Features Of Alzheimer's Disease Research Articles

The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer's disease: Anti-neurodegenerative benefits of acetylcholinesterase inhibitors.

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering.

Alzheimer's Disease : Current Landscape and Future Directions

Introduction: Alzheimer's disease (AD) is the most prevalent form of dementia, constituting up to 72% of cases, and poses a significant financial burden on global healthcare. The aging population is expected to triple the cost of dementia to over $600 billion in the US alone by 2050. Dementia, a major cause of dependency and dysfunction, accounted for 11.4% of all reported deaths in Britain and Wales in 2022. Recent studies suggest a potential decline in dementia incidence, especially in males in Occident countries, possibly linked to better management of vascular risk. While 89% of dementia costs are attributed to high-income countries, middle and low-income nations face significant challenges in addressing the epidemiology of dementia. The prevalence of AD in developing nations is estimated at 3.4%, varying widely. Women exhibit a 1.17 times higher age-specific global prevalence compared to men, and their age-normalized death rate is also higher, suggesting factors beyond life expectancy contribute to their vulnerability. AD primarily affects individuals aged 75 or older, with 80% of cases in this age group. Acetylcholinesterase inhibitors are commonly used in all stages of dementia, though their efficacy in mild cognitive impairment and prodromal AD is uncertain. Distinguishing AD from depression symptoms can be challenging. The pathological features of AD involve neurofibrillary tangles (NFTs) and senile plaques, leading to neural and synaptic loss. Multiple mechanisms contribute to AD pathogenesis, including amyloid/tau toxicity and oxidative stress. Diagnosis : traditionally relies on clinical criteria, but biomarkers like CSF Aβ and tau proteins, as well as blood-based biomarkers, have shown promise in early detection. Noveltrearment: Promising treatment options include anti-amyloid monoclonal antibodies like aducanumab, lecanemab, and gantenerumab, with varying degrees of success in clinical trials. Donanemab, targeting a specific type of Aβ, has shown significant slowing of mental degradation in early-stage patients.

Tau, synapse loss and gliosis progress in an Alzheimer's mouse model after amyloid-β immunotherapy.

While preclinical studies assessing drugs for Alzheimer's disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well-established that amyloid (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict how targeting one might influence the other, as well as downstream degeneration. We developed a transgenic mouse model, APP/PS1xTau22, with progressive cortical Aβ deposition and hippocampal tau neurofibrillary inclusions to investigate how both neuropathologies act jointly to bring about neural degeneration, synapse loss, and glial phenotypes. We then assessed whether applying murine chimeric Aducanumab, an anti-amyloid immunotherapy, could impact the synergistic relationship between amyloid and tau. Drug treatment resulted in a ∼70% reduction in Aβ deposition in hippocampal and cortical areas and produced a robust peri-plaque microglial and astrocytic response. Removing amyloid from the brain did not reverse or slow tau pathology or alter synapse loss. Our findings suggest that, once the interaction between amyloid and tau is set in motion, reducing plaque burden by Aβ immunotherapy may stimulate glial responses, but is insufficient to curb degenerative phenotypes in this model.

Analysis of Speech Features in Alzheimer's Disease with Machine Learning: A Case-Control Study.

Changes in the speech and language of patients with Alzheimer's disease (AD) have been reported. Using machine learning to characterize these irregularities may contribute to the early, non-invasive diagnosis of AD. We conducted cognitive function assessments, including the Mini-Mental State Examination, with 83 patients with AD and 75 healthy elderly participants, and recorded pre- and post-assessment conversations to evaluate participants' speech. We analyzed the characteristics of the spectrum, intensity, fundamental frequency, and minute temporal variation (∆) of the intensity and fundamental frequency of the speech and compared them between patients with AD and healthy participants. Additionally, we evaluated the performance of the speech features that differed between the two groups as single explanatory variables. We found significant differences in almost all elements of the speech spectrum between the two groups. Regarding the intensity, we found significant differences in all the factors except for the standard deviation between the two groups. In the performance evaluation, the areas under the curve revealed by logistic regression analysis were higher for the center of gravity (0.908 ± 0.036), mean skewness (0.904 ± 0.023), kurtosis (0.932 ± 0.023), and standard deviation (0.977 ± 0.012) of the spectra. This study used machine learning to reveal speech features of patients diagnosed with AD in comparison with healthy elderly people. Significant differences were found between the two groups in all components of the spectrum, paving the way for early non-invasive diagnosis of AD in the future.

Repositioning Canagliflozin for Mitigation of Aluminium Chloride-Induced Alzheimer’s Disease: Involvement of TXNIP/NLRP3 Inflammasome Axis, Mitochondrial Dysfunction, and SIRT1/HMGB1 Signalling

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the world. Due to failure of the traditional drugs to produce a complete cure for AD, the search for new safe and effective lines of therapy has attracted the attention of ongoing research. Canagliflozin is an anti-diabetic agent with proven efficacy in the treatment of neurological disorders in which mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy play a pathophysiological role. Elucidation of the potential effects of different doses of canagliflozin on AD induced by aluminium chloride in rats and exploration of the molecular mechanisms that may contribute to these effects were the primary objectives of the current study. Materials and Methods: In a rat model of AD, the effect of three different doses of canagliflozin on the behavioural, biochemical, and histopathological alterations induced by aluminium chloride was assessed. Results: Canagliflozin administered to aluminium chloride-treated animals induced dose-dependent normalisation in the behavioural tests, augmentation of the antioxidant defence mechanisms, inhibition of TXNIP/NLRP3 inflammasome signalling, modulation of the SIRT1/HMGB1 axis, interference with the pro-inflammatory and the pro-apoptotic mechanisms, and restoration of the mitochondrial functions and autophagy in the hippocampal tissues to approximately baseline values. In addition, canagliflozin exhibited an interesting dose-dependent ability to repress aluminium chloride-induced histopathological changes in the brain. Conclusions: The effects of canagliflozin on oxidative stress, mitochondrial functions, inflammatory pathways, and autophagy signals may open new gates towards the mitigation of the pathologic features of AD.

Photobiomodulation as a Potential Treatment for Alzheimer’s Disease: A Review Paper

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life. Objective: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease’s underlying biomechanical mechanisms. Method: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms. Conclusions: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer’s disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.

β-Amyloid impairs Proteasome structure and function. Proteasome activation mitigates amyloid induced toxicity and cognitive deficits.

Alzheimer's Disease (AD) is the leading cause of dementia globally, affecting around 50 million people and marked by cognitive decline and the accumulation of β-amyloid plaques and hyperphosphorylated tau. The limited treatment options and numerous failed clinical trials targeting β-amyloid (Aβ) highlight the need for novel approaches. Lowered proteasome activity is a consistent feature in AD, particularly in the hippocampus. Impaired proteasome function in AD is hypothesized to stem from direct inhibition by β-amyloid or hyperphosphorylated tau, disrupting critical neuronal processes such as memory formation and synaptic plasticity. This study tests the hypothesis that AD related deficits are driven in part by impaired proteasome function as a consequence of inhibition by Aβ. We evaluated how proteasome function is modulated by Aβ and the capacity of two proteasome-activating compounds, TAT1-8,9-TOD and TAT1-DEN to rescue Aβ-induced impairment in vitro, as well as survival deficits in cell culture and Aβ-induced cognitive deficits in Drosophila and mouse models. Our study demonstrates that oligomeric β-amyloid binds to the 20S proteasome and impairs its activity and conformational stability. The oligomers also destabilize the 26S proteasome to release the free 20S proteasome. Treatment with proteasome activators TAT1-8,9TOD and TAT1-DEN rescue the 20S proteasome function and reduces cell death caused by Aβ42 toxicity in SK-N-SH cells. In Drosophila models overexpressing Aβ42, oral administration of proteasome agonists delayed mortality and restored cognitive function. Chronic treatment with TAT1-DEN protected against deficits in working memory caused by Aβ42 in mice and in hAPP(J20) mice with established deficits, acute TAT1-DEN treatment significantly improved spatial learning, with treated mice performing comparably to controls. Aβ has dual impacts on 20S and 26S proteasome function and stability. Proteasome activation using TAT1-8,9TOD and TAT1-DEN shows promise in mitigating AD-like deficits by protecting against amyloid toxicity and enhancing proteasome function. These findings suggest that targeting proteasome activity could be a viable therapeutic approach for AD, warranting further investigation into the broader impacts of proteasome modulation on AD pathology.

Cerebral hyperactivation across the Alzheimer's disease pathological cascade.

Neuronal dysfunction in specific brain regions or across distributed brain networks is a known feature of Alzheimer's disease. An often reported finding in the early stage of the disease is the presence of increased functional MRI (fMRI) blood oxygenation level-dependent signal under task conditions relative to cognitively normal controls, a phenomenon known as 'hyperactivation'. However, research in the past decades yielded complex, sometimes conflicting results. The magnitude and topology of fMRI hyperactivation patterns have been found to vary across the preclinical and clinical spectrum of Alzheimer's disease, including concomitant 'hypoactivation' in some cases. These incongruences are likely due to a range of factors, including the disease stage at which the cohort is examined, the brain areas or networks studied and the fMRI paradigm utilized to evoke these functional abnormalities. Additionally, a perennial question pertains to the nature of hyperactivation in the context of Alzheimer's disease. Some propose it reflects compensatory mechanisms to sustain cognitive performance, while others suggest it is linked to the pathological disruption of a highly regulated homeostatic cycle that contributes to, or even drives, disease progression. Providing a coherent narrative for these empirical and conceptual discrepancies is paramount to develop disease models, understand the synergy between hyperactivation and the Alzheimer's disease pathological cascade and tailor effective interventions. We first provide a comprehensive overview of functional brain changes spanning the course from normal ageing to the clinical spectrum of Alzheimer's disease. We then highlight evidence supporting a close relationship between fMRI hyperactivation and in vivo markers of Alzheimer's pathology. We primarily focus on task-based fMRI studies in humans, but also consider studies using different functional imaging techniques and animal models. We then discuss the potential mechanisms underlying hyperactivation in the context of Alzheimer's disease and provide a testable framework bridging hyperactivation, ageing, cognition and the Alzheimer's disease pathological cascade. We conclude with a discussion of future challenges and opportunities to advance our understanding of the fundamental disease mechanisms of Alzheimer's disease, and the promising development of therapeutic interventions incorporating or aimed at hyperactivation and large-scale functional systems.

Inhibiting mtDNA transcript translation alters Alzheimer's disease-associated biology.

Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features. To address whether mitochondrial dysfunction alters AD-implicated genes and proteins, we treated SH-SY5Y cells and induced pluripotent stem cell (iPSC)-derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA-generated transcript translation. We characterized adaptive, AD-associated gene, and AD-associated protein responses. SH-SY5Y cells and iPSC neurons responded to mtDNA transcript translation inhibition by increasing mtDNA copy number and transcription. Nuclear-expressed respiratory chain mRNA and protein levels also changed. There were AD-consistent concordant and model-specific changes in amyloid precursor protein, beta amyloid, apolipoprotein E, tau, and α-synuclein biology. Primary mitochondrial dysfunction induces compensatory organelle responses, changes nuclear gene expression, and alters the biology of AD-associated genes and proteins in ways that may recapitulate brain aging and AD molecular phenomena. In AD, mitochondrial dysfunction could represent a disease cause or consequence. We inhibited mitochondrial translation in human neuronal cells and neurons. Mitochondrial and nuclear gene expression shifted in adaptive-consistent patterns. APP, Aβ, APOE, tau, and α-synuclein biology changed in AD-consistent patterns. Mitochondrial stress creates an environment that promotes AD pathology.

TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model.

Alzheimer's disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD. We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia. Chronic LPS treatment led to a significant increase in the number of Iba-1+ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model. These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.

Oxidative Stress in Alzheimer's Disease: The Shortcomings of Antioxidant Therapies.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease's neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability-epitomized by the dictum "no on-site protection, no protection"-and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success.

Application of CRISPR/Cas9 gene-editing technology in Alzheimers disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. It triggers metabolic disorders within the body due to genetic mutations, thus leading to irreversible damage to one's memory and brain. The primary pathogenic features of AD are intracellular neurofibrillary tangles caused by hyperphosphorylated Tau and extracellular amyloid plaques created by the buildup of -amyloid -protein (A). However, up to now, there has been no effective treatment program for Alzheimer's disease. And after a long time of development, many gene editing technologies have been perfected and utilized in practice. Among them, CRISPR-Cas9 technology is the most efficient and practical. As a result, an increasing number of scientists have examined and debated the potential use of CRISPR-Cas9 technology in the management of Alzheimer's disease. This review addresses the use of the CRISPR/Cas9 system to treat Alzheimer's disease and presents the disease's pathophysiology, including the establishment of AD models, genetic screening for the cause of AD, and targeted therapy for AD.

The Gut Microbiota Modulates Neuroinflammation in Alzheimer's Disease: Elucidating Crucial Factors and Mechanistic Underpinnings.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuronal loss, commonly linked to amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Recent research highlights the gut microbiota as a key player in modulating neuroinflammation, a critical pathological feature of AD. Understanding the role of the gut microbiota in this process is essential for uncovering new therapeutic avenues and gaining deeper insights into AD pathogenesis. This review provides a comprehensive analysis of how gut microbiota influences neuroinflammation and glial cell function in AD. A systematic literature search was conducted, covering studies from 2014 to 2024, including reviews, clinical trials, and animal studies. Keywords such as "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "blood-brain barrier" were used. Dysbiosis, or the imbalance in gut microbiota composition, has been implicated in the modulation of key AD-related mechanisms, including neuroinflammation, blood-brain barrier integrity, and neurotransmitter regulation. These disruptions may accelerate the onset and progression of AD. Additionally, therapeutic strategies targeting gut microbiota, such as probiotics, prebiotics, and fecal microbiota transplantation, show promise in modulating AD pathology. The gut microbiota is a pivotal factor in AD pathogenesis, influencing neuroinflammation and disease progression. Understanding the role of gut microbiota in AD opens avenues for innovative diagnostic, preventive, and therapeutic strategies.

Microwave-assisted synthesis of indoloquinoxaline derivatives as promising anti-alzheimer agents: DFT and molecular docking study

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. One of the major pathological features of AD is the degeneration of cholinergic neurons and associated loss of acetylcholine (ACh), a key neurotransmitter involved in memory and cognition. Reduced ACh levels correlate with the severity of cognitive symptoms in AD. Thus, inhibition of acetylcholinesterase (AChE), the enzyme responsible for breaking down ACh, is a leading treatment strategy. This study aimed to synthesize and evaluate novel AChE inhibitors based on an indolo[2,3-b]quinoxaline scaffold. A series of indolo[2,3-b]quinoxaline derivatives were designed by molecular hybridization of indole and quinoxaline privileged structures. Microwave-assisted synthesis improved the efficiency of obtaining the desired compounds. In vitro screening identified several potent AChE inhibitors, with IC50 values down to 0.02 µM. The most active compounds contained electron-withdrawing groups like nitro and benzoyl moieties. DFT calculations provided insights into geometrical, thermal, and electronic properties of the compounds. FMO analysis revealed variations in HOMO and LUMO energies that impact reactivity. Molecular docking elucidated binding modes, highlighting the pi-pi, pi-H, and H-bonding interactions with key amino acids in the catalytic gorge of AChE. Overall, the indole-quinoxaline hybrids represent promising candidates for development of novel dual binding site AChE inhibitors and multifunctional anti-Alzheimer agents.

Exploring the Association between Pro-Inflammation and the Early Diagnosis of Alzheimer’s Disease in Buccal Cells Using Immunocytochemistry and Machine Learning Techniques

The progressive aging of the global population and the high impact of neurodegenerative diseases, such as Alzheimer’s disease (AD), underscore the urgent need for innovative diagnostic and therapeutic strategies. AD, the most prevalent neurodegenerative disorder among the elderly, is expected to affect 75 million people in developing countries by 2030. Despite extensive research, the precise etiology of AD remains elusive due to its heterogeneity and complexity. The key pathological features of AD, including amyloid-beta plaques and hyperphosphorylated tau protein, are established years before clinical symptoms appear. Recent studies highlight the pivotal role of neuroinflammation in AD pathogenesis, with the chronic activation of the brain’s immune system contributing to the disease’s progression. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, are elevated in AD and mild cognitive impairment (MCI) patients, suggesting a strong link between peripheral inflammation and CNS degeneration. There is a pressing need for minimally invasive, cost-effective diagnostic methods. Buccal mucosa cells and saliva, which share an embryological origin with the CNS, show promise for AD diagnosis and prognosis. This study integrates cellular observations with advanced data processing and machine learning to identify significant biomarkers and patterns, aiming to enhance the early diagnosis and prevention strategies for AD.

Aducanumab in Alzheimer's Disease: A Critical Update.

Alzheimer's disease (AD) is a complex neurological disorder that results in cognitive decline. The incidence rates of AD have been increasing, particularly among individuals 60 years of age or older. In June 2021, the US FDA approved aducanumab, the first humanized monoclonal antibody, as a potential therapeutic option for AD. Clinical trials have shown this drug to effectively target the accumulation of Aβ (beta-amyloid) plaques in the brain, and its effectiveness is dependent on the dosage and duration of treatment. Additionally, aducanumab has been associated with improvements in cognitive function. Biogen, the pharmaceutical company responsible for developing and marketing aducanumab, has positioned it as a potential breakthrough for treating cerebral damage in AD. However, the drug has raised concerns due to its high cost, limitations, and potential side effects. AD is a progressive neurological condition that affects memory, cognitive function, and behaviour. It significantly impacts the quality of life of patients and caregivers and strains healthcare systems. Ongoing research focuses on developing disease-modifying therapies that can halt or slow down AD progression. The pathogenesis of AD involves various molecular cascades and signaling pathways. However, the formation of extracellular amyloid plaques is considered a critical mechanism driving the development and progression of the disease. Aducanumab, as a monoclonal antibody, has shown promising results in inhibiting amyloid plaque formation, which is the primary pathological feature of AD. This review explores the signaling pathways and molecular mechanisms through which aducanumab effectively prevents disease pathogenesis in AD.

Path Integration Detects Prodromal Alzheimer's Disease and Predicts Cognitive Decline.

The entorhinal cortex is the very earliest involvement of Alzheimer's disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI-). Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI-. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12-15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD.

Characteristics of Alzheimer’s Disease and Mild Cognitive Impairment Influenced by the Time of Onset

Introduction: Although the prevalence of Alzheimer’s disease (AD) is higher in older people compared to younger people, dementia has also been documented in younger adults. Although early-onset dementia and late-onset dementia had been considered a single disease in pathological investigations, many studies revealed differences in cognitive and neuroimaging changes between them. We evaluated differences in cognitive and neuroimaging changes among the following groups: individuals with early-onset AD (EOAD), late-onset AD (LOAD), early-onset mild cognitive impairment (EOMCI), or late-onset MCI (LOMCI), and healthy controls (HCs). Methods: Patients underwent both a 1.5 Tesla magnetic resonance imaging scan and the Mini-Mental State Examination (MMSE). Differences in regional gray matter volumes and MMSE subscales were investigated among the five diagnostic groups. Results: Compared to the EOAD group, the LOAD group had significantly higher scores on orientation in place. Compared to the LOMCI patients, the EOMCI patients achieved significantly higher recall scores. The LOAD and LOMC groups showed significant volume reductions in bilateral medial temporal regions compared to the HCs. The EOAD and EOMCI groups did not show significant atrophy of the medial temporal region compared to the HC group. Conclusions: The hippocampal volume and memory were preserved in the patients with EOMCI or EOAD compared to those with LOMCI or LOAD. These findings may indicate that the distinct and differing patterns of neuropsychological changes between EOAD and LOAD are also common in MCI, which is intermediate between normal cognition and AD.

Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

ABSTRACT Hyperphosphorylation and aggregation of MAPT (microtubule-associated protein tau) is a pathogenic hallmark of tauopathies and a defining feature of Alzheimer disease (AD). Pathological MAPT/tau is targeted by macroautophagy/autophagy for clearance after being sequestered within autophagosomes, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic deficits have been shown to precede MAPT/tau pathology in tauopathy brains, it is unclear whether energy metabolism deficiency is involved in the pathogenesis of autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy neurons which, strikingly, leads to pronounced MAPT/tau clearance by boosting autophagy functionality through enhancements of mitochondrial biosynthesis and supply of phosphatidylethanolamine for autophagosome biogenesis. Furthermore, early anaplerotic stimulation of OXPHOS elevates autophagy activity and attenuates MAPT/tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of mitochondrial bioenergetic deficiency in tauopathy-related autophagy defects and suggests a new therapeutic strategy to prevent the buildup of pathological MAPT/tau in AD and other tauopathy diseases. Abbreviation: AA: antimycin A; AD, Alzheimer disease; ATP, adenosine triphosphate; AV, autophagosome/autophagic vacuole; AZ, active zone; Baf-A1: bafilomycin A1; CHX, cycloheximide; COX, cytochrome c oxidase; DIV, days in vitro; DRG, dorsal root ganglion; ETN, ethanolamine; FRET, Förster/fluorescence resonance energy transfer; FTD, frontotemporal dementia; Gln, glutamine; HA: hydroxylamine; HsMAPT/Tau, human MAPT; IMM, inner mitochondrial membrane; LAMP1, lysosomal-associated membrane protein 1; LIs, lysosomal inhibitors; MDAV, mitochondria-derived autophagic vacuole; MmMAPT/Tau, murine MAPT; NFT, neurofibrillary tangle; OCR, oxygen consumption rate; Omy: oligomycin; OXPHOS, oxidative phosphorylation; PPARGC1A/PGC-1alpha: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PE, phosphatidylethanolamine; phospho-MAPT/tau, hyperphosphorylated MAPT; PS, phosphatidylserine; PISD, phosphatidylserine decarboxylase;SQSTM1/p62, sequestosome 1; STX1, syntaxin 1; SYP, synaptophysin; Tg, transgenic; TCA, tricarboxylic acid; TEM, transmission electron microscopy.

Brain Microvascular Pericyte Pathology Linking Alzheimer's Disease to Diabetes.

The brain microvasculature, which delivers oxygen and nutrients and forms a critical barrier protecting the central nervous system via capillaries, is deleteriously affected by both Alzheimer's disease (AD) and type 2 diabetes (T2D). T2D patients have an increased risk of developing AD, suggesting potentially related microvascular pathological mechanisms. Pericytes are an ideal cell type to study for functional links between AD and T2D. These specialized capillary-enwrapping cells regulate capillary density, lumen diameter, and blood flow. Pericytes also maintain endothelial tight junctions to ensure blood-brain barrier integrity, modulation of immune cell extravasation, and clearance of toxins. Changes in these phenomena have been observed in both AD and T2D, implicating "pericyte pathology" as a common feature of AD and T2D. This review examines the mechanisms of AD and T2D from the perspective of the brain microvasculature, highlighting how pericyte pathology contributes to both diseases. Our review identifies voids in understanding how AD and T2D negatively impact the brain microvasculature and suggests future studies to examine the intersections of these diseases.