Decline In Alzheimer's Disease Patients Research Articles

Correlations between SHBG, Sex Hormones, Inflammation, and Neurocognitive Decline in Alzheimer's Disease:A Retrospective Study.

Alzheimer's Disease (AD) is characterized by a progressive neurodegenerative process leading to cognitive decline and functional impairment. Endocrine factors, particularly sex hormones and their binding proteins, play a critical role in AD pathophysiology. Understanding the relationship between these factors and AD is essential for developing targeted interventions. To investigate the potential links between sex hormone binding globulin (SHBG) levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in patients with AD. A retrospective case-control investigation was conducted with 110 AD patients who were admitted to our hospital from January 2021 to December 2023, and the patients were classified into either a mild neurocognitive impairment group (n=59) or a moderate to severe neurocognitive impairment group (n=51) according to their cognitive function. Correlation and regression analyses were conducted to examine relationships between variable factors. The study revealed a significant neurocognitive decline in AD patients with lower Mini-- Mental State Examination (MMSE) and higher AD Assessment Scale-Cognitive Subscale (ADAS- Cog) scores in the moderate to severe neurocognitive impairment group compared to the mild neurocognitive impairment group. Additionally, the moderate to severe neurocognitive impairment group significantly increased for SHBG, estradiol, progesterone inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β)). It decreased for follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. Moreover, significant positive correlations were found between SHBG levels and ADAS-Cog scores, and significant negative correlations were found between SHBG levels and MMSE scores. FSH showed significant negative correlations with the MMSE score, while certain inflammatory markers demonstrated significant correlations with neurocognitive abilities. The correlation between sex hormones and inflammatory factors is weak. FSH, LH, SHBG, CRP, IL-6, TNF-α, and IL-1β are risk factors for neurocognitive impairment, while E2 and P are protective factors. The study provides evidence of significant correlations between SHBG levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in AD patients.

Combined Effect of tDCS and Motor or Cognitive Activity in Patients with Alzheimer's Disease: A Proof-of-Concept Pilot Study.

(1) Background: Alzheimer's disease (AD) accounts for 70% of dementia cases and with no effective pharmacological treatments, new rehabilitation methods are needed. Motor and cognitive activities and transcranial direct current stimulation (tDCS) have shown promise in stabilizing and enhancing cognitive functions. Objective: we want to investigate the effects of tDCS combined with motor or cognitive activity on cognitive functions in AD patients. (2) Methods: Patients with mild or moderate AD were randomized between anodic tDCS groups (MotA or CogA) and sham tDCS groups (MotS or CogS). They received two weeks of treatment (45 min, five days/week), with the first 15 min using tDCS stimulation on the dorsolateral prefrontal cortex. Cognitive assessments were conducted pre-treatment (T0), post-treatment (T1), and one week after (T2). (3) Results: Twenty-three patients were included. Statistical analysis showed significant differences between anodic tDCS groups (MotA + CogA) and sham tDCS groups (MotS + CogS) with advantages for the first in improving global cognitive status (p = 0.042), selective attention (p = 0.012), and sustained attention (p = 0.012). Further analysis indicated no differences between the two anodic tDCS groups between T0 and T1. (4) Conclusions: combined anodal tDCS with motor or cognitive activity could improve global cognitive state and attention, slowing cognitive decline in AD patients. The trial was registered on Clinical Trials: NCT06619795.

The effects of omega-3, DHA, EPA, Souvenaid® in Alzheimer's disease: A systematic review and meta-analysis.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Omega-3 fatty acids (n-3-PUFA) are essential to normal neural development and function. Souvenaid®, a medical supplement that contains n-3-PUFA's: eicosatetraenoic acid (EPA) and docosahexaenoic acid (DHA), has emerged as an alternative, slowing cognitive decline in AD patients. In this study, we investigated the effect of dietary supplementation with n-3-PUFA, EPA, DHA, and Souvenaid® in AD patients. This systematic review and meta-analysis aim to establish the relationship between n-3-PUFA, EPA, DHA, and Souvenaid® with cognitive effects, ventricular volume and adverse events in AD patients. A systematic search of randomized control trials (RCT), cohorts, and case-control studies was done in PubMed, Scopus, Web of Science, Cochrane, and Embase for AD adult patients with dietary supplementation with n-3-PUFA, EPA, DHA, or Souvenaid® between 2003 and 2024. We identified 14 studies with 2766 subjects aligned with our criteria. Most publications described positive cognitive outcomes from supplements (58%). The most common adverse events reported were gastrointestinal symptoms. CDR scale showed reduced progression of cognitive decline (SMD = -0.4127, 95% CI: [-0.5926; -0.2327]), without subgroup differences between different dietary supplement interventions. ADCS-ADL, MMSE, ADAS-cog, adverse events, and ventricular volume did not demonstrate significant differences. However, Souvenaid® showed a significant negative effect (SMD = -0.3593, 95% CI: -0.5834 to -0.1352) in ventricular volumes. The CDR scale showed reduced progression of cognitive decline among patients with n-3-PUFA supplemental interventions, with no differences between different n-3-PUFA supplements.

Role of Neurocellular Endoplasmic Reticulum Stress Response in Alzheimer's Disease and Related Dementias Risk.

Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's Disease and Related Dementias (ADRD) accounts for nearly 60-70% of all those cases. The spread of Alzheimer's Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD's causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs' ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs' transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

C5aR1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer's disease.

Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. Genetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD. C5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease.

Mitochondrial Targeting against Alzheimer's Disease: Lessons from Hibernation.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and yet remains without effective therapy. Amongst the many proposed causes of AD, the mitochondrial cascade hypothesis is gaining attention. Accumulating evidence shows that mitochondrial dysfunction is a driving force behind synaptic dysfunction and cognitive decline in AD patients. However, therapies targeting the mitochondria in AD have proven unsuccessful so far, and out-of-the-box options, such as hibernation-derived mitochondrial mechanisms, may provide valuable new insights. Hibernators uniquely and rapidly alternate between suppression and re-activation of the mitochondria while maintaining a sufficient energy supply and without acquiring ROS damage. Here, we briefly give an overview of mitochondrial dysfunction in AD, how it affects synaptic function, and why mitochondrial targeting in AD has remained unsuccessful so far. We then discuss mitochondria in hibernation and daily torpor in mice, covering current advancements in hibernation-derived mitochondrial targeting strategies. We conclude with new ideas on how hibernation-derived dual mitochondrial targeting of both the ATP and ROS pathways may boost mitochondrial health and induce local synaptic protein translation to increase synaptic function and plasticity. Further exploration of these mechanisms may provide more effective treatment options for AD in the future.

The Association between Metformin Use and Risk of Developing Severe Dementia among AD Patients with Type 2 Diabetes.

This study explores the potential impact of metformin on the development of severe dementia in individuals with Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). With an emerging interest in the role of the APOE genotype in mediating metformin's effects on cognitive decline in AD patients, we sought to investigate whether metformin usage is associated with a reduced risk of severe dementia. Using data from the National Alzheimer's Coordinating Center (NACC) database (2005-2021), we identified 1306 participants with both AD and T2DM on diabetes medications. These individuals were categorized based on metformin usage, and a propensity score-matched cohort of 1042 participants was analyzed. Over an average follow-up of 3.6 years, 93 cases of severe dementia were observed. A Kaplan-Meier analysis revealed that metformin users and non-users had similar probabilities of remaining severe dementia-free (log-rank p = 0.56). Cox proportional hazards models adjusted for covariates showed no significant association between metformin usage and a lower risk of severe dementia (HR, 0.96; 95% CI, 0.63-1.46; p = 0.85). A subgroup analysis based on APOE ε4 carrier status demonstrated consistent results, with metformin use not correlating with a reduced severe dementia risk. In conclusion, our findings from a substantial cohort of AD and T2DM patients suggest that metformin usage is not significantly associated with a decreased risk of severe dementia. This observation persists across APOE ε4 carriers and non-carriers, indicating a lack of genotype-mediated effect.

Triptolide activates the Nrf2 signaling pathway and inhibits the NF-κB signaling pathway to improve Alzheimer disease.

Alzheimer disease (AD) is a common neurodegenerative disease with pathological features of accumulated amyloid plaques, neurofibrillary tangles, and the significant inflammatory environment. These features modify the living microenvironment for nerve cells, causing the damage, dysfunction, and death. Progressive neuronal loss directly leads to cognitive decline in AD patients and is closely related to brain inflammation. Therefore, impairing inflammation via signaling pathways may facilitate either the prevention or delay of the degenerative process. Triptolide has been evidenced to possess potent anti-inflammatory effect. In this review, we elaborate on two signaling pathways (the NF-κB and Nrf2 signaling pathways) that are involved in the anti-inflammatory effect of triptolide.

Single nucleotide polymorphisms in aquaporin-4 associate with cognitive impairment status in people with HIV.

Neurocognitive impairments are more frequent in people with HIV (PWH) compared to their uninfected counterparts. HIV-associated neurocognitive disorder (HAND) is a spectrum disorder and up to 50% of PWH are reported to suffer from HAND. Altered waste clearancefrom the brain, chronic neuroinflammation and impaired metabolic processes may contribute to abnormal aging in PWH and are more common among those who suffer from HAND. Thus, it is important to identify earlier predictors for development of HAND. A key contributor to cognitive impairment in HIV and in Alzheimer's disease (AD) is formation and accumulation of aberrant proteins including hyperphosphorylated Tau (pTau). Previous data from AD and traumatic brain injury studies report that impaired waste clearance from the brain contributes in part to cognitive impairments. Evidence suggests that the aquaporin 4 (aqp4) gene may have an important role in waste clearance from the brain as single nucleotide polymorphisms (SNPs) in aqp4 have been reported to associate with changes in cognitive decline in AD patients. Given some similarities between HAND and AD, we assessed potential associations of several aqp4 SNPS with cognitive impairment in PWH. Our data show that homozygous carriers of the minor allele in SNPs rs3875089 and rs3763040 had significantly lower neuropsychological test Z-scores in multiple domains compared to the other genotypes. Interestingly, this decrease in Z-scores was only observed in PWH and not in HIV-control participants. Conversely, homozygosity of the minor allele of rs335929 associated with better executive function in PWH. Based on these data, tracking large cohorts of PWH to determine if the presence of these SNPs associate with cognitive changes during disease progression is of interest. Furthermore, screening PWH for SNPs that may be associated with cognitive impairment risk after diagnosis could be considered in alignment with traditional treatment plans to potentially work on skills in areas shown to have cognitive decline with these SNPs present.

Ethanol Induces Blood-Brain Barrier Dysfunction in a Familial Alzheimer’s Human Stem Cell-Derived Model


 
 
 Background:
 Alcohol consumption has been directly linked to neurodegenerative diseases, including Alzheimer's disease (AD). Additionally, heavy consumption of alcohol has been shown to cause a faster cognitive decline in AD patients. A subset of studies demonstrated that alcohol can diminish BBB integrity and independently AD patients have suppressed barrier properties, but the direct effect of alcohol on barrier integrity in AD patients remains unclear. In this study, we utilize a human stem cell-derived AD BBB model with near in vivo properties to investigate the effects of alcohol on critical barrier properties.
 Methods:
 Brain microvascular endothelial cells (BMECs) were derived from healthy (IMR90) and AD (PSEN 1, PSEN 2, and APP) human induced pluripotent stem cells (iPSCs). Healthy and AD cell lines were treated with physiologically relevant concentrations of alcohol (5, 25, and 50 mM). Following exposure, several critical barrier properties were monitored for up to 5 days post-exposure, including trans-endothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction localization.
 Results:
 Moderate to severe alcohol exposure (25mM and 50mM) decreased barrier integrity in both healthy and AD-derived BMECs, as observed by an increase in sodium fluorescein permeability and a reduction in TEER. Furthermore, alcohol increased the number of discontinuous tight junctions directly contributing to the diminished barrier integrity. Interestingly, our preliminary results demonstrate that AD-derived BMECs are more susceptible to ethanol- induced barrier injury at lower concentrations of ethanol (5mM) compared to healthy-derived BMECs.
 Conclusion and Potential Impact:
 Our results indicate that alcohol can diminish critical barrier properties in healthy-derived BMECs similarly to other non-human established BBB models. For the first time, we observed an increase sensitivity to alcohol-induced BBB dysfunction in a familial AD-derived BBB model. These data suggest that mild alcohol consumption could significantly alter the BBB and contribute to the development or exacerbation of AD-induced barrier dysfunction.
 
 

Progressive structural and covariance connectivity abnormalities in patients with Alzheimer's disease.

Alzheimer's disease (AD) is one of most prevalent neurodegenerative diseases worldwide and characterized by cognitive decline and brain structure atrophy. While studies have reported substantial grey matter atrophy related to progression of AD, it remains unclear about brain regions with progressive grey matter atrophy, covariance connectivity, and the associations with cognitive decline in AD patients. This study aims to investigate the grey matter atrophy, structural covariance connectivity abnormalities, and the correlations between grey matter atrophy and cognitive decline during AD progression. We analyzed neuroimaging data of healthy controls (HC, n = 45) and AD patients (n = 40) at baseline (AD-T1) and one-year follow-up (AD-T2) obtained from the Alzheimer's Disease Neuroimaging Initiative. We investigated AD-related progressive changes of grey matter volume, covariance connectivity, and the clinical relevance to further understand the pathological progression of AD. The results showed clear patterns of grey matter atrophy in inferior frontal gyrus, prefrontal cortex, lateral temporal gyrus, posterior cingulate cortex, insula, hippocampus, caudate, and thalamus in AD patients. There was significant atrophy in bilateral superior temporal gyrus (STG) and left caudate in AD patients over a one-year period, and the grey matter volume decrease in right STG and left caudate was correlated with cognitive decline. Additionally, we found reduced structural covariance connectivity between right STG and left caudate in AD patients. Using AD-related grey matter atrophy as features, there was high discrimination accuracy of AD patients from HC, and AD patients at different time points.

Intranasal interferon-beta as a promising alternative for the treatment of Alzheimer's disease

Deterioration in cognitive abilities, especially memory, is characteristic of Alzheimer's disease (AD), a type of neurodegenerative disease. AD's pathological lesions include intracellular neurofibrillary tangles and extracellular amyloid-β plaques. So far, many efforts have been made to find a cure for AD, but there are still no effective pharmacotherapeutic options that relieve the symptoms and enhance the life quality of AD patients. The intranasal (IN) route has been previously used to treat a wide variety of central nervous system disorders as it is a direct, non-invasive method for delivering drugs to the brain. Our prior in vivo preclinical research employing a rat model of AD revealed that intranasally administered interferon-beta (IFNβ) exhibited pro-cognitive and protective benefits. Therefore, we hypothesize that IN administration of IFNβ can be an effective and promising strategy to slow down cognitive decline in AD patients at least partly by reducing amyloid deposition and tau hyperphosphorylated protein accumulation, promoting anti-inflammatory response and anti-apoptotic pathways, increasing neurotrophic factor expression, activating mitochondrial biogenesis, modulating neurogenesis, and improving cerebral glucose metabolism.

Oligomer Formation by Amyloid-β42 in a Membrane-Mimicking Environment in Alzheimer's Disease.

The brains of Alzheimer's disease (AD) patients contain numerous amyloid plaques that are diagnostic of the disease. The plaques are primarily composed of the amyloidogenic peptides proteins Aβ40 and Aβ42, which are derived by the processing of the amyloid pre-cursor protein (APP) by two proteases called β-secretase and γ-secretase. Aβ42 differs from Aβ40 in having two additional hydrophobic amino acids, ILE and ALA, at the C-terminus. A small percentage of AD is autosomal dominant (ADAD) and linked either to the genes for the presenilins, which are part of γ-secretase, or APP. Because ADAD shares most pathogenic features with widespread late-onset AD, Aβ peptides have become the focus of AD research. Fibrils formed by the aggregation of these peptides are the major component of plaques and were initially targeted in AD therapy. However, the fact that the abundance of plaques does not correlate well with cognitive decline in AD patients has led investigators to examine smaller Aβ aggregates called oligomers. The low levels and heterogeneity of Aβ oligomers have made the determination of their structures difficult, but recent structure determinations of oligomers either formed or initiated in detergents have been achieved. We report here on the structures of these oligomers and suggest how they may be involved in AD.

The Ketogenic Diet and Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the most common form of dementia. There are currently FDA-approved symptomatic therapies for AD and a recently approved, potentially disease-modifying drug, Aducanumab; however, there are no curative or preventative therapies. Research suggests that diet may play a role in AD, but it is inconclusive relative to which dietary approach provides the most neuroprotective effects. There are other life-style approaches that have been found to possibly play a role in AD prevention/treatment. These include exercise, brain training, and social interaction. A combined approach may be more effective than any one modality alone. The ketogenic diet (KD) is one specific diet that has been studied vis a vis neurodegenerative diseases. Similar benefits to those of a KD can also be achieved through consuming a normal diet and supplementing with ketogenic agents. The purpose of this review is to compare the methods of inducing hyperketonemia and their impact on AD prevention/treatment, as well as to explore the possible benefits of a combined approach. The PubMed database was searched for clinical trials and randomized, controlled trials involving the KD or exogenous ketone administration and AD. Key search terms used included "ketogenic diet and Alzheimer's disease," "ketosis and Alzheimer's disease," "MCT and Alzheimer's disease," and "exercise and diet and Alzheimer's disease." Only studies involving patients diagnosed with AD were included in this paper, but for the combined approach section, studies included patients diagnosed with MCI due to a paucity of combined approach studies involving AD patients alone. There is evidence that the KD and exogenous ketone supplementation may provide treatment benefits in AD patients. It is unclear whether one method is better than the other. The specific food composition of the KD should be considered, because certain types of fat sources are healthier than others. Many forms of the KD require strict monitoring of carbohydrate intake, which would often fall under the responsibility of the caregiver. Future studies may be more feasible in an institutional setting, where it would be easier to administer and to monitor a dietary protocol. Exogenous supplementation may be more likely to be adhered to as a long-term treatment, because the dietary changes are not as drastic. A multidomain approach may be the most effective in possibly preventing/delaying AD and in improving/stabilizing and possibly slowing disease progression in those with AD. Most current studies are small, often uncontrolled, and only look at the short-term effects of ketosis on cognition. Large, long-term, randomized, controlled trials relative to the impact of the KD in patients with cognitive impairment and AD are lacking and thus needed. Combined approaches may prove to be more beneficial in possibly preventing/delaying AD and in improving/stabilizing and possibly slowing disease progression in those with MCI or AD. Future research should investigate the effect of additional combined approaches relative to neurocognitive decline in AD patients.

Association Between Blood Biochemical Factors Contributing to Cognitive Decline and B Vitamins in Patients With Alzheimer's Disease.

BackgroundMalnutrition, metabolism stress, inflammation, peripheral organs dysfunction, and B vitamins deficiency significantly contribute to the progression and mortality of Alzheimer's disease (AD). However, it is unclear which blood biochemical indicators are most closely related to cognitive decline and B vitamins deficiency (thiamine, folate, vitamin B12) in patients with AD.MethodsThis was a cross-sectional study of 206 AD patients recruited from six hospitals in China. Thiamine diphosphate (TDP), the bioactive form of thiamine, was measured by high-performance liquid chromatography fluoroscopy (HPLC) at a single center. Levels of biochemical indicators (except TDP) were measured by regular and standard laboratory tests in each hospital. Pearson's rank correlation analysis was used to assess relationships between B vitamins and biochemical indicators. T-test was used to compare the difference between ApoE ε4 and non-ApoE ε4 groups. Differences were considered statistically significant as P < 0.05.ResultsAmong the biochemical results, in AD population, malnutrition indicators (erythrocyte, hemoglobin, serum albumin, and total protein) were most significantly associated with cognitive function, as was free triiodothyronine (FT3) levels which had been observed in previous study. Malnutrition and FT3 levels depend on age but not apolipoprotein E (ApoE) genotype. Meanwhile, Among the B vitamins, TDP was the most significantly associated with malnutrition indicators and FT3.ConclusionOur results indicated that TDP reduction could be a modifiable risk factor for malnutrition and FT3 that contributed to cognitive decline in AD patients. Correcting thiamine metabolism could serve as an optional therapy target for AD treatment.

Functional (un-)Coupling: Impairment, Compensation, and Future Progression in Alzheimer's Disease.

Background: Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Method: Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age: M = 73.8 years; SD = 9.0). Of these, 68 patients (M = 73.9 years; SD = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. Results: The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (β = .340; p < .001; β = .274; P = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (β = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (β = -.402; P = .010). Conclusion: These findings suggest an important role of functional coupling mechanisms in left anterior-posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.

GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease.

To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD). Synaptic dysfunction and E/I imbalance emerge decades before the appearance of cognitive decline in AD patients, which contribute to neurodegeneration. Initially, E/I imbalance was thought to occur first, due to dysfunction of the glutamatergic and cholinergic systems. However, new evidence has demonstrated that the GABAergic system, the counterpart of E/I balance and the major inhibitory neurotransmitter system in the central nervous system, is altered enormously and that this contributes to E/I imbalance and further AD pathogenesis. Alterations to the GABAergic system, induced by multiple AD pathogenic or risk factors, contribute to E/I imbalance and AD pathogenesis. This GABAergic hypothesis accounts for many critical questions and common challenges confronting a new hypothesis of AD pathogenesis. More specifically, it explains why amyloid beta (Aβ), β-secretase (BACE1), apolipoprotein E4 gene (APOE ε4), hyperactive glia cells, contributes to AD pathogenesis and why age and sex are the risk factors of AD. GABAergic dysfunction promotes the spread of Aβ pathology throughout the AD brain and associated cognitive impairments, and the induction of dysfunction induced by these varied risk factors shares this common neurobiology leading to E/I imbalance. In turn, some of these factors exacerbate GABAergic dysfunction and E/I imbalance. Moreover, the GABAergic system modulates various brain functions and thus, the GABAergic hypothesis accounts for nonamnestic manifestations. Furthermore, corrections of E/I balance through manipulation of GABAergic functions have shown positive outcomes in preclinical and clinical studies, suggesting the potential of the GABAergic system as a therapeutic target in AD. Dysfunction of the GABAergic system is induced by multiple critical signaling pathways, which include the existing major theories of AD pathogenesis, such as the Aβ and neuroinflammation hypotheses. In a new perspective, this GABAergic hypothesis accounts for the E/I imbalance and related excitotoxicity, which contribute to cognitive decline and AD pathogenesis. Therefore, the GABAergic system could be a key target to restore, at least partially, the E/I balance and cognitive function in AD patients.

The Neuroprotective Effects of Exercise on Cognitive Decline: A Preventive Approach to Alzheimer Disease.

Alzheimer's disease (AD) is a progressive disorder that causes brain cells to slowly degenerate and die. This leads to a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. AD is the most common cause of dementia globally. Neuroinflammation caused by intracellular neurofibrillary tangles and extracellular amyloid deposits leads to atrophy of brain cells especially the hippocampus, which is associated with memory formation. This atrophy leads to dementia and cognitive decline. Among the many preventive factors being studied, exercise is thought to play a vital role in not only preventing the pre-clinical stage of AD but also slowing the clinical progression of AD. It is also deployed as a treatment option for late-stage AD along with pharmacological treatment options. Various studies and clinical trials in both human and animal models are of the opinion that exercise slows the onset and progression of cognitive decline in AD patients. Some studies suggest that this effect is due to a decrease in neurofibrillary tangles and amyloid deposits in brain parenchyma. Others suggest that exercise causes an increase in angiogenesis, neurogenesis, and synaptogenesis mainly due to an increase in blood flow, brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), hormones, and second messengers.

Can Healthy Diets, Regular Exercise, and Better Lifestyle Delay the Progression of Dementia in Elderly Individuals?

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Current healthcare costs for over 50 million people afflicted with AD are about $818 million and are projected to be $2 billion by 2050. Unfortunately, there are no drugs currently available that can delay and/or prevent the progression of disease in elderly individuals and in AD patients. Loss of synapses and synaptic damage are largely correlated with cognitive decline in AD patients. Women are at a higher lifetime risk of developing AD encompassing two-thirds of the total AD afflicted population. Only about 1-2% of total AD patients can be explained by genetic mutations in APP, PS1, and PS2 genes. Several risk factors have been identified, such as Apolipoprotein E4 genotype, type 2 diabetes, traumatic brain injury, depression, and hormonal imbalance, are reported to be associated with late-onset AD. Strong evidence reveals that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive function in elderly populations. Current available data on the use of antioxidants in mouse models of AD and antioxidant(s) supplements in diets of elderly individuals were investigated. The use of antioxidants in randomized clinical trials in AD patients was also critically assessed. Based on our survey of current literature and findings, we cautiously conclude that healthy diets, regular exercise, and improved lifestyle can delay dementia progression and reduce the risk of AD in elderly individuals and reverse subjects with mild cognitive impairment to a non-demented state.

Neuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer's Disease: Are We There Yet?

Alzheimer’s disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality.