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Background: There is evidence that chronic exercise can benefit the brain, but the effects vary markedly between studies. One potential mechanism for exercise-related benefit is the increase in systemic lactate concentration that is well-characterized to occur during exercise. Lactate is known to cross the blood brain barrier and can be used readily as a fuel for neurons. This may be particularly important in Alzheimer's Disease, which is characterized by cerebral hypometabolism. However, little is known about how whole-body lactate metabolism differs between older adults and individuals with cognitive impairment. This information is critical when considering potential differences in responses to exercise in various cognitive diagnosis groups., Methods: Here we describe the use of a "lactate clamp" procedure to adjust blood lactate levels to approximate those achieved during exercise, but while at rest. This trial will compare lactate oxidation between cognitively healthy older adults and cognitively impaired participants. We will further evaluate the effect of acute lactate infusion on cognitive performance., Discussion: The findings of the study described here, the Lactate for Energy and Neurocognition trial (clinicaltrials.gov # NCT05207397) will add to our understanding of systemic lactate mechanics in cognitively healthy older adults and individuals with Alzheimer's Disease. These findings will be applicable to ongoing exercise trials and to future studies aimed at modulating systemic bioenergetic function in aging and Alzheimer's Disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, we performed high-throughput steady-state metabolite profiling on heads in wildtype Drosophila and in Drosophila models relevant to AD and PD. Intriguingly, we found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. Our findings support a "two-hit model" to explain the pathological manifestations associated with AD where both aging- and Tau/Synuclein- driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Emerging studies suggest that Wnt signaling is dysregulated in the brains of AD patients, suggesting that this pathway may also contribute to disease progression. However, it remains to be determined whether alterations in the Wnt pathway are the cause or consequence of this disease and which elements of Wnt signaling mainly contribute to the appearance of AD histopathological markers early in disease compared to what occurs during normal aging. The present study aimed to describe the status of several canonical Wnt pathway components and the expression of the AD marker p-tau in the hippocampi of female and male 3xTg-AD mice during disease progression compared to those during normal aging. We analyzed the levels of the canonical Wnt components Wnt7a, Dkk-1, LRP6 and GSK3β as well as the levels of p-tau and BDNF at 3, 6, 9-12 and 18 months of age. We found a gradual increase in Dkk-1 levels during aging prior to Wnt7a and LRP5/6 depletion, which was strongly exacerbated in 3xTg-AD mice even at young ages and correlated with GSK3β activation and p-tau-S202/Thr205 expression. Dkk-1 upregulation, as well as the level of p-tau, was significantly greater in females than in males. Our results suggest that Dkk-1 upregulation is involved in the expression of several features of AD at early stages, which supports the possibility of positively modulating the canonical Wnt pathway as a therapeutic tool to delay this disease at early stages., (© 2024. The Author(s).)

The hypothalamus plays an important role in aging, but it remains unclear regarding the underlying epigenetics and whether this hypothalamic basis can help address aging-related diseases. Here, by comparing mouse hypothalamus with two other limbic system components, we show that the hypothalamus is characterized by distinctively high-level DNA methylation during young age and by the distinct dynamics of DNA methylation and demethylation when approaching middle age. On the other hand, age-related DNA methylation in these limbic system components commonly and sensitively applies to genes in hypothalamic regulatory pathways, notably oxytocin (OXT) and gonadotropin-releasing hormone (GnRH) pathways. Middle age is associated with transcriptional declines of genes which encode OXT, GnRH and signaling components, which similarly occur in an Alzheimer's disease (AD)-like model. Therapeutically, OXT-GnRH combination is substantially more effective than individual peptides in treating AD-like disorders in male 5×FAD model. In conclusion, the hypothalamus is important for modeling age-related DNA methylation and developing hypothalamic strategies to combat AD., (© 2024. The Author(s).)

While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer's disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ) peptide is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans, we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a mechanism by which CTSB aggravates Aβ-mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

ANRIL is known as a lncRNA that has many linear and circular isoforms and its polymorphisms are observed to be associated with the pathogenesis of many diseases including age-related diseases. Age-related diseases including atherosclerosis, ischemic heart disease, and Alzheimer's and Parkinson's disease are the most common cause of mortality in both developed and undeveloped countries and that is why a better understanding of their pathogenesis and underlying mechanisms is necessary for controlling their healthcare burden.In this review, we aim to gather the data of researches which have investigated the role of ANRIL in aging and its related diseases. The conclusions of this paper might give a new insight for decreasing the mortality rate of these diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Loss of proteostasis is a highly conserved feature of aging across model organisms and results in the accumulation of insoluble protein aggregates. Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven generalized protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. Specifically, we uncovered that Aβ expression drives proteome-wide protein insolubility in C. elegans, even in young animals, and this insoluble proteome is highly similar to the insoluble proteome driven by normal aging, this vulnerable sub-proteome we term the core insoluble proteome (CIP). We show that the CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedforward cycle in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the geroprotective, gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases., (© 2024. The Author(s).)

Purpose: Alzheimer's disease (AD) is the most common form of tauopathy that usually occursduring aging and unfolded protein response (UPR), oxidative stress and autophagy play a crucialrole in tauopathy-induced neurotoxicity. The aim of this study was to investigate the effects oftauopathy on normal brain aging in a Drosophila model of AD., Method: We investigated the interplay between aging (10, 20, 30, and 40 days) and human tauR406W (htau)-induced cell stress in transgenic fruit flies., Results: Tauopathy caused significant defects in eye morphology, a decrease in motor function and olfactory memory performance (after 20 days), and an increase in ethanol sensitivity (after 30 days). Our results showed a significant increase in UPR (GRP78 and ATF4), redox signalling (p-Nrf2, total GSH, total SH, lipid peroxidation, and antioxidant activity), and regulatory associated protein of mTOR complex 1 (p-Raptor) activity in the control group after 40 days, while the tauopathy model flies showed an advanced increase in the above markers at 20 days of age. Interestingly, only the control flies showed reduced autophagy by a significant decrease in the autophagosome formation protein (dATG1)/p-Raptor ratio at 40 days of age. Our results were also confirmed by bioinformatic analysis of microarray data from tauPS19 transgenic mice (3, 6, 9, and 12 months), in which tauopathy increased expression of heme oxygenase 1, and glutamate-cysteine ligase catalytic subunit and promote aging in transgenic animals., Conclusions: Overall, we suggest that the neuropathological effects of tau aggregates may be accelerated brain aging, where redox signaling and autophagy efficacy play an important role.

Low aerobic capacity is strongly associated with all-cause mortality and risk for Alzheimer's disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aβ 42 ) and tau hyperphosphorylation (pTau thr181 /total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aβ42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging., (© 2024. The Author(s).)

Sodium serves as one of the primary cations in the central nervous system, playing a crucial role in maintaining normal brain function. In this study, we investigated alterations in sodium concentrations in the brain and/or cerebrospinal fluid across multiple models, including an aging model, a stroke model, a nitroglycerin (NTG)-induced rat migraine model, a familial hemiplegic migraine type 2 (FHM2) mouse model, and a transgenic mouse model of Alzheimer's disease (AD). Our results reveal that older rats exhibited higher sodium concentrations in cerebrospinal fluid (CSF), plasma, and various brain regions compared to their younger counterparts. Additionally, findings from the stroke model demonstrated a significant increase in sodium in the ischemic/reperfused region, accompanied by a decrease in potassium and an elevated sodium/potassium ratio. However, we did not detect significant changes in sodium in the NTG-induced rat migraine model or the FHM2 mouse model. Furthermore, AD transgenic mice showed no significant differences in sodium levels compared to wild-type mice in CSF, plasma, or the hippocampus. These results underscore the nuanced regulation of sodium homeostasis in various neurological conditions and aging, providing valuable insights into potential mechanisms underlying these alterations., (© 2024. The Author(s).)

Alzheimer's disease (AD) has recently been associated with diverse cell states 1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Aging, a complex and profound journey, leads us through a labyrinth of physiological and pathological transformations, rendering us increasingly susceptible to aging-related diseases. Emerging investigations have unveiled the function of bromodomain containing protein 4 (BRD4) in manipulating the aging process and driving the emergence and progression of aging-related diseases., Aim of Review: This review aims to offer a comprehensive outline of BRD4's functions involved in the aging process, and potential mechanisms through which BRD4 governs the initiation and progression of various aging-related diseases., Key Scientific Concepts of Review: BRD4 has a fundamental role in regulating the cell cycle, apoptosis, cellular senescence, the senescence-associated secretory phenotype (SASP), senolysis, autophagy, and mitochondrial function, which are involved in the aging process. Several studies have indicated that BRD4 governs the initiation and progression of various aging-related diseases, including Alzheimer's disease, ischemic cerebrovascular diseases, hypertension, atherosclerosis, heart failure, aging-related pulmonary fibrosis, and intervertebral disc degeneration (IVDD). Thus, the evidence from this review supports that BRD4 could be a promising target for managing various aging-related diseases, while further investigation is warranted to gain a thorough understanding of BRD4's role in these diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Chronic systemic inflammation (CSI) results in neuroinflammation and neurodegeneration. Cofilin1 is a stress protein that activates microglia and induces neuroinflammation, but its role in CSI at different aging stages remains unidentified. Therefore, the study aims to identify cofilin1 and its upstream regulators LIMK1 and SSH1 after CSI in young-, middle-, and advanced-aged mice. CSI was induced by injecting the male and female mice with a sub-lethal dose of Lipopolysaccharide weekly for six weeks. The results showed that normal male mice did not show cofilin pathway dysregulation, but a significant dysregulation was observed in CSI advanced-aged mice. In females, cofilin1 dysregulation was observed in healthy and CSI advanced-aged mice, while significant cofilin1 dysregulation was observed in middle-aged mice during CSI. Furthermore, cofilin1 pathway dysregulations correlated with Alzheimer's disease (AD) biomarkers in the brain and saliva, astrocyte activation, synaptic degeneration, neurobehavioral impairments, gut-microbiota abnormalities, and circulatory inflammation. These results provide new insights into cofilin1 sex and age-dependent mechanistic differences that might help identify targets for modulating neuroinflammation and early onset of AD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by abnormal accumulation of tau proteins and amyloid-β, leading to neuronal death and cognitive impairment. Recent studies have implicated aging pathways, including dysregulation of tau and cellular senescence in AD pathogenesis. In AD brains, tau protein, which normally stabilizes microtubules, becomes hyperphosphorylated and forms insoluble neurofibrillary tangles. These tau aggregates impair neuronal function and are propagated across the brain's neurocircuitry. Meanwhile, the number of senescent cells accumulating in the aging brain is rising, releasing a pro-inflammatory SASP responsible for neuroinflammation and neurodegeneration. This review explores potential therapeutic interventions for AD targeting tau protein and senescent cells, and tau -directed compounds, senolytics, eliminating senescent cells, and agents that modulate the SASP-senomodulators. Ultimately, a combined approach that incorporates tau-directed medications and targeted senescent cell-based therapies holds promise for reducing the harmful impact of AD's shared aging pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The meninges, choroid plexus (CP) and blood-brain barrier (BBB) are recognized as important gateways for peripheral immune cell trafficking into the central nervous system (CNS). Accumulation of peripheral immune cells in brain parenchyma can be observed during aging and Alzheimer's disease (AD). However, the mechanisms by which peripheral immune cells enter the CNS through these three pathways and how they interact with resident cells within the CNS to cause brain injury are not fully understood. In this paper, we review recent research on T cells recruitment in the brain during aging and AD. This review focuses on the possible pathways through which T cells infiltrate the brain, the evidence that T cells are recruited to the brain, and how infiltrating T cells interact with the resident cells in the CNS during aging and AD. Unraveling these issues will contribute to a better understanding of the mechanisms of aging and AD from the perspective of immunity, and hopefully develop new therapeutic strategies for brain aging and AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aging, a complex biological process, involves the progressive decline of physiological functions across various systems, leading to increased susceptibility to neurodegenerative diseases. In society, demographic aging imposes significant economic and social burdens due to these conditions. This review specifically examines the association of protein glycosylation with aging and neurodegenerative diseases. Glycosylation, a critical post-translational modification, influences numerous aspects of protein function that are pivotal in aging and the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. We highlight the alterations in glycosylation patterns observed during aging, their implications in the onset and progression of neurodegenerative diseases, and the potential of glycosylation profiles as biomarkers for early detection, prognosis, and monitoring of these age-associated conditions, and delve into the mechanisms of glycosylation. Furthermore, this review explores their role in regulating protein function and mediating critical biological interactions in these diseases. By examining the changes in glycosylation profiles associated with each part, this review underscores the potential of glycosylation research as a tool to enhance our understanding of aging and its related diseases.

Epigenetics plays a vital role in aging and Alzheimer's disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, using 3-, 12- and 18- month-old APP/PS1 mice and age matched WT littermates, we conducted a series of memory tests, measured synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters in the hippocampus and prefrontal cortex (PFC). Our results showed impaired recognition and long-term spatial memory in 18-month-old WT mice and impaired recognition, short-term working, and long-term spatial reference memory in 12-and 18- month-old APP/PS1 mice. These memory impairments are associated with changes of synapse-related gene (nr2a, glur1, glur2, psd95) expression, HDAC abundance, and H3K9ac levels; more specifically, increased HDAC2 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during aging and AD progression in the hippocampus. Conversely, increased HDAC3 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during AD progression in the PFC. These findings suggest memory impairments in aging and AD may associated with a differential HDAC modulation of synapse-related gene expression in the brain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Generation and accumulation of amyloid-β (Aβ) protein in the brain are the primary causes of Alzheimer's disease (AD). Alcadeins (Alcs composed of Alcα, Alcβ and Alcγ family) are a neuronal membrane protein that is subject to proteolytic processing, as is Aβ protein precursor (APP), by APP secretases. Previous observations suggest that Alcs are involved in the pathophysiology of Alzheimer's disease (AD). Here, we generated new mouse App NL-F (APP-KI) lines with either Alcα- or Alcβ-deficient background and analyzed APP processing and Aβ accumulation through the aging process. The Alcα-deficient APP-KI (APP-KI/Alcα-KO) mice enhanced brain Aβ accumulation along with increased amyloidogenic β-site cleavage of APP through the aging process whereas Alcβ-deficient APP-KI (APP-KI/Alcβ-KO) mice neither affected APP metabolism nor Aβ accumulation at any age. More colocalization of APP and BACE1 was observed in the endolysosomal pathway in neurons of APP-KI/Alcα-KO mice compared to APP-KI and APP-KI/Alcβ-KO mice. These results indicate that Alcα plays an important role in the neuroprotective function by suppressing the amyloidogenic cleavage of APP by BACE1 in the brain, which is distinct from the neuroprotective function of Alcβ, in which p3-Alcβ peptides derived from Alcβ restores the viability in neurons impaired by toxic Aβ., (© 2024. The Author(s).)

Objectives: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults., Design: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year., Setting: Community-dwelling participants assessed at research visits in an academic medical center., Participants: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6)., Measurements: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment., Results: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aβ, we observed an association between AES-I and inferior temporal tau., Conclusions: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy., Competing Interests: DISCLOSURES Dr. Gad Marshall receives salary support from NIH/NIA R01 AG071074, R01 AG067021, R01 AG053184, R21 AG064413, R42 AG069629, and R21 AG070877. Dr. Marshall also receives salary support for serving as site principal investigator for clinical trials funded by Eisai Inc., Eli Lilly and Company, and Genentech. These relationships are not related to the content in the manuscript. Dr. Catherine Munro has a research fellowship from the Alzheimer's Association (AARF-23-1150240). This relationship is not related to the content in the manuscript. Dr. Jennifer Gatchel receives salary support from NIH/NIA K23AG05880, NIH/NIA R01AG07819. She is paid from the MEDVAMC. These relationships are not relevant to the content of the manuscript. Dr. Kathryn Papp receives support in the form of consulting fees from Cogstate and Novoic. These relationships are not relevant to the content of the manuscript. Dr. Hyun-Sik Yang receives salary support from NIH/NIA K23AG062750 and NIH/NIA R01AG080667. This relationship is not relevant to the content of the manuscript. Zoe Katz received support from R01AG065234 in the last 36 months. This relationship is not relevant to the content of the manuscript. Dr. Dorene Rentz receives payments from AAAS and IMPACT AD for lectures/speakership events. She also participates on a Data Safety Monitoring/Advisory Board for Washington University, Northwestern, UC-Davis, and Boston University. These relationships are not relevant to the content of the manuscript. Dr. Keith Johnson receives support from the following: NIH-NIA 5R01AG046396-05. Moreover, he is paid as a consultant for Merck and Novartis. These relationships are not relevant to the content of the manuscript. Dr. Reisa Sperling receives support from the NIH (P01AG036694) as funding to institution. She also has the following grants/contracts: Alzheimer's Association (to institution), NIA (to institution), GHR foundation (to institution), Eli Lilly (research funding on clinical trial sites), Eisai (research funding on clinical trial sites). Moreover, she is paid directly as a consultant for the following companies: AC Immunce, Acumen, Alector, Alnylam, Genetech, Janssen, JOMDD, Nervgen, Neuraly, Neurocentria, Oligomerix, Prothena, Renew, Shionogi, Vigil Neuroscience, Ionis, Vaxxinity, Bristol Myers Squibb. These relationships are not related to the content in the manuscript. Dr. Yakeel Quiroz receives support from the following grants/contracts: Alzheimer's Association, NIA, Massachusetts General Hospital ECOR which are all paid to her institution. She also has payment support from Biogen. These relationships are not related to the content in the manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Aim: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain., Methods: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry., Results: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age., Conclusions: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Alzheimer's disease (AD) is characterized by the accumulation of amyloid β and phosphorylated τ protein aggregates in the brain, which leads to the loss of neurons. Under the microscope, the function of mitochondria is uniquely primed to play a pivotal role in neuronal cell survival, energy metabolism, and cell death. Research studies indicate that mitochondrial dysfunction, excessive oxidative damage, and defective mitophagy in neurons are early indicators of AD. This review article summarizes the latest development of mitochondria in AD: 1) disease mechanism pathways, 2) the importance of mitochondria in neuronal functions, 3) metabolic pathways and functions, 4) the link between mitochondrial dysfunction and mitophagy mechanisms in AD, and 5) the development of potential mitochondrial-targeted therapeutics and interventions to treat patients with AD., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Alzheimer's disease (AD) is the most common neurodegenerative disease. The late stage of AD typically develops after 60 years of age and AD pathogenesis can be detected predominately in the frontal lobe, which is responsible for memory. Multiple alterations in cellular mechanisms have been associated with AD, but there is no clear information on AD pathogenesis during brain aging. This study aimed to explore the differentially expressed genes (DEGs) in the frontal lobe of aging brains and to identify shared crucial mechanisms in the aging brain linked to AD pathogenesis. Three datasets were downloaded from the Gene Expression Omnibus (GEO). Biological function analysis was performed by DAVID and KEGG databases. An AD patient's cohort (GSE150696) was collected for verification of the enriched pathway. The results demonstrated that multiple neurochemical synapsis and regulation of the cytoskeleton are linked to AD pathogenesis during aging. Taken together, this study contributes to our further understanding of neural alterations during aging in AD that could be used to develop therapeutics for early intervention to prevent or slow progression., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human brain aging is characterized by the production and deposition of β-amyloid (Aβ) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aβ is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aβ pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aβ deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aβ deposition is the most common Alzheimer's disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.

Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledgebase containing manually curated summary statistics from 98 published tables in 38 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels-at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. Database URL: https://miami-ad.org/., (© The Author(s) 2024. Published by Oxford University Press.)

Ageing is inherent to all human beings, most mechanistic explanations of ageing results from the combined effects of various physiological and pathological processes. Additionally, aging pivotally contributes to several chronic diseases. Activating transcription factor 4 (ATF4), a member of the ATF/cAMP response element-binding protein family, has recently emerged as a pivotal player owing to its indispensable role in the pathophysiological processes of Alzheimer's disease and aging-related diseases. Moreover, ATF4 is integral to numerous biological processes. Therefore, this article aims to comprehensively review relevant research on the role of ATF4 in the onset and progression of aging-related diseases, elucidating its potential mechanisms and therapeutic approaches. Our objective is to furnish scientific evidence for the early identification of risk factors in aging-related diseases and pave the way for new research directions for their treatment. By elucidating the signaling pathway network of ATF4 in aging-related diseases, we aspire to gain a profound understanding of the molecular and cellular mechanisms, offering novel strategies for addressing aging and developing related therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Age is the number one risk factor for developing a neurodegenerative disease (ND), such as Alzheimer's disease (AD) or Parkinson's disease (PD). With our rapidly ageing world population, there will be an increased burden of ND and need for disease-modifying treatments. Currently, however, translation of research from bench to bedside in NDs is poor. This may be due, at least in part, to the failure to account for the potential effect of ageing in preclinical modelling of NDs. While ageing can impact upon physiological response in multiple ways, only a limited number of preclinical studies of ND have incorporated ageing as a factor of interest. Here, we evaluate the aged phenotype and highlight the critical, but unmet, need to incorporate aspects of this phenotype into both the in vitro and in vivo models used in ND research. Given technological advances in the field over the past several years, we discuss how these could be harnessed to create novel models of ND that more readily incorporate aspects of the aged phenotype. This includes a recently described in vitro panel of ageing markers, which could help lead to more standardised models and improve reproducibility across studies. Importantly, we cannot assume that young cells or animals yield the same responses as seen in the context of ageing; thus, an improved understanding of the biology of ageing, and how to appropriately incorporate this into the modelling of ND, will ensure the best chance for successful translation of new therapies to the aged patient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Ferroptosis has been recognized as being closely associated with cognitive impairment. Research has established that Alzheimer's disease (AD)-associated proteins, such as amyloid precursor protein (APP) and phosphorylated tau, are involved in brain iron metabolism. These proteins are found in high concentrations within senile plaques and neurofibrillary tangles. Repetitive transcranial magnetic stimulation (rTMS) offers a non-pharmacological approach to AD treatment. This study aims to explore the potential therapeutic effects of rTMS on cognitive impairment through the modulation of the ferroptosis pathway, thereby laying both a theoretical and experimental groundwork for the application of rTMS in treating Alzheimer's disease., Methods: The study utilized senescence-accelerated mouse prone 8 (SAMP8) mice to model brain aging-related cognitive impairment, with senescence-accelerated-mouse resistant 1 (SAMR1) mice acting as controls. The SAMP8 mice were subjected to high-frequency rTMS at 25 Hz for durations of 14 and 28 days. Cognitive function was evaluated using behavioral tests. Resting-state functional magnetic resonance imaging (rs-fMRI) assessed alterations in cerebral activity by measuring the fractional amplitude of low-frequency fluctuations (fALFF) of the blood oxygen level-dependent signal. Neuronal recovery post-rTMS in the SAMP8 model was examined via HE and Nissl staining. Immunohistochemistry was employed to detect the expression of APP and Phospho-Tau (Thr231). Oxidative stress markers were quantified using biochemical assay kits. ELISA methods were utilized to measure hippocampal levels of Fe 2+ and Aβ1-42. Finally, the expression of proteins related to the ferroptosis pathway was determined through western blot analysis., Results: The findings indicate that 25 Hz rTMS enhances cognitive function and augments cerebral activity in SAMP8 model mice. Treatment with rTMS in these mice resulted in diminished oxidative stress and safeguarded neurons against damage. Additionally, iron accumulation was mitigated, and the expression of ferroptosis pathway proteins Gpx4, system Xc-, and Nrf2 was elevated., Conclusions: The Tau/APP-Fe-GPX4/system Xc-/Nrf2 pathway is implicated in the remedial effects of rTMS on cognitive dysfunction, offering a theoretical and experimental basis for employing rTMS in AD treatment., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest. Data availability statement The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD., Competing Interests: Declaration of Competing Interest There is no conflict of interest to be declared., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Aging and sex are major risk factors for developing late-onset Alzheimer's disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer's disease, no longer consistently exhibit standard Alzheimer's neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer's disease signatures in males and females, which could be harnessed for therapeutic and biomarker development., Methods: We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans (n = 3-8 mice per sex, strain, and age group) and longitudinally assessed neuropathological hallmarks of Alzheimer's disease, markers of hepatic inflammation, splenic mass and morphology, as well as plasma cytokine levels. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and B6129 samples and across ages in each sex. We also examined DEGs between clinical Alzheimer's and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank study in each sex., Results: 3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer's neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and minimal Alzheimer's neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females. Our clinical investigations revealed that individuals with Alzheimer's disease develop similar sex-specific alterations in neuronal and immune function. In diseased males of both species, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide was predicted as the top upstream regulator of DEGs., Conclusions: Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, indicating that age-related changes in immune response contribute to sex differences in Alzheimer's disease trajectories. We provide evidence that aging and transgene-driven disease progression trigger a widespread inflammatory response in 3xTg-AD males, which mimics the impact of lipopolysaccharide stimulation despite the absence of infection., (© 2024. The Author(s).)

Methionine oxidation to the sulfoxide form (MS ox ) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MS ox site occupancy is, in some cases, under enzymatic regulatory control, mediating cellular signaling, including phosphorylation and/or calcium signaling, and raising questions as to the speciation and functional nature of MS ox across the proteome. The 5XFAD lineage of the C57BL/6 mouse has well-defined Alzheimer's and aging states. Using this model, we analyzed age-, sex-, and disease-dependent MS ox speciation in the mouse hippocampus. In addition, we explored the chemical stability and statistical variance of oxidized peptide signals to understand the needed power for MS ox -based proteome studies. Our results identify mitochondrial and glycolytic pathway targets with increases in MS ox with age as well as neuroinflammatory targets accumulating MS ox with AD in proteome studies of the mouse hippocampus. Further, this paper establishes a foundation for reproducible and rigorous experimental MS ox -omics appropriate for novel target identification in biological discovery and for biomarker analysis in ROS and other oxidation-linked diseases.

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related., (© 2024. The Author(s).)

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system., (© 2024. The Author(s).)

Microglia, the brain's resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes. RNA-sequencing of hippocampal microglia revealed more aging-associated changes in female microglia than male microglia, and more sex differences in old microglia than young microglia. Pathway analyses and subsequent validation assays revealed a stronger AKT-mTOR-HIF1α-driven shift to glycolysis among old female microglia and indicated that C3a production and detection was elevated in old microglia, especially in females. Recombinant C3a induced AKT-mTOR-HIF1α signaling and increased the glycolytic and phagocytic activity of young microglia. Single cell analyses attributed the aging-associated sex dimorphism to more abundant disease-associated microglia (DAM) in old female mice than old male mice, and evaluation of an Alzheimer's Disease mouse model revealed that the metabolic and complement changes are also apparent in the context of neurodegenerative disease and are strongest in the neuroprotective DAM2 subset. Collectively, our data implicate autocrine C3a-C3aR signaling in metabolic reprogramming of microglia to neuroprotective DAM during aging, especially in females, and also in Alzheimer's Disease., (© 2024. The Author(s).)

Background: Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD., Methods: We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aβ positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers., Results: OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aβ positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aβ pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR., Discussion: Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Jagust has served as a consultant to Clario, Lilly and Eisai. Dr. Baker consults for Genentech. There are no other disclosures. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Denkinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Alzheimer's disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Neurodegeneration, known as the progressive loss of neurons in terms of their structure and function, is the principal pathophysiological change found in the majority of brain-related disorders. Ageing has been considered the most well-established risk factor in most common neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). There is currently no effective treatment or cure for these diseases; the approved therapeutic options to date are only for palliative care. Ageing and neurodegenerative diseases are closely intertwined; reversing the aspects of brain ageing could theoretically mitigate age-related neurodegeneration. Ever since the regenerative properties of young blood on aged tissues came to light, substantial efforts have been focused on identifying and characterizing the circulating factors in the young and old systemic milieu that may attenuate or accentuate brain ageing and neurodegeneration. Later studies discovered the superiority of old plasma dilution in tissue rejuvenation, which is achieved through a molecular reset of the systemic proteome. These findings supported the use of therapeutic blood exchange for the treatment of degenerative diseases in older individuals. The first objective of this article is to explore the rejuvenating properties of blood-based therapies in the ageing brains and their therapeutic effects on AD. Then, we also look into the clinical applications, various limitations, and challenges associated with blood-based therapies for AD patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aging is the main risk factor for Alzheimer's disease (AD). AD is linked to alterations in metal homeostasis and changes in stable metal isotopic composition can occur, possibly allowing the latter to serve as relevant biomarkers for potential AD diagnosis. Copper stable isotopes are used to investigate changes in Cu homeostasis associated with various diseases. Prior work has shown that in AD mouse models, the accumulation of 63Cu in the brain is associated with the disease's progression. However, our understanding of how the normal aging process influences the brain's isotopic composition of copper remains limited. In order to determine the utility and predictive power of Cu isotopes in AD diagnostics, we aim-in this study-to develop a baseline trajectory of Cu isotopic composition in the normally aging mouse brain. We determined the copper concentration and isotopic composition in brains of 30 healthy mice (WT) ranging in age from 6 to 12 mo, and further incorporate prior data obtained for 3-mo-old healthy mice; this range approximately equates to 20-50 yr in human equivalency. A significant 65Cu enrichment has been observed in the 12-mo-old mice compared to the youngest group, concomitant with an increase in Cu concentration with age. Meanwhile, literature data for brains of AD mice display an enrichment in 63Cu isotope compared to WT. It is acutely important that this baseline enrichment in 65Cu is fully constrained and normalized against if any coherent diagnostic observations regarding 63Cu enrichment as a biomarker for AD are to be developed., (© The Author(s) 2024. Published by Oxford University Press.)

In their recent Nature paper, Oh et al. use 4979 plasma proteins collected across multiple cohorts, publicly available gene expression data, and machine learning models to identify 11 organ-specific aging scores that are linked to organ-specific disease and mortality risk, including heart failure, cognitive decline, and Alzheimer's disease., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Published by Elsevier Ltd.)

The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer's disease risk: the APOE4 allele increases risk, while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in the brain of humans and mice. We hypothesized that the protective effects of APOE2 are, in part, mediated through the endosomal pathway. Messenger RNA analyses showed that APOE2 leads to an enrichment of endosomal pathways in the brain when compared with both APOE3 and APOE4. Moreover, we show age-dependent alterations in the recruitment of key endosomal regulatory proteins to vesicle compartments when comparing APOE2 to APOE3. In contrast to the early endosome enlargement previously shown in Alzheimer's disease and APOE4 models, we detected similar morphology and abundance of early endosomes and retromer-associated vesicles within cortical neurons of aged APOE2 targeted-replacement mice compared with APOE3. Additionally, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, consistent with enhanced endosomal cargo clearance by exosomes to the extracellular space. Our findings thus demonstrate that APOE2 enhances an endosomal clearance pathway, which has been shown to be impaired by APOE4 and which may be protective due to APOE2 expression during brain aging., (© 2024 The Authors. Traffic published by John Wiley & Sons Ltd.)

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β 42 oligomer-induced bioenergetic changes, suggesting that amyloid-β 42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APP Swe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1 + cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization. Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model. An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During pathogenesis of Alzheimer's disease (AD), mitochondria suffer alterations that lead to low energy production and reactive oxygen species formation. However, the mechanism of impaired mitochondria homeostasis in AD is not fully understood. We hypothesized that abnormal sphingolipid metabolism in mitochondria could be one of the contributing factors to mitochondrial dysfunction. Synaptic and non-synaptic mitochondria were isolated from 5xFAD and wild type (WT) mice at 3 and 7 months using Ficoll gradient ultracentrifugation, and their function was analyzed using Seahorse assay. Additionally, mitochondria were analyzed using mass spectrometry for proteomics and sphingolipidomics analyses. Sphingolipid levels were also determined in synaptic and non-synaptic mitochondria isolated from AD patients and healthy controls. We found that synaptic mitochondria isolated from 3-months old 5xFAD mice manifest diminished oxygen consumption as compared to WT. Consistently, proteomics analysis showed that proteins related to respiratory electron transport and oxidative phosphorylation were altered in 5xFAD mice. When quantifying the main sphingolipids in mitochondria, we found that Cer 18:0, Cer 22:0, and Cer 24:1 were increased already at 3 months in 5xFAD mice. No increase in ceramides was detected in mitochondria isolated from AD patients. However, increased levels of sphingosine were found in both 5xFAD mice and AD patients when compared to respective controls. We report that the regulation of sphingolipids in mitochondria is abnormal at 3 months of age in 5xFAD mice, as indicated by the accumulation of long-chain ceramides, which increases with age. Sphingosine levels are increased in both the mitochondria of 5xFAD mice and AD patients. Our data suggest that the sphingolipid composition is dysregulated in mitochondria early during AD pathogenesis.

Aging is the main risk for neurodegenerative disorders like Alzheimer's disease. In this short review, I will comment on how delaying brain aging through the addition of Yamanaka Factors or small compounds that bind to the folate receptor alpha, which promote the expression of the Yamanaka Factors or by the decrease tau levels in brain cells from older subjects could serve as strategies to prevent Alzheimer's disease.

Aging is an intrinsic aspect of an organism's life cycle and is characterized by progressive physiological decline and increased susceptibility to mortality. Many age-associated disorders, including neurological disorders, are most commonly linked with the aging process, such as Alzheimer's disease (AD). This review aims to provide a comprehensive overview of the effects of aging and AD on the molecular pathways and levels of different proteins in the brain, including metalloproteins, neurotrophic factors, amyloid proteins, and tau proteins. AD is caused by the aggregation of amyloid proteins in the brain. Factors such as metal ions, protein ligands, and the oligomerization state of amyloid precursor protein significantly influence the proteolytic processing of amyloid-β protein precursor (AβPP). Tau, a disordered cytosolic protein, serves as the principal microtubule-associated protein in mature neurons. AD patients exhibit decreased levels of nerve growth factor within their nervous systems and cerebrospinal fluid. Furthermore, a significant increase in brain-derived neurotrophic factor resulting from the neuroprotective effect of glial cell line-derived neurotrophic factor suggests that the synergistic action of these proteins plays a role in inhibiting neuronal degeneration and atrophy. The mechanism through which Aβ and AβPP govern Cu2+ transport and their influence on Cu2+ and other metal ion pools requires elucidation in future studies. A comprehensive understanding of the influence of aging and AD on molecular pathways and varying protein levels may hold the potential for the development of novel diagnostic and therapeutic methods for the treatment of AD.

Introduction: Aging is characterized by the deterioration of a wide range of functions in tissues and organs, and Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Hypothyroidism occurs when there is insufficient production of thyroid hormones (THs) by the thyroid. The relationship between hypothyroidism and aging as well as AD is controversial at present., Methods: We established an animal model of AD (FAD4T) with mutations in the APP and PSEN1 genes, and we performed a thyroid function test and RNA sequencing (RNA-Seq) of the thyroid from FAD4T and naturally aging mice. We also studied gene perturbation correlation in the FAD4T mouse thyroid, bone marrow, and brain by further single-cell RNA sequencing (scRNA-seq) data of the bone marrow and brain., Results: In this study, we found alterations in THs in both AD and aging mice. RNA-seq data showed significant upregulation of T-cell infiltration- and cell proliferation-related genes in FAD4T mouse thyroid. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that upregulated genes were enriched in the functional gene modules of activation of immune cells. Downregulated energy metabolism-related genes were prominent in aging thyroids, which reflected the reduction in THs. GSEA showed a similar enrichment tendency in both mouse thyroids, suggesting their analogous inflammation state. In addition, the regulation of leukocyte activation and migration was a common signature between the thyroid, brain, and bone marrow of FAD4T mice., Conclusions: Our findings identified immune cell infiltration of the thyroid as the potential underlying mechanism of the alteration of THs in AD and aging., (© 2024 S. Karger AG, Basel.)

Background: Alzheimer's disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease., Objective: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs., Methods: High resolution 1H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the "preclinical" period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control., Results: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups., Conclusions: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans.