensing has been implicated in the pathogenesis of dementia. Compounds that inhibit the glycogen synthase kinase-3 (GSK3) pathway have been investigated as a possible treatment to attenuate the progression of the disease, particularly the suppression of the hyper-phosphorylation process of the tau protein. Aims: Systematically summarizing compounds which have been tested to inhibit the GSK3 pathway to treat cognitive impairment and dementia. Methods: PubMed, Embase and Web of Science databases were searched from inception until 28 July 2021 for articles published in English. Interventional animal studies inhibiting the GSK3 pathway in Alzheimer's disease (AD), Parkinson's dementia, Lewy body dementia, vascular dementia, mild cognitive impairment (MCI) and normal cognitive ageing investigating the change in cognition as the outcome were included. The Systematic Review Centre for Laboratory animal Experimentation's risk of bias tool for animal studies was applied. Results: Out of 4,154 articles, 29 described compounds inhibiting the GSK3 pathway. All studies were based on animal models of MCI, AD or normal cognitive ageing. Thirteen out of 21 natural compounds and five out of nine synthetic compounds tested in MCI and dementia animal models showed an overall positive effect on cognition. No articles reported human studies. The risk of bias was largely unclear. Conclusion: Novel therapeutics involved in the modulation of the GSK3 nutrient sensing pathway have the potential to improve cognitive function. Overall, there is a clear lack of translation from animal models to humans., Competing Interests: AM is a scientific co-founder of Cognescence Ltd. and Immunidex Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matysek, Kimmantudawage, Feng and Maier.)

Alzheimer's disease (AD) is a neurodegenerative disorder which spans several years from preclinical manifestations to dementia. In recent years, interest in the application of machine learning (ML) algorithms to personalized medicine has grown considerably, and a major challenge that such models face is the transferability from the research settings to clinical practice. The objective of this work was to demonstrate the transferability of the Subtype and Stage Inference (SuStaIn) model from well-characterized research data set, employed as training set, to independent less-structured and heterogeneous test sets representative of the clinical setting. The training set was composed of MRI data of 1043 subjects from the Alzheimer's disease Neuroimaging Initiative (ADNI), and the test set was composed of data from 767 subjects from OASIS, Pharma-Cog, and ViTA clinical datasets. Both sets included subjects covering the entire spectrum of AD, and for both sets volumes of relevant brain regions were derived from T1-3D MRI scans processed with Freesurfer v5.3 cross-sectional stream. In order to assess the predictive value of the model, subpopulations of subjects with stable mild cognitive impairment (MCI) and MCIs that progressed to AD dementia (pMCI) were identified in both sets. SuStaIn identified three disease subtypes, of which the most prevalent corresponded to the typical atrophy pattern of AD. The other SuStaIn subtypes exhibited similarities with the previously defined hippocampal sparing and limbic predominant atrophy patterns of AD. Subject subtyping proved to be consistent in time for all cohorts and the staging provided by the model was correlated with cognitive performance. Classification of subjects on the basis of a combination of SuStaIn subtype and stage, mini mental state examination and amyloid-β 1-42 cerebrospinal fluid concentration was proven to predict conversion from MCI to AD dementia on par with other novel statistical algorithms, with ROC curves that were not statistically different for the training and test sets and with area under curve respectively equal to 0.77 and 0.76. This study proves the transferability of a SuStaIn model for AD from research data to less-structured clinical cohorts, and indicates transferability to the clinical setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Archetti, Young, Oxtoby, Ferreira, Mårtensson, Westman, Alexander, Frisoni and Redolfi.)

Alzheimer's disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ 1-42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ 1-42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ 1-42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ 1-42 -injected mice compared with controls. These molecular changes in Aβ 1-42 -injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ 1-42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits., (Copyright © 2020 Calvo-Flores Guzmán, Chaffey, Palpagama, Waters, Boix, Tate, Peppercorn, Dragunow, Waldvogel, Faull and Kwakowsky.)