Search

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? Are there specific anxiety symptoms associated with Alzheimer's disease pathologies, amyloid-β and tau, in cognitively unimpaired older adults? • What is the main finding of this study? Greater amyloid-β deposition was associated with higher levels of self-reported worry but not global anxiety, independent of subjective and objective cognition and depression. No associations were found between regional tau deposition and either worry or global anxiety. • What is the meaning of the finding? These findings implicate worry as an early, specific behavioral marker and possible therapeutic target in preclinical AD. Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory–6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD. [ABSTRACT FROM AUTHOR]

Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered—meningeal lymphatic vessels (mLVs)—which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF's actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer's disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging. [ABSTRACT FROM AUTHOR]

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = –0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = –0.035(0.009), p = 0.001), inferior temporal (β (SE) = –0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = –0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology and neuroinflammation. Methods: Within the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline. Results: The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), total tau (T-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), P-tau/Aβ42 ratio (Model 1: PFDR = 0.023; Model 2: PFDR = 0.028), T-tau/Aβ42 ratio (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: PFDR = 0.005; Model 2: PFDR < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), and higher score on the Alzheimer's Disease Assessment Scale (ADAS13, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001). Discussion: The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid‐β (Aβ) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to cell in a prion‐like manner and induce native proteins to become pathological. The entorhinal cortex (EC) is among the earliest areas affected by tau accumulation along with volume reduction and neurodegeneration. Neuron–glia interactions have recently come into focus; however, the role of microglia and astroglia in the pathogenesis of AD remains unclear. Proteomic approaches allow the determination of changes in the proteome to better understand the pathology underlying AD. Bioinformatic analysis of proteomic data was performed to compare ECs from AD and non‐AD human brain tissue. To validate the proteomic results, western blot, immunofluorescence, and confocal studies were carried out. The findings revealed that the most disturbed signaling pathway was synaptogenesis. Because of their involvement in synapse function, relationship with Aβ and tau proteins and interactions in the pathway analysis, three proteins were selected for in‐depth study: HSP90AA1, PTK2B, and ANXA2. All these proteins showed colocalization with neurons and/or astroglia and microglia and with pathological Aβ and tau proteins. In particular, ANXA2, which is overexpressed in AD, colocalized with amoeboid microglial cells and Aβ plaques surrounded by astrocytes. Taken together, the evidence suggests that unbalanced expression of HSP90AA1, PTK2B, and ANXA2 may play a significant role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells in the human EC in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is the most prevalent form of age-related dementia. Even though a century has passed since the discovery of AD, the exact cause of the disease still remains unknown. As a result, this poses a major hindrance in developing effective therapies for treating AD. Glycogen synthase kinase-3 (GSK-3) is one of the kinases that has been investigated recently as a potential therapeutic target for the treatment of AD. It is also known as human tau protein kinase and is a proline-directed serine-threonine kinase. Since dysregulation of this kinase affects all the major characteristic features of the disease, such as tau phosphorylation, amyloid formation, memory, and synaptic function, it is thought to be a major player in the pathogenesis of AD. In this review, we present the most recent information on the role of this kinase in the onset and progression of AD, as well as significant findings that identify GSK-3 as one of the most important targets for AD therapy. We further discuss the potential of treating AD by targeting GSK-3 and give an overview of the ongoing studies aimed at developing GSK-3 inhibitors in preclinical and clinical investigations. [ABSTRACT FROM AUTHOR]

Abstract Background Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. Methods This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. Results A total of 367 participants (48 A + T + , 86 A + T − , 63 A − T + , and 170 A − T − ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T − and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A − T − group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P

BackgroundAlzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear.ObjectiveTo examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition.MethodsIn 586 older adults without dementia, linear regressions tested the interaction between amyloid-β (Aβ) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aβ-PET.ResultsAdjusting for tau-PET, the quadratic effect of WMH interacted with Aβ-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aβ-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure.ConclusionResults suggest that cerebrovascular lesions act synergistically with Aβ to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Mounting evidence suggest that genetic factors play crucial roles in the pathogenesis of AD. The triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for AD. Here, our previous findings and the recent high-quality studies are comprehensively reviewed regarding the association of TREM2 variants with AD risk, the structure, ligand and downstream signaling of TREM2, the involvement of TREM2 in AD progression, and targeting TREM2 for AD treatment. This review will offer further insights into the genetic and pathogenic mechanisms of AD and provide reference for the development of novel AD therapies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We assessed whether macro‐ and/or micro‐structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid‐β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS: Higher global efficiency of the limbic network, as well as free‐water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks. DISCUSSION: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties. Highlights: Aβ and tau were associated with longitudinal memory change over ∼7.5 years.White matter properties attenuated the impact of tau pathology on memory change.Health/risk factors were associated with white matter properties. [ABSTRACT FROM AUTHOR]

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant. Conclusions: The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD. [ABSTRACT FROM AUTHOR]

Background: Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. Methods: This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. Results: A total of 367 participants (48 A + T + , 86 A + T − , 63 A − T + , and 170 A − T − ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T − and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A − T − group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P <.001 for A + T − , and β = 0.889 cm3/year [0.523 to 1.255], P <.001 for A + T + ; PACC: β = − 0.19 /year [− 0.36 to − 0.02], P =.029 for A + T − , and β = − 0.59 /year [− 0.80 to − 0.37], P <.001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = − 2.782 cm3/year [− 4.060 to − 1.504], P <.001), hippocampus (β = − 0.057 cm3/year [− 0.085 to − 0.029], P <.001), and AD-signature regions (β = − 0.02 mm/year [− 0.03 to − 0.01], P <.001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A − T − group (adjusted hazard ratio = 3.35 [1.76 to 6.39]). Conclusions: In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression. [ABSTRACT FROM AUTHOR]

A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer's disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka "nucleolar satellite") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer's, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases. [ABSTRACT FROM AUTHOR]

Cerebrovascular pathology often co-exists with Alzheimer's disease pathology and can contribute to Alzheimer's disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer's disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ɛ4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ɛ4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = −0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = −0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology—in the presence of amyloid-β pathology—modifies tau accumulation in early stages of Alzheimer's disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer’s disease (AD), characterized by the deposition of amyloid-β (Aβ) in senile plaques and neurofibrillary tangles of phosphorylated tau (pTau), is increasingly recognized as a complex disease with multiple pathologies. AD sometimes pathologically overlaps with age-related tauopathies such as four repeat (4R)-tau predominant argyrophilic grain disease (AGD). While AGD is often detected with AD pathology, the contribution of APOE4 to AGD risk is not clear despite its robust effects on AD pathogenesis. Specifically, how APOE genotype influences Aβ and tau pathology in co-occurring AGD and AD has not been fully understood. Using postmortem brain samples (N = 353) from a neuropathologically defined cohort comprising of cases with AD and/or AGD pathology built to best represent different APOE genotypes, we measured the amounts of major AD-related molecules, including Aβ40, Aβ42, apolipoprotein E (apoE), total tau (tTau), and pTau181, in the temporal cortex. The presence of tau lesions characteristic of AD (AD-tau) was correlated with cognitive decline based on Mini-Mental State Examination (MMSE) scores, while the presence of AGD tau lesions (AGD-tau) was not. Interestingly, while APOE4 increased the risk of AD-tau pathology, it did not increase the risk of AGD-tau pathology. Although APOE4 was significantly associated with higher levels of insoluble Aβ40, Aβ42, apoE, and pTau181, the APOE4 effect was no longer detected in the presence of AGD-tau. We also found that co-occurrence of AGD with AD was associated with lower insoluble Aβ42 and pTau181 levels. Overall, our findings suggest that different patterns of Aβ, tau, and apoE accumulation mediate the development of AD-tau and AGD-tau pathology, which is affected by APOE genotype.

Abstract Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson’s disease (PD). We have established an upstream effect of DAPK1 on Aβ and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aβ deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders.

Recent studies have demonstrated that neuroplasticity, such as synaptic plasticity and neurogenesis, exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease. Hence, promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated. Due to their significant ability to self-renew, differentiate, and migrate, neural stem cells play an essential role in reversing synaptic and neuronal damage, reducing the pathology of Alzheimer’s disease, including amyloid-β, tau protein, and neuroinflammation, and secreting neurotrophic factors and growth factors that are related to plasticity. These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain. Consequently, neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases. In this review, we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.

Alzheimer's disease (AD), characterized by the deposition of amyloid-β (Aβ) in senile plaques and neurofibrillary tangles of phosphorylated tau (pTau), is increasingly recognized as a complex disease with multiple pathologies. AD sometimes pathologically overlaps with age-related tauopathies such as four repeat (4R)-tau predominant argyrophilic grain disease (AGD). While AGD is often detected with AD pathology, the contribution of APOE4 to AGD risk is not clear despite its robust effects on AD pathogenesis. Specifically, how APOE genotype influences Aβ and tau pathology in co-occurring AGD and AD has not been fully understood. Using postmortem brain samples (N = 353) from a neuropathologically defined cohort comprising of cases with AD and/or AGD pathology built to best represent different APOE genotypes, we measured the amounts of major AD-related molecules, including Aβ40, Aβ42, apolipoprotein E (apoE), total tau (tTau), and pTau181, in the temporal cortex. The presence of tau lesions characteristic of AD (AD-tau) was correlated with cognitive decline based on Mini-Mental State Examination (MMSE) scores, while the presence of AGD tau lesions (AGD-tau) was not. Interestingly, while APOE4 increased the risk of AD-tau pathology, it did not increase the risk of AGD-tau pathology. Although APOE4 was significantly associated with higher levels of insoluble Aβ40, Aβ42, apoE, and pTau181, the APOE4 effect was no longer detected in the presence of AGD-tau. We also found that co-occurrence of AGD with AD was associated with lower insoluble Aβ42 and pTau181 levels. Overall, our findings suggest that different patterns of Aβ, tau, and apoE accumulation mediate the development of AD-tau and AGD-tau pathology, which is affected by APOE genotype. [ABSTRACT FROM AUTHOR]

Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising antemortem MRI and postmortem histopathology to assess polypathologic associations with atrophy in a clinically heterogeneous sample of 125 human dementia patients (41 female, 84 male) with T1-weighted MRI=5 years before death and postmortem ordinal ratings of amyloid-β, tau, TDP-43, and α-synuclein. Regional volumes were related to pathology using linear mixed-effects models; approximately 25% of data were held out for testing. We contrasted a polypathologic model comprising independent factors for each proteinopathy with two alternatives: a model that attributed atrophy entirely to the protein(s) associated with the patient's primary diagnosis and a protein-agnostic model based on the sum of ordinal scores for all pathology types. Model fits were evaluated using log-likelihood and correlations between observed and fitted volume scores. Additionally, we performed exploratory analyses relating atrophy to gliosis, neuronal loss, and angiopathy. The polypathologic model provided superior fits in the training and testing datasets. Tau, TDP-43, and α-synuclein burden were inversely associated with regional volumes, but amyloid-β was not. Gliosis and neuronal loss explained residual variance in and mediated the effects of tau, TDP-43, and α-synuclein on atrophy. Regional brain atrophy reflects not only the primary molecular pathology but also co-occurring proteinopathies; inflammatory immune responses may independently contribute to degeneration. Our findings underscore the importance of antemortem biomarkers for detecting mixed pathology. [ABSTRACT FROM AUTHOR]

Protein misfolding disorders are a group of diseases characterized by supra-physiologic accumulation and aggregation of pathogenic proteoforms resulting from improper protein folding and/or insufficiency in clearance mechanisms. Although these processes have been historically linked to neurodegenerative disorders, such as Alzheimer's disease, evidence linking protein misfolding to other pathologies continues to emerge. Indeed, the deposition of toxic protein aggregates in the form of oligomers or large amyloid fibrils has been linked to type 2 diabetes, various types of cancer, and, in more recent years, to preeclampsia, a life-threatening pregnancy-specific disorder. While extensive physiological mechanisms are in place to maintain proteostasis, processes, such as aging, genetic factors, or environmental stress in the form of hypoxia, nutrient deprivation or xenobiotic exposures can induce failure in these systems. As such, pregnancy, a natural physical state that already places the maternal body under significant physiological stress, creates an environment with a lower threshold for aberrant aggregation. In this review, we set out to discuss current evidence of protein misfolding in pregnancy and potential mechanisms supporting a key role for this process in preeclampsia pathogenesis. Improving our understanding of this emerging pathophysiological process in preeclampsia can lead to vital discoveries that can be harnessed to create better diagnoses and treatment modalities for the disorder. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by several pathological hallmarks, including the deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier (BBB) dysfunction, increased oxidative stress, and neuroinflammation. Current treatment options include monoclonal antibody drugs, acetylcholinesterase, and n-methyl-d-aspartate (NMDA) antagonists. Although those treatments provide some improvements in patients' quality of life, they fail to prevent or cure AD. Current research aims to identify novel targets and tools for AD prevention and modification. In this context, several studies showed the beneficial effect of the Mediterranean diet in the prevention and treatment of AD. One integral component of the Mediterranean diet is olive oil and extra-virgin olive oil (EVOO), which is high in phenolic compounds. EVOO and other olive-related phenolic compounds have been shown to reduce the risk of developing mild cognitive impairment (MCI) and AD. In this review, we discuss the mechanisms by which EVOO and phenolic compounds exert neuroprotective effects, including modulation of AD pathologies and promotion of cognitive health. Findings indicate that EVOO and its phenolic constituents influence key pathological processes of AD, such as Aβ aggregation, tau phosphorylation, and neuroinflammation, while also enhancing BBB integrity and reducing oxidative stress. The human studies cited reveal a consistent trend where the consumption of olive oil is associated with cognitive benefits and a decreased risk of AD and related dementias. In conclusion, EVOO and its phenolic compounds hold promising potential for the prevention and treatment of AD, representing a significant shift towards more effective strategies against this complex neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson's disease (PD). We have established an upstream effect of DAPK1 on Aβ and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aβ deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders. [ABSTRACT FROM AUTHOR]

Pathologies characteristic of Alzheimer's disease (i.e., hyperphosphorylated tau and amyloid-β (Aβ) plaques), cardiovascular disease, and limbic predominant TDP-43 encephalopathy (LATE) often co-exist in patients with Parkinson's disease (PD), in addition to Lewy body pathology (α-synuclein). Numerous studies point to a putative synergistic relationship between hyperphosphorylation tau, Aβ, cardiovascular lesions, and TDP-43 with α-synuclein, which may alter the stereotypical pattern of pathological progression and accelerate cognitive decline. Here we discuss the prevalence and relationships between common concomitant pathologies observed in PD. In addition, we highlight shared genetic risk factors and developing biomarkers that may provide better diagnostic accuracy for patients with PD that have co-existing pathologies. The tremendous heterogeneity observed across the PD spectrum is most likely caused by the complex interplay between pathogenic, genetic, and environmental factors, and increasing our understanding of how these relate to idiopathic PD will drive research into finding accurate diagnostic tools and disease modifying therapies. [ABSTRACT FROM AUTHOR]

Background: The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. Objective: To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. Methods: A total of 989 non-demented ADNI participants were included. The associations of APOEɛ2 and APOEɛ4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aβ mediated the associations between APOE genotypes and tau. Results: APOEɛ2 carriers only showed higher Aβ levels (β [95% CI] = 0.07 [0.01, 0.13], p = 0.026). Conversely, APOEɛ4 carriers exhibited lower Aβ concentration (β [95% CI] = –0.27 [–0.31, –0.24], p < 0.001), higher t-Tau (β [95% CI] = 0.25 [0.08, 0.18], p < 0.001) and higher p-Tau (β [95% CI] = 0.31 [0.25, 0.37], p < 0.001). Subgroup analysis showed that APOE ɛ2 was significantly positively associated with Aβ only in females (β [95% CI] = 0.12 [0.04, 0.21], p = 0.005) and older people (β [95% CI] = 0.06 [0.001, 0.12], p = 0.048). But the effects of APOE ɛ4 were independent of gender and age. Besides, the associations of APOE ɛ4 with t-Tau and p-Tau were both mediated by baseline Aβ. Conclusions: Our data suggested that APOEɛ2 could promote Aβ clearance, while the process could be modified by sex and age. However, APOEɛ4 might cause the accumulation of Aβ and tau pathology independent of sex and age. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is currently the most prevalent neurological disease, and no effective and practical treatments and therapies exist. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (NLRP3) inflammasome is vital in the human innate immune response. However, when the NLRP3 inflammasome is overactivated by persistent stimulation, several immune-related diseases, including AD, atherosclerosis, and obesity, result. This review will focus on the composition and activation mechanism of the NLRP3 inflammasome, the relevant mechanisms of involvement in the inflammatory response to AD, and AD treatment targeting NLRP3 inflammasome. This review aims to reveal the pathophysiological mechanism of AD from a new perspective and provide the possibility of more effective and novel strategies for preventing and treating AD. [ABSTRACT FROM AUTHOR]

The search for effective treatment for neurodegeneration implies attacking the multiple mechanisms of this pathology. Such properties were found in disaccharide trehalose, which shows therapeutic effects in models of many diseases and has been approved by the FDA for use in humans. Trehalose consists of two glucose residues bonded together by a flexible α-1-1'-glycosidic bond, giving it chaperone-like activity. Due to this, it prevents abnormal folding of aberrant proteins and has the properties of a cryo- and bioprotector. However, the main therapeutic effect is determined by the induction of mTOR-independent autophagy mediated by AMPK kinase as the main target. The result is a weakening of the accumulation of cytotoxic proteins and factors and an increase in cell viability. Autophagy activation depends on trehalose-induced lysosome and autophagosome biogenesis through activation of transcription factors TFEB and FOXO1. Trehalose has an anti-inflammatory effect closely related to the inhibition of oxidative stress. Trehalose-induced enhancement of endogenous antioxidant defense involves the regulator Nrf2. The review considers the neuroprotective effects of trehalose in models of major neurodegenerative diseases such as Parkinson's, Alzheimer's, Huntington's and others. Overall, trehalose shows high therapeutic potential in the treatment of experimental neurodegeneration and thus stimulating the study of its clinical application. [ABSTRACT FROM AUTHOR]

Background: The role of amyloid-β (Aβ) and tau in reversion and conversion in patients with mild cognitive impairment (MCI) remains unclear. This study aimed to investigate the influence of cerebrospinal fluid (CSF) Aβ and tau on reversion and conversion and the temporal sequence of their pathogenicity in MCI patients. Methods: 179 MCI patients were recruited from the Alzheimer's Disease Neuroimaging Initiative database and classified into two groups based on cognitive changes after follow-up: reversal group (MCI to cognitively normal) and conversion group (MCI to Alzheimer's disease). CSF biomarkers and cognitive function were measured at baseline and 2-year follow-up. Partial correlation was used to analyze the association between CSF biomarkers and cognitive function, and multivariable logistic regression to identify independent risk factors for cognitive changes at baseline and 2-year follow-up. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive ability of these risk factors for cognitive changes. Results: The differences in cognitive function and CSF biomarkers between the two groups remained consistent with baseline after 2-year follow-up. After controlling for confounding variables, there was still a correlation between CSF biomarkers and cognitive function at baseline and 2-year follow-up. Multivariable regression analysis found that at baseline, only Aβ level was independently associated with cognitive changes, while Aβ and tau were both predictive factors after 2-year follow-up. ROC curve analysis revealed that the combination of Aβ and tau [area under the curve (AUC) 0.91, sensitivity 84%, specificity 86%] in predicting cognitive changes after 2-year follow-up had better efficacy than baseline Aβ alone (AUC 0.81). Conclusion: Aβ may precede Tau in causing cognitive changes, and the interaction between the two mediates cognitive changes in patients. This study provides new clinical evidence to support the view that Aβ pathology precedes tau pathology, which together contribute to the changes in cognitive function.

Mechanisms underlying the initial accumulation of tau pathology across the human brain are largely unknown. We examined whether baseline factors including age, amyloid-β (Aβ), and neural activity predicted longitudinal tau accumulation in temporal lobe regions that reflect distinct stages of tau pathogenesis. Seventy cognitively normal human older adults (77 ± 6 years, 59% female) received two or more 18F-flortaucipir (FTP) and 11C-Pittsburgh Compound B (PiB) PET scans (mean follow-up, 2.5 ± 1.1 years) to quantify tau and (Aβ). Linear mixed-effects models were used to calculate the slopes of FTP change in entorhinal cortex (EC), parahippocampal cortex (PHC), and inferior temporal gyrus (IT), and slopes of global PiB change. Thirty-seven participants underwent functional MRI to measure baseline activation. Older age predicted EC tau accumulation, and baseline EC tau levels predicted subsequent tau accumulation in EC and PHC. In IT, however, baseline EC tau interacted with Aβ to predict IT tau accumulation. Higher baseline local activation predicted tau accumulation within EC and PHC, and higher baseline hippocampal activation predicted EC tau accumulation. Our findings indicate that factors predicting tau accumulation vary as tau progresses through the temporal lobe. Older age is associated with initial tau accumulation in EC, while baseline EC tau and neural activity drive tau accumulation within medial temporal lobe. Aβ subsequently facilitates tau spread from medial to lateral temporal lobe. Our findings elucidate potential drivers of tau accumulation and spread in aging, which are critical for understanding Alzheimer's disease pathogenesis.SIGNIFICANCE STATEMENT To further understand the mechanisms leading to tau pathogenesis and spread, we tested whether baseline factors such as age, amyloid-β pathology, and activation predicted longitudinal tau accumulation in cognitively normal older adults. We found that distinct mechanisms contribute to tau accumulation as tau progresses across the temporal lobe, with initial tau accumulation in entorhinal cortex driven by age and subsequent spread driven by neural activity and amyloid-β. We demonstrate that higher baseline activation predicts increased longitudinal tau accumulation, providing novel evidence that activation-dependent tau production may occur in the human brain. Our findings support major hypotheses generated from preclinical research, and have important translational implications, suggesting that the reduction of hyperactivation may help prevent the development of tau pathology.

BackgroundStudies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.MethodsOur sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.ResultsTotal and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = -2.10 [-3.97 to -0.27], p = 0.027 and β = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).ConclusionsMMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ deposition, tauopathy, neuroinflammation, and impaired cognition. The recent identification of associations between protein kinases and AD pathology has spurred interest in tyrosine kinase inhibitors (TKIs) as potential strategic therapeutic agents for AD. In the present study, we investigated whether the TKIs ibrutinib, PD180970, and cabozantinib, which have different on-targets, selectively regulate AD pathology in 3.5- to 4-month-old 5xFAD mice (a model of the early phase of AD). Ibrutinib (10 mg/kg, i.p.) effectively reduced amyloid-β (Aβ) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aβ plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib (10 mg/kg, i.p.) had no effect on amyloidopathy but partially relieved tau hyperphosphorylation and astrogliosis. Taken together, our results suggest that not all TKIs have therapeutic effects on AD pathology in a mouse model of AD. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics.

The lack of effective therapies that slow the progression of Alzheimer's disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular pathways regulating proteostasis and stress response in these organisms facilitates the study of genetic factors that contribute to, or protect against, neurodegeneration. Here, we review genetic modifiers of neurodegeneration and related cellular pathways identified in the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, focusing on models of AD and related tauopathies. We further address the potential of simple model systems to better understand the fundamental mechanisms that lead to AD and other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism of action remains unclear. By studying CSF biomarkers reflecting different types of AD-related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers. Methods: The study population consisted of 229 AD patients for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. This included 28 PTC mutation and 16 pathogenic expansion carriers. CSF levels of Aβ1–42, Aβ1–40, P-tau181, T-tau, sAPPα, sAPPβ, YKL-40, and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers and the Aβ ratio between AD patients with or without an ABCA7 PTC mutation or expansion using linear regression on INT-transformed data with APOE-status, age and sex as covariates. Results: Carriers of ABCA7 expansion mutations had significantly lower Aβ1–42 levels (P = 0.022) compared with non-carrier patients. The effect of the presence of ABCA7 mutations on CSF levels was especially pronounced in APOE ε4-negative carriers. In addition, VNTR expansion carriers had reduced Aβ1–40 (P = 0.023), sAPPα (P = 0.047), sAPPβ (P = 0.016), and YKL-40 (P = 0.0036) levels. Conclusions: Our results are suggestive for an effect on APP processing by repeat expansions given the changes in the amyloid-related CSF biomarkers that were found in carriers. The decrease in YKL-40 levels in expansion carriers moreover suggests that these patients potentially have a reduced inflammatory response to AD damage. Moreover, our findings suggest the existence of a mechanism, independent of lowered expression, affecting neuropathology in expansion carriers. [ABSTRACT FROM AUTHOR]

Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene‐based optical ligands, denoted bi‐thiophene‐vinyl‐benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimer's disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid‐β (Aβ), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene‐vinylene building block displayed selectivity to aggregated Aβ pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD. [ABSTRACT FROM AUTHOR]

Background: Impaired gait can precede dementia. The associations between gait parameters and brain pathologies are therefore of interest. Objective: To explore how different brain pathologies (i.e., vascular and Alzheimer's) are associated with specific gait parameters from various gait components in persons with mild cognitive impairment (MCI), who have an increased risk of developing dementia. Methods: This cross-sectional study included 96 patients with MCI (mean 72, ±7.5 years; 52% women). Gait was evaluated by using an electronic walkway, GAITRite®. Four gait parameters (step velocity variability; step length; step time; stance time asymmetry) were used as dependent variables in multivariable linear regression analyses. Independent variables included Alzheimer's disease pathologies (amyloid-β and tau) by using PET imaging and white matter hyperintensities (WMH) by using MRI. Covariates included age, sex, comorbidities (and intracranial volume in analyses that includedWMH). Results: Increased tau-PET (Braak I–IV region of interest [ROI]) was associated with step velocity variability (standardized regression coefficient, β= 0.383, p < 0.001) and step length (β= 0.336, p < 0.001), which remained significant when using different Braak ROIs (I-II, III-IV, V-VI). The associations remained significant when adjusting for WMH (p < 0.001). When also controlling for gait speed, tau was no longer significantly (p = 0.168) associated with an increased step length. No significant associations between gait and Aβ-PET load or WMH were identified. Conclusions: The results indicate that one should pay specific attention to assess step velocity variability when targeting single task gait in patients with MCI. Future studies should address additional gait variability measures and dual tasking in larger cohorts. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed. METHODS: We assessed the diagnostic performance of p‐tau181, p‐tau217, and p‐tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid‐PET and tau‐PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid‐PET and tau‐PET positivity. RESULTS: Plasma p‐tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p‐tau. Plasma p‐tau181 (AUC = 76%) and p‐tau231 (AUC = 82%) assessments performed inferior to CSF p‐tau181 (AUC = 87%) and p‐tau231 (AUC = 95%) for amyloid‐PET positivity. However, plasma p‐tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid‐PET positivity. DISCUSSION: Plasma and CSF p‐tau217 had equivalent diagnostic performance for biomarker‐defined AD. Our results suggest that plasma p‐tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD. Highlights: p‐tau217 in plasma performed equivalent to p‐tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p‐tau217 is not offset by lower accuracy.p‐tau biomarkers in plasma had lower mean fold‐changes between amyloid‐PET negative and positive groups than p‐tau biomarkers in CSF.CSF p‐tau biomarkers had greater effect sizes than plasma p‐tau biomarkers when differentiating between amyloid‐PET positive and negative groups.Plasma p‐tau181 and plasma p‐tau231 performed worse than p‐tau181 and p‐tau231 in CSF for AD diagnosis. [ABSTRACT FROM AUTHOR]

Background: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. Methods: We examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. Results: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. Conclusions: Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. Trial registration: NCT02798185. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without a cure. Innovative disease models, such as induced neurons (iNs), could enhance our understanding of AD mechanisms and accelerate treatment development. However, a review of AD human iN studies is necessary to consolidate knowledge. Objective: The objective of this review is to examine the current body of literature on AD human iN cells and provide an overview of the findings to date. Methods: We searched two databases for relevant studies published between 2010 and 2023, identifying nine studies meeting our criteria. Results: Reviewed studies indicate the feasibility of generating iNs directly from AD patients' fibroblasts using chemical induction or viral vectors. These cells express mature neuronal markers, including MAP-2, NeuN, synapsin, and tau. However, most studies were limited in sample size and primarily focused on autosomal dominant familial AD (FAD) rather than the more common sporadic forms of AD. Several studies indicated that iNs derived from FAD fibroblasts exhibited abnormal amyloid-β metabolism, a characteristic feature of AD in humans. Additionally, elevated levels of hyperphosphorylated tau, another hallmark of AD, were reported in some studies. Conclusion: Although only a limited number of small-scale studies are currently available, AD patient-derived iNs hold promise as a valuable model for investigating AD pathogenesis. Future research should aim to conduct larger studies, particularly focusing on sporadic AD cases, to enhance the clinical relevance of the findings for the broader AD patient population. Moreover, these cells can be utilized in screening potential novel treatments for AD. [ABSTRACT FROM AUTHOR]

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = −0.37, P = 0.03) and memory functioning (β = −0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = −0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = −0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs. [ABSTRACT FROM AUTHOR]

BackgroundDepressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.ObjectiveThe study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.MethodsParticipants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.ResultsDepressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).ConclusionAlthough longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ deposition, tauopathy, neuroinflammation, and impaired cognition. The recent identification of associations between protein kinases and AD pathology has spurred interest in tyrosine kinase inhibitors (TKIs) as potential strategic therapeutic agents for AD. In the present study, we investigated whether the TKIs ibrutinib, PD180970, and cabozantinib, which have different on-targets, selectively regulate AD pathology in 3.5- to 4-month-old 5xFAD mice (a model of the early phase of AD). Ibrutinib (10 mg/kg, i.p.) effectively reduced amyloid-β (Aβ) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aβ plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib (10 mg/kg, i.p.) had no effect on amyloidopathy but partially relieved tau hyperphosphorylation and astrogliosis. Taken together, our results suggest that not all TKIs have therapeutic effects on AD pathology in a mouse model of AD. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics. [ABSTRACT FROM AUTHOR]

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]