AD-related Dementia Research Articles

Individualized estimated years from onset of Alzheimer's disease- related decline for adults with Down syndrome.

Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) and vary in their age of transition from AD preclinical to prodromal or more advanced clinical stages. An empirically based method is needed to determine individual "estimated years from symptom onset (EYO)," the same construct used in studies of autosomal dominant AD . Archived data from a previous study of > 600 adults with DS were examined using survival analysis methods. Age-specific prevalence of prodromal AD or dementia, cumulative risk, and EYOs were determined. Individualized EYOs for adults with DS ranging in age from 30 to 70+ were determined, dependent upon chronological age and clinical status. EYOs can be a useful tool for studies focused on biomarker changes during AD progression in this and other populations at risk, studies that should contribute to improved methods for diagnosis, prediction of risk, and identification of promising treatment targets. Years from Alzheimer's disease (AD) onset (EYO) was estimated for adults with Down syndrome (DS).EYOs were informed by AD clinical status and age, ranging from 30 to > 70 years.Influences of biological sex and apolipoprotein E genotype on EYOs were examined.EYOs have advantages for predicting risk of AD-related dementia compared to age.EYOs can be extremely informative in studies of preclinical AD progression.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.

Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality. We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

1463. Association between Herpes Simplex Virus Type 1 and the Risk of Alzheimer’s Disease

Abstract Background There is significant unmet need of novel therapeutics for Alzheimer’s Disease (AD). A growing body of evidence suggests a role for herpesviruses in the development of AD and reduced risk of AD among patients receiving antivirals. We investigated the association between herpes simplex virus type 1 (HSV-1) diagnoses, antiviral use, and AD using real-world data. Methods In a matched case-control study, AD patients aged ≥ 50 years diagnosed between 2006 and 2021 were identified from IQVIA PharMetrics Plus® claims database using International Classification of Disease (ICD) codes (ICD 9 331.0; ICD 10 G30.x). Controls without any history of neurological disorders were matched in a 1:1 ratio with AD subjects on age, sex, region, database entry year, and healthcare visit numbers. HSV-1 diagnoses were identified using relevant ICD codes. Conditional logistic regression was used to evaluate the association between HSV-1 and AD. The association between antiviral use (e.g., acyclovir, famciclovir, valacyclovir) and AD was assessed by multivariate Cox proportional hazards model in patients with HSV-1 diagnosis. Results The study included 344,628 AD patient-control pairs. Most patients were female (65%) with a mean age of 73 (± 5) years. AD patients had more comorbidities (50% vs. 45% with ≥ 2 comorbidities) and shorter follow up time (median of 33 vs. 48 months) when compared to controls. History of HSV-1 diagnosis was present in 1507 (0.44%) AD patients vs. 823 (0.24%) controls. HSV-1 diagnosis was associated with AD (adjusted odds ratio [OR] 1.80; 95% confidence interval [CI] 1.65-1.96). In a stratified analysis, this association was more pronounced in the older age group (75+ years: OR 2.10, 95% CI 1.88-2.35; 71-74 years: OR 1.51, 95% CI 1.27-1.80; 50-70 years: OR 1.14, 95% CI 0.91-1.44). Patients with HSV-1 who used antivirals were less likely to have AD compared to those who did not use antivirals (adjusted hazard ratio 0.83, 95% CI 0.74-0.92). Similar results were observed when the analysis was extended to include all patients with AD-related dementia and matched controls. The association between herpes simplex virus type 1 (HSV-1) and Alzheimer’s Disease (AD)/AD-related Dementia(ADRD) Conclusion Findings from this large real-world data study is consistent with emerging literature on HSV-1 and risk of AD and the possible protective role of antiviral drugs. Disclosures Luke Liu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Christine Johnston, MD, MPH, AbbVie: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant Simon P. Fletcher, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Shahed Iqbal, PhD, MBBS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds.

DSCR1 deficiency ameliorates the Aβ pathology of Alzheimer's disease by enhancing microglial activity.

Microglial phagocytosis and clearance are important for the removal of amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Chronic exposure of microglia to Aβ plaques leads to microglial metabolic dysfunction, and dysregulation of microglia can accelerate the deposition of Aβ plaques and cause learning and memory impairment. Thus, regulating microglial Aβ clearance is crucial for the development of therapeutics for AD-related dementia. Here, Down syndrome critical region 1 (DSCR1) deficiency ameliorated Aβ plaque deposition in the 5xFAD mouse model of AD by altering microglial activity; however, the Aβ synthesis pathway was not affected. DSCR1 deficiency improved spatial learning and memory impairment in 5xFAD mice. Furthermore, DSCR1-deficient microglia exhibited accelerated lysosomal degradation of Aβ after phagocytosis, and BV2 cells with stable knockdown of DSCR1 demonstrated enhanced lysosomal activity. RNA-sequencing analysis showed that the transcriptional signatures associated with responses to IFN-γ were significantly up-regulated in DSCR1-knockdown BV2 cells treated with Aβ. Our data strongly suggest that DSCR1 is a critical mediator of microglial degradation of amyloid plaques and a new potential microglial therapeutic target in AD.

The economic and societal burden of Alzheimer disease: managed care considerations.

Alzheimer disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. Today, more than 6 million Americans are living with AD and that number is expected to increase to 13.8 million by 2060. The progressive debilitating nature of this illness and the absence of disease-modifying treatments contributes to a substantial economic and societal burden on the healthcare system. In 2022, the estimated healthcare costs associated with AD treatment were $321 billion, with costs projected to exceed $1 trillion by 2050. These cost-of-care projections are based on direct healthcare costs and are likely underestimated because indirect costs associated with AD treatment are usually not included. Indirect costs such as loss in productivity, diminished quality of life, and an increasing dependence on informal unpaid care provided by family caregivers augments the economic and societal burden of this disease. As drug development continues to evolve, the emergence of disease-modifying therapy may help to offset the burden associated with AD-related dementia. Managed care organizations are uniquely positioned to mitigate costs and positively impact outcomes through the promotion of disease awareness, early diagnosis, and treatment and disease management programs focused on multidisciplinary care coordination and caregiver support.

Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of mortality, disability, and long-term care burden in the United States, with women comprising the majority of AD diagnoses. While AD-related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO-mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO-∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type-1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT-qPCR and protein analyses suggest that aged (9-12 months) female mice bearing tau- and amyloid beta-producing transgenic mutations (3xTg-AD) express higher levels of PRMT4 in the hippocampus when compared to age- and sex-matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg-AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free-radical ONOO-, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's-related cerebrovascular derangement.

Alzheimer's Disease and Stroke: A Tangled Neurological Conundrum.

A neurodegenerative disorder, Alzheimer's disease (AD), is characterized by dementia in which there is an age-related decline in cognition and higher functions. Stroke is a cerebrovascular disorder that frequently presents in old age and is a known risk factor for AD development. However, the association that AD can be a risk factor for stroke is not well-studied. This review article compiled various studies that pointed out the association between stroke development in patients with dementia, particularly AD-related dementia. The pathophysiological progression of stroke in AD cases and the genetic makeup possibly affecting the interrelation between these disorders were analyzed in detail using currently available data and studies. Therapeutic and management modalities already in use for AD were put together, and the possibility of early intervention in such patients benefitting cerebrovascular pathologies, particularly stroke-related, was explored. Prognostic differences between patients of stroke with and without AD were also reviewed, and how appropriate management can reduce the burden on health care settings when both present simultaneously was emphasized.

Promise of irisin to attenuate cognitive dysfunction in aging and Alzheimer’s disease

Strategies proficient for relieving cognitive impairments in aging and Alzheimer’s disease (AD) have an enormous impact. Regular physical exercise (PE) can prevent age-related dementia and slow down AD progression. However, such a lifestyle change is likely not achievable for individuals displaying age-related frailty. Hence, drugs or biologics that could simulate the benefits of PE have received much attention. Previous studies suggested that the fibronectin-domain III containing 5 (FNDC5) underlies the PE-mediated improved cognitive function. A recent study reports that PE-related cognitive benefits in aging and AD are mediated by irisin, the cleaved form of FNDC5 released into the blood after PE. Such a conclusion was apparent from the deletion of irisin through a global knockout of FNDC5, leading to the loss of PE-induced cognitive benefits or inducing memory impairments in adult or aged models. Furthermore, in AD models, peripherally administered irisin mimicked the cognitive benefits of PE by modulating neuroinflammation. This short review discusses the promise of irisin to simulate the cognitive benefits of PE in age- and AD-related dementia. In addition, critical issues such as how blood-borne irisin acts on neural cells, the role of the brain-derived neurotrophic factor in irisin-mediated cognitive benefits, and irisin’s ability to inhibit neuroinflammatory cascades in aging and AD are discussed.

Phenothiazines to Treat Alzheimer’s Disease

Current treatments of Alzheimer’s Disease (AD) are largely ineffective and do not address underlying pathophysiological processes. The model organism C. elegans has been successfully used to discover compounds to treat human diseases, some now in clinical trials. To develop novel drugs and explore pathways to treat AD, we took on a forward pharmacological approach with a C. elegans model for AD, completed with studies to expand results to lifespan as well as healthspan. We screened 2560 drugs from the Microsource Spectrum library for their ability to delay proteotoxicity (indicated by paralysis) in an Abeta transgenic C. elegans muscle model of AD (CL2006) in liquid medium. Among the most protective drugs were phenothiazines, which are orally active and cross the blood-brain barrier, desirable properties of drugs to treat AD. 80 phenothiazines congeners were further assessed; 60% were protective in CL2006 worms. 9/20 tested phenothiazines increased lifespan in N2 worms and 2/3 phenothiazines tested promoted significantly higher pharyngeal pumping rates compared with control till day 10 of adulthood in N2 worms. 2 of the drugs were protective in the C. elegans neuronal model of AD. This phenotypic screening approach led to the discovery of potential drugs to treat AD. These phenothiazines protect against Abeta toxicity, and assessment of efficacy to protect against other forms of proteotoxicity are ongoing. These studies suggest the utility of C. elegans to discover drugs to treat human diseases. Future studies will assess molecular mechanisms mediating the protective effects of these compounds.

Systemic Bioenergetic Capacity Changes with Cognitive Status and Insulin Sensitivity in Older Adults

Systemic mitochondrial dysfunction is reported with AD progression, suggesting that peripheral blood cells may be used to investigate systemic mitochondrial alterations related to cognitive decline. We aimed to identify bioenergetic signatures associated with AD-related dementia and differences in insulin sensitivity associated with AD risk. We analyzed mitochondrial bioenergetics in peripheral blood cells collected from 365 older adults with varying cognitive status (normal, mild cognitive impairment, and AD) and insulin sensitivity. Normoglycemic individuals exhibited lower maximal bioenergetic capacity with AD (PBMCs: 239.6 pmol·min−1, p = 0.02; Platelets: 151.7 pmol·min−1, p = 0.06) compared to normal cognition (PBMCs: 271.5 pmol·min−1; Platelets: 171.7 pmol·min−1). Individuals with impaired insulin sensitivity exhibited lower maximal bioenergetic capacity in platelets with AD (171.6 pmol·min−1, p = 0.008) compared to normal cognition (210.6 pmol.min−1). Participants with impaired insulin sensitivity also exhibited unique bioenergetic profiles exemplified by overall higher levels of mitochondrial respiration, indicating that comorbidities such as diabetes can significantly influence bioenergetic capacity. We observed strong positive associations between maximal respiration in normoglycemic individuals with cognitive function, as measured by Modified Preclinical Alzheimer’s Cognitive Composite (mPACC5) (p = 0.06), and fatty acid oxidation in individuals with impaired insulin sensitivity with cortical thickness (p = 0.05). This study demonstrates that circulating cells may provide a cost-effective and minimally invasive way to monitor systemic bioenergetic changes associated with AD risk, progression, and insulin sensitivity. These findings also suggest that blood-based bioenergetics are related to key features of AD development and progression and should be further developed as a potential biomarker.

Shared genetic susceptibility between diabetes and dementia in the Million Veteran Program.

Diabetes and dementia are diseases of high healthcare burden worldwide, and there is evidence that diabetes is a risk factor for dementia. Compared to those without diabetes, the relative risk of dementia in individuals with diabetes ranges from 1.4 to 2.2. Our goal was to evaluate shared genetic susceptibility for diabetes and dementia. Using imputed genotype data from MVP, we built a weighted genetic risk score (GRS) for T2D using 331 variants and their effect sizes from published genome-wide association studies of T2D. We evaluated associations with four nested definitions of dementia: strict Alzheimer's Disease (AD), AD plus non-specific dementias (AD-Plus), AD-related dementia (AD-RD), and all-cause dementia. We used logistic regression to assess associations of the GRS with dementia sub-types, stratified by European, African, and Hispanic ancestries, using a significance threshold of 0.0033 to account for multiple testing. As a sensitivity test, we removed the rs429358 variant near the APOE gene from the GRS as it has known genome-wide significant associations with AD. In 19,562 cases and 252,893 controls of European ancestry, we found associations of the T2D GRS with all-cause dementia (p=1.30e-07, OR 1.06), and in 14,455 cases and 258,000 controls with AD-RD (p=3.35e-07, OR = 1.07), but not with AD-Plus or strict AD. The T2D GRS was not associated with any of the dementia outcomes in participants of African (p =0.27 to 0.48) or Hispanic (p = 0.15 to 0.94) ancestries. When removing the APOE locus, we found that the effect size estimates for the GRS increased and the probability of association by chance decreased: all-cause dementia (p=2.08e-12, OR = 1.08), AD-RD (p=1.37e-12, OR = 1.10), and AD-Plus (p=3.97e-06, OR = 1.08). We found evidence of shared genetic susceptibility between diabetes and dementia. Future work will evaluate causality of the diabetes-dementia association using Mendelian Randomization. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards MVP009 and MVP022. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Association of neighborhood socioeconomic disadvantage and cognitive decline

AbstractBackgroundThere is increasing emphasis on research recruitment of persons of color to understand the influence of race/ethnicity on Alzheimer’s disease (AD) and AD‐related dementia (ADRD) risk. Normal persons with subjective cognitive decline (SCD) are considered at risk for future decline as SCD is thought to be a preclinical stage of AD/ADRD. Yet the validity of SCD across racial and ethnic groups is unclear. Race/ethnicity‐related conditions such as socio‐economic disadvantage, neighborhood segregation, and poor housing quality (neighborhood deprivation) are important factors in stress, discrimination and other social determinants of health and may provide more in‐depth explanations for SCD than race/ethnicity alone.MethodWe examined the role of neighborhood deprivation and compared this to the role of race/ethnicity in SCD using a validated instrument, the Brief Cognitive Rating Scale (BCRS). Using the Area Deprivation Index (ADI), we cross‐sectionally examined the relationship between neighborhood characteristics and SCD in a racially and ethnically diverse group of community‐residing older adults in New York City. For those having available addresses, we used data from participants with normal cognition in the NYU Alzheimer’s Disease Research Center (n=313) and conducted multivariable logistic regressions, comparing two models with the BCRS as our outcome: using the ADI without race/ethnicity and then with race/ethnicity, both adjusting for age, sex, education (years).ResultParticipant mean age was 72.8.0 ± 7.4 years; mean education was 16.3± 3.1 years. Seventy‐six percent of the cohort was female (n=232); 12.1% (n= 38) reported as Hispanic, 73.5% (n=230) non‐Hispanic (NH) White; 13.4% reported as NH Black or African‐American (n=42); and 3 were other. In multivariable logistic regressions of BCRS domain‐specific analysis, ADI was a significant predictor of BCRS‐measured SCD even when race/ethnicity was included as a covariate (p&lt;0.05), suggesting independent influence of neighborhood deprivation.ConclusionNeighborhood characteristics may play an influential role in SCD regardless of race/ethnicity and thus are likely important risk factors for AD/ADRD. If larger and more diverse studies generate similar findings, neighborhood investment and recruitment goals for AD/ADRD studies will require more focus on neighborhoods with greater deprivation.

Dementia friendly community outreach improves research participation and dementia resource utilization among African Americans

AbstractBackgroundAfrican Americans are at greater risk of Alzheimer’s disease (AD) and AD‐related dementia (ADRD). They are also less likely to access dementia resources or participate in dementia research. The National Alzheimer’s Project Act (NAPA) calls for special attention to dementia‐related health disparities in high risk groups. Identifying effective tools to improve rates of dementia resource utilization and research participation by African Americans is essential to achieving dementia health equity.MethodTwo neighborhoods of Jacksonville, FL, defined by zip codes, were the focus of this study. Both zip codes have a large population of African American residents per 2010 US Census, and a history of hosting outreach activities by our Alzheimer’s Disease Research Center (ADRC). In one neighborhood, we modified the NAPA Dementia Friendly (DF) America toolkit to serve as a model of outreach. The second neighborhood served as a control (CON), in which we maintained our traditional outreach model of community‐based lectures. Primary outcome measures were: (1) enrollment in ADRC center‐related studies and (2) phone call volumes from individuals seeking dementia resource information. The outcomes in the DF and CON neighborhoods were compared via Fisher’s exact test to those in other zip codes in Jacksonville (OT).ResultIn the 18 months following implementation of the DF intervention, 54 African Americans enrolled in ADRC‐related research (19 DF, 3 CON, 32 OT), compared to 21 during the 18 months prior (2 DF, 0 CON, and 19 OT). The increase in DF residents enrolling in research following the intervention was statistically significant (p =0 .02) relative to OT residents. The increase observed in the CON residents was not statistically significant (p=1.0) compared to OT residents. Call volumes from African Americans increased from 13 prior to program implementation (all from OT) to 62 calls after implementation (22 DF, 1 CON, 39 OT). The increase among DF residents seeking information following the intervention was statistically significant (p =0.008) whereas the increase was not significant in the CON residents (p=0.54).ConclusionResults suggest that the NAPA DFA can be leveraged to improve dementia resource utilization and research participation among community‐dwelling African Americans.

Early Functional and Cognitive Declines Measured by Auditory-Evoked Cortical Potentials in Mice With Alzheimer's Disease.

Alzheimer’s disease (AD) is characterized by a progressive loss of memory and cognitive decline. However, the assessment of AD-associated functional and cognitive changes is still a big challenge. Auditory-evoked cortical potential (AECP) is an event-related potential reflecting not only neural activation in the auditory cortex (AC) but also cognitive activity in the brain. In this study, we used the subdermal needle electrodes with the same electrode setting as the auditory brainstem response (ABR) recording and recorded AECP in normal aging CBA/CaJ mice and APP/PS1 AD mice. AECP in mice usually appeared as three positive peaks, i.e., P1, P2, and P3, and three corresponding negative peaks, i.e., N1, N2, and N3. In normal aging CBA mice, the early sensory peaks P1, N1, and P2 were reduced as age increased, whereas the later cognitive peaks N2, P3, and N3 were increased or had no changes with aging. Moreover, the latency of the P1 peak was increased as age increased, although the latencies of later peaks had a significant reduction with aging. In AD mice, peak P1 was significantly reduced in comparison with wild-type (WT) littermates at young ages, proceeding AD phenotype presentation. In particular, the later cognitive peak P3 was diminished after 3 months old, different from the normal aging effect. However, the latencies of AECP peaks in AD mice generally had no significant delay or changes with aging. Finally, consistent with AECP changes, the accumulation of amyloid precursor protein (APP) at the AC was visible in AD mice as early as 2 months old. These data suggest that AECP could serve as an early, non-invasive, and objective biomarker for detecting AD and AD-related dementia (ADRD).

Decoding perineuronal net glycan sulfation patterns in the Alzheimer's disease brain.

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a re-coding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.

National Institute on Aging seed funding enables Alzheimer's disease startups to reach key value inflection points.

IntroductionThe National Institute on Aging (NIA) provides funding to academic researchers and small businesses working in the Alzheimer's Disease (AD) and AD‐related dementia (ADRD) fields to help commercialize their products. The NIA uses Small Business Innovation Research (SBIR) awards to bridge the funding gap in the diagnostic, therapeutic, and care interventions areas, enabling startups to reach key value inflection points to achieve scientific milestones.MethodsOnly publicly available information is reported. The National Institutes of Health Report Portfolio Online Reporting Tool database and the commercial database Global Data, were used to track the progress of companies that received SBIR or Small Business Technology Transfer (STTR) funding from the NIA.ResultsSince 2008, the NIA has awarded $280 million—including $207 million from fiscal year (FY) 2015 to FY 2019—in new small business program awards for AD/ADRD research.DiscussionNIA seed capital and mentoring programs are critical resources to help small businesses reach key value inflection points and advance their research from concept to commercialization.

Potential Ayurvedic Herbs for Neurodegenerative Diseases: A review

In herbal medicine, there is a substantial amount of variety of plants have been used to treat neurodegenerative disorders including Alzheimer's (AD)as well as other memory-related issues. Dementia is a neurological condition characterised by a progressive loss in emotional and cognitive abilities. Dementia is linked to a number of conditions like inadequate cerebral blood flow, poison toxicity, and other risk factors and conditions mitochondrial dysfunction, oxidative injury, and, in certain cases coexistence with other diseases like Alzheimer's disease (AD), Huntington's disease, Parkinson's syndrome (PD) and Attention Deficit Hyperactivity Disorder (ADHD).Despite the fact that there are well-established semi-synthetic medications for the treatment of AD and AD-related dementia, the majority of them have a number of side effects. As a result, conventional medicine offers a variety of plant-derived lead molecules that may be valuable in future medical studies. In this paper, we look at how ayurvedic plants are used to treat neurodegenerative disease around the world. Plants are also neuroprotective against proinflammatory cytokines including IL-6, IL-1b, TNF-a and it was reported that Antioxidant activity was increased, oxidant levels were reduced, and acetylcholinesterase activity was inhibited in the nervous system by these medicinal plants. We've highlighted the most essential ayurvedic medicinal plants as well as their biochemical effects. As a result, the effects of the above medicinals plants and their active constituents strengthened neurodegenerative conditions, indicating their therapeutic potential in ailments like Alzheimer's disease. and depression that are linked to neuroinflammation and neurotransmitter dysfunction.

Alzheimer's disease as a chronic maladaptive polyamine stress response.

Polyamines are nitrogen-rich polycationic ubiquitous bioactive molecules with diverse evolutionary-conserved functions. Their activity interferes with numerous genes' expression resulting in cell proliferation and signaling modulation.The intracellular levels of polyamines are precisely controlled by an evolutionary-conserved machinery. Their transient synthesis is induced by heat stress, radiation, and other traumatic stimuli in a process termed the polyamine stress response (PSR).Notably, polyamine levels decline gradually with age; and external supplementation improves lifespan in model organisms. This corresponds to cytoprotective and reactive oxygen species scavenging properties of polyamines. Paradoxically, age-associated neurodegenerative disorders are characterized by upsurge in polyamines levels, indicating polyamine pleiotropic, adaptive, and pathogenic roles. Specifically, arginase overactivation and arginine brain deprivation have been shown to play an important role in Alzheimer’s disease (AD) pathogenesis.Here, we assert that a universal short-term PSR associated with acute stimuli is beneficial for survival. However, it becomes detrimental and maladaptive following chronic noxious stimuli, especially in an aging organism. Furthermore, we regard cellular senescence as an adaptive response to stress and suggest that PSR plays a central role in age-related neurodegenerative diseases' pathogenesis.Our perspective on AD proposes an inclusive reassessment of the causal relationships between the classical hallmarks and clinical manifestation. Consequently, we offer a novel treatment strategy predicated upon this view and suggest fine-tuning of arginase activity with natural inhibitors to preclude or halt the development of AD-related dementia.

Mild Cognitive Impairment Patients Have Higher Regulatory T-Cell Proportions Compared With Alzheimer's Disease-Related Dementia Patients.

Objectives: The role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD) has attracted much attention recently. Regulatory T-cells (Tregs) play an important role in modulating inflammation. We aimed to explore the Treg-related immunosuppression status at different stages of AD.Methods: Thirty healthy control (HC) subjects, 26 patients with mild cognitive impairment (MCI), 30 patients with mild probable AD-related dementia, and 28 patients with moderate-to-severe probable AD-related dementia underwent detailed clinical history taking, structural MRI scanning, and neuropsychological assessment. Peripheral blood samples were taken to measure the percentage of CD4+CD25+CD127low/− Tregs by flow cytometry and the levels of interleukin (IL-10), interleukin (IL-35), and transforming growth factor β (TGF-β) by ELISA.Results: The percentage of Tregs in the blood of MCI patients was the highest (9.24%); there was a significant difference between patients with MCI and patients with probable AD-related dementia. The level of TGF-β in patients with MCI (47.02 ng/ml) was significantly increased compared with patients with AD-related dementia. There were positive correlations between Treg percentage, IL-35, and Mini-mental state evaluation scores in patients with MCI and probable AD-related dementia.Conclusions: Patients with MCI have stronger Treg-related immunosuppression status compared with patients with probable AD-related dementia.