Late-onset Alzheimer's Disease Research Articles

Serum proteomics reveals early biomarkers of Alzheimer's disease: The dual role of APOE-ε4.

Alzheimer's disease (AD), the leading cause of dementia, significantly impacts global public health, with cases expected to exceed 150 million by 2050. Late-onset Alzheimer's disease (LOAD), predominantly influenced by the APOE-ε4 allele, exhibits complex pathogenesis involving amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) disruption. Proteomics has emerged as a pivotal technology in uncovering molecular mechanisms and identifying biomarkers for early diagnosis and intervention in AD. This paper reviews the genetic and molecular roles of APOE-ε4 in the pathology of AD, including its effects on Aβ aggregation, tau phosphorylation, neuroinflammation, and BBB integrity. Additionally, it highlights recent advances in serum proteomics, revealing APOE-ε4-dependent and independent protein signatures with potential as early biomarkers for AD. Despite technological progress, challenges such as population diversity, standardization, and distinguishing AD-specific biomarkers remain. Directions for future research emphasize multicenter longitudinal studies, multi-omics integration, and the clinical translation of proteomic findings to enable early detection of AD and personalized treatment strategies. Proteomics advances in AD research hold the promise of improving patient outcomes and reducing the global disease burden.

APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology

BackgroundApolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.MethodsWe introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain’s response to plaques and tau.ResultsIn 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice.ConclusionsThese findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.Graphical

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease

Down syndrome (DS) is strongly associated with Alzheimer’s disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R2 = .77), DS and LOAD (R2 = .73), and EOAD and LOAD (R2 = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10−5) for DS, immune system regulation (p = 4.33 × 10−5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R2 = .59) and LOAD (R2 = .33) compared to the correlation between EOAD and LOAD (R2 = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein–DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

Blood biomarker profiles in young-onset neurocognitive disorders: A cohort study.

Young-onset neurocognitive symptoms result from a heterogeneous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the Biomarkers in Younger-Onset Neurocognitive Disorders cohort, a study of individuals <65 years old presenting with neurocognitive symptoms for a diagnosis and who have undergone cognitive and biomarker analyses. Sixty-five participants (median age at assessment of 56 years, 45% female) were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia, and categorized as either early-onset Alzheimer's disease (n = 18), non-Alzheimer's disease neurodegeneration (n = 23) or primary psychiatric disorders (n = 24). Levels of neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181, apolipoprotein E genotype and late-onset Alzheimer's disease polygenic risk scores were determined. Information-theoretic model selection identified discriminatory factors. Neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181 levels were elevated in early-onset Alzheimer's disease compared with other diagnostic categories. A multi-omic model selection identified that a combination of cognitive and blood biomarkers, but not the polygenic risk score, discriminated between early-onset Alzheimer's disease and primary psychiatric disorders (area under the curve ⩾ 0.975, 95% confidence interval: 0.825-1.000). Phosphorylated-tau 181 alone significantly discriminated between early-onset Alzheimer's disease and non-Alzheimer's disease neurodegeneration causes (area under the curve = 0.950, 95% confidence interval: 0.877-1.00). Discriminating between early-onset Alzheimer's disease, non-Alzheimer's disease neurodegeneration and primary psychiatric disorders causes of young-onset neurocognitive symptoms is possible by combining cognitive profiles with blood biomarkers. These results support utilizing blood biomarkers for the work-up of young-onset neurocognitive symptoms and highlight the need for the development of a young-onset Alzheimer's disease-specific polygenic risk score.

Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder with both genetic and environmental factors contributing to its pathogenesis. While early-onset AD has well-established genetic determinants, the genetic basis for late-onset AD remains less clear. This study investigates a large Italian family with late-onset autosomal dominant AD, identifying a novel rare missense variant in GRIN2C gene associated with the disease, and evaluates the functional impact of this variant.MethodsAffected and unaffected members from a Northern Italian family were included. Genomic DNA from family members was extracted and initially screened for pathogenic mutations in APP, PSEN1, and PSEN2, and screened for 77 genes associated with neurodegenerative conditions using NeuroX array assay. Exome sequencing was performed on three affected individuals and two healthy relatives. Bioinformatics analyses were conducted. Functional analysis was performed using primary neuronal cultures, and the impact of the variant was assessed through immunocytochemistry and electrophysiology.ResultsPathogenic variants were not identified in APP, PSEN1, or PSEN2, nor in the 77 genes in NeuroX array assay. Exome Sequencing revealed the c.3215C > T p.(A1072V) variant in GRIN2C gene (NM 000835.6), encoding for the glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 2C (GluN2C). This variant segregated in 6 available AD patients in the family and was absent in 9 healthy relatives. Primary rat hippocampal neurons overexpressing GluN2CA1072V showed an increase in NMDAR-induced currents, suggesting altered glutamatergic transmission. Surface expression assays demonstrated an elevated surface/total ratio of the mutant GluN2C, correlating with the increased NMDAR current. Additionally, immunocytochemistry revealed in neurons expressing the mutant variant a reduced colocalization between the GluN2C subunit and 14-3-3 proteins, which are known to facilitate membrane trafficking of NMDARs.DiscussionWe identified a rare missense variant in GRIN2C associated with late-onset autosomal dominant Alzheimer's disease. These findings highlight the role of GluN2C-containing NMDARs in glutamatergic signaling and their potential contribution to AD pathogenesis.

Effect of genetic and vascular risk factors on rates of cognitive decline in early-onset and late-onset Alzheimer's disease.

Although previous studies have shown that cognitive decline in Alzheimer's disease (AD) is associated with various risk factors, they primarily focused on late-onset AD (LOAD). We aim to evaluate the differential impact of risk factors on the cognitive decline between early-onset AD (EOAD, onset < 65 years) and LOAD (onset 65 years) and explore the longitudinal effect of Apolipoprotein E allele 4 (APOE ε4) on cortical atrophy in both cohorts. Using data from 212 EOAD and 1101 LOAD participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), we conducted multivariable mixed-effect models to evaluate the impact of APOE ε4, education, hypertension, diabetes, dyslipidemia, and body mass index on cognitive performance. Preprocessed MRI data were utilized for longitudinal parametric mapping. APOE ε4 carriers in both groups showed significantly accelerated declines in language, verbal memory, executive function, and general cognition. By controlling other significant risk factors, APOE ε4 carriers showed faster declines in language and verbal memory in both groups. Females exhibited accelerated declines in Language and verbal memory in the EOAD and LOAD cohorts respectively. LOAD individuals with hypertension showed faster declines while overweight and obese participants displayed slower declines in both cohorts across all domains except visuospatial. Notably, APOE ε4 status was associated with longitudinal cortical atrophy in the LOAD cohort but not in the EOAD cohort. Known risk factors for AD were associated with cognitive decline in both EOAD and LOAD cohorts.

EBP1 potentiates amyloid β pathology by regulating γ-secretase.

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in Aβ deposition, amyloid plaques and cognitive dysfunction. In postmortem brains of patients with AD and 5x-FAD mice, we found that EBP1 is proteolytically cleaved by asparagine endopeptidase at N84 and N204 residues, compromising its inhibitory effect on γ-secretase, increasing Aβ aggregation and neurodegeneration. Accordingly, injection of AAV2-Ebp1 wild-type or an asparagine endopeptidase-uncleavable mutant into the brains of 5x-FAD mice decreased Aβ generation and alleviated the behavioral impairments. Thus, our study suggests that EBP1 acts as an inhibitor of γ-secretase on amyloid precursor protein cleavage and preservation of functional EBP1 could be a therapeutic strategy for AD.

Clinical characteristics and biomarker profile in early- and late-onset Alzheimer's disease: the Shanghai Memory Study.

Early-onset Alzheimer's disease constitutes ∼5-10% of Alzheimer's disease. Its clinical characteristics and biomarker profiles are not well documented. To compare the characteristics covering clinical, neuropsychological and biomarker profiles between patients with early- and late-onset Alzheimer's disease, we enrolled 203 patients (late-onset Alzheimer's disease = 99; early-onset Alzheimer's disease = 104) from a Chinese hospital-based cohort, the Shanghai Memory Study. A full panel of plasma biomarkers under the amyloid/tau/neurodegeneration framework including plasma amyloid beta 40, amyloid beta 42, total-tau, neurofilament light chain and phosphorylated tau 181 were assayed using ultra-sensitive Simoa technology. Seventy-five patients underwent an amyloid molecular positron emission tomography scan whereas 43 received comprehensive amyloid, Tau deposition and hypometabolism analysis. Clinical features, plasma and imaging biomarkers were compared cross-sectionally. Compared to those with late-onset Alzheimer's disease, patients with early-onset Alzheimer's disease presented more severe impairment in language function, lower frequency of APOE ɛ4 and lower levels of plasma neurofilament light chain (all P < 0.05). The plasma phosphorylated tau 181 concentration and phosphorylated tau 181/amyloid beta 42 ratios were higher in early-onset Alzheimer's disease than in late-onset Alzheimer's disease (all P < 0.05). More severe Tau deposition as indicated by 18F-florzolotau binding in the precuneus, posterior cingulate cortex and angular gyrus was observed in the early-onset Alzheimer's disease group. Plasma phosphorylated tau 181 was associated with earlier age at onset and domain-specific cognitive impairment, especially in patients with early-onset Alzheimer's disease. We concluded that patients with early-onset Alzheimer's disease differed from late-onset Alzheimer's disease in cognitive performance and biomarker profile. A higher burden of pathological tau was observed in early-onset Alzheimer's disease and was associated with earlier age at onset and more profound cognitive impairment.

Mendelian randomization and genetic pleiotropy analysis for the connection between inflammatory bowel disease and Alzheimer's disease.

The gut-microbiome-brain axis (GMBA) implies the connection between inflammatory bowel disease (IBD) and Alzheimer's disease (AD). We aimed to comprehensively explore the relation between IBD (and its subtypes) and AD, early-onset AD (EOAD) and late-onset AD (LOAD) from a genetic pleiotropy perspective. Relying on summary statistics (N=472,868 for AD, 185,204 for EOAD, 191,061 for LOAD, 59,957 for IBD, 45,975 for CD, and 40,266 for UC), we first performed Mendelian Randomization to examine the causal association between IBD and AD by leveraging vertical pleiotropy. Then, we estimated global and local genetic correlations, followed by cross-trait association analysis to identify SNPs and genes with horizontal pleiotropy. Particularly, we utilized multi-trait colocalization analysis to assess the role of microbes in the common genetic etiology underlying the two types of diseases. Finally, we conducted functional enrichment analysis for pleiotropic genes. We discovered suggestively causal relations between IBD (and its subtypes) and EOAD (ORIBD=1.06 [1.01-1.11], ORCD=1.05 [1.01-1.10], ORUC=1.08 [1.01-1.15]) as well as between UC and LOAD (OR=1.04 [1.01-1.08]), and discovered 44 local regions showing suggestively significant genetic correlations between IBD (and its subtypes) and AD (and EODA and LOAD). We further detected substantial genetic overlap, as characterized by 182 AD-associated, 3 EOAD-associated and 51 LOAD-associated pleiotropic SNPs as well as 291 pleiotropic genes. Pleiotropic genes more likely enriched in the GMBA-relevant tissues such as brain, intestine and esophagus. Moreover, we identified three microorganisms related to these disease pairs, including the Catenibacterium, Clostridia, and Prevotella species. The suggestively causal associations and shared genetic basis between IBD and its subtypes with AD, EOAD and LOAD may commonly drive their co-occurrence, and gut microbes might partly explain the shared genetic etiology. Further studies are warranted to elaborate the possibly biological mechanisms underlying the two types of diseases.

The Ameliorative Effects of AT2 Receptor Activation with the Hexapeptide Novokinin on Streptozotocin-induced Model of Alzheimer's Disease in SHR

Alzheimer's disease (AD), a form of dementia, presents a global concern. This study investigates the connection between hypertension and AD and the effects of the peptide novokinin (NVK), an AT2 receptor agonist in spontaneously hypertensive rats (SHRs). The brain's renin-angiotensin system (RAS) influences cognitive and emotional processes, suggesting potential intersections with AD. Streptozotocin (STZ), administered intracerebroventricularly (ICV), is used as a model of late-onset Alzheimer's disease. This model reveals a memory impairment associated with an insulin-resistant brain state, marked by neuroinflammatory processes contributing to cognitive deficits, oxidative stress, and reduced cerebral energy metabolism. NVK is an angiotensin AT2 receptor agonist, studied for its potential neuroprotective role. Female SHRs were used to investigate the effects of STZ-ICV (twice) and chronic NVK-ICV. NVK was administered for 14 days ICV using osmotic minipumps (ALZET®). The control group exhibited strain-typical increased exploratory activity, reduced anxiety in new environments, and impaired spatial memory, as expected for SHRs. The STZ-ICV negative control group showed signs of impaired memory and object recognition. In the `Open Field’ test, STZ-treated groups with and without NVK-ICV displayed heightened exploratory behaviour. Data from the `Elevated plus maze' test showed decreased anxiety in the STZ-ICV group while combining STZ and NVK normalized the anxiety behaviour. In the `T-maze' test, STZ-ICV-treated rats made fewer correct decisions. The STZ+NVK group exhibited enhanced spatial memory and improved anxiety-like behaviour in novel environments, potentially attributable to the proposed neuroprotective effects of NVK. These findings emphasize the association of RAS in the progression of AD and the potential protective role of the brain's AT2 receptors in this type of dementia.

Differences in baseline cognitive performance between participants with early-onset and late-onset Alzheimer's disease: Comparison of LEADS and ADNI.

Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller-scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. Z-score cognitive-domain composites for 311 amyloid-positive sporadic EOAD and 314 amyloid-positive LOAD participants were calculated from baseline data from age-appropriate control cohorts. Z-score composites were compared between AD groups for each domain. After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non-amnestic impairments in younger patients to ensure proper identification and intervention using disease-modifying treatments. Both early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same-aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv-PPA), and frontal-variant AD.

Sodium Thiosulfate: An Innovative Multi-Target Repurposed Treatment Strategy for Late-Onset Alzheimer's Disease.

Late-onset Alzheimer's disease (LOAD) is a chronic, multifactorial, and progressive neurodegenerative disease that associates with aging and is highly prevalent in our older population (≥65 years of age). This hypothesis generating this narrative review will examine the important role for the use of sodium thiosulfate (STS) as a possible multi-targeting treatment option for LOAD. Sulfur is widely available in our environment and is responsible for forming organosulfur compounds that are known to be associated with a wide range of biological activities in the brain. STS is known to have (i) antioxidant and (ii) anti-inflammatory properties; (iii) chelation properties for calcium and the pro-oxidative cation metals such as iron and copper; (iv) donor properties for hydrogen sulfide production; (v) possible restorative properties for brain endothelial-cell-derived bioavailable nitric oxide. Thus, it becomes apparent that STS has the potential for neuroprotection and neuromodulation and may allow for an attenuation of the progressive nature of neurodegeneration and impaired cognition in LOAD. STS has been successfully used to prevent cisplatin oxidative-stress-induced ototoxicity in the treatment of head and neck and solid cancers, cyanide and arsenic poisoning, and fungal skin diseases. Most recently, intravenous STS has become part of the treatment plan for calciphylaxis globally due to vascular calcification and ischemia-induced skin necrosis and ulceration. Side effects have been minimal with reports of metabolic acidosis and increased anion gap; as with any drug treatment, there is also the possibility of allergic reactions, possible long-term osteoporosis from animal studies to date, and minor side-effects of nausea, headache, and rhinorrhea if infused too rapidly. While STS poorly penetrates the intact blood-brain barrier(s) (BBBs), it could readily penetrate BBBs that are dysfunctional and disrupted to deliver its neuroprotective and neuromodulating effects in addition to its ability to penetrate the blood-cerebrospinal fluid barrier of the choroid plexus. Novel strategies such as the future use of nano-technology may be helpful in allowing an increased entry of STS into the brain.

Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles.

Aging and apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer's disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells, including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4-dependent phenotypes. Toll-like receptor 4 (TLR4) is a key macromolecule in inflammation, and its regulation is associated with the cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. This study found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activates ABCA1, and dampens LPS-dependent NFκB activation. In vivo, two-week injections of nanoparticle F12511, which consists of DSPE-PEG2000, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines, including IL-1β in mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.

Oxidative stress and metabolic syndrome in Alzheimer’s disease: the search for a relationship

The article addresses the problem of Alzheimer’s disease (AD) from the perspective of the interaction between two important pathological processes: oxidative stress and metabolic disorders. Although histopathological changes in early and senile dementia are similar, and both variants are attributed to AD, individuals with early-onset AD (EOAD) demonstrate a more aggressive course of the disease with rapid cognitive decline and fewer concomitant morphological changes. The development of late-onset AD (LOAD) depends on multiple environmental factors, lifestyle, and, among other things, the functioning of general adaptation mechanisms, including redox, immunological, and hormonal systems.The article pays special attention to the role of metabolic syndrome (MS) as an important risk factor not only for cardiovascular and cerebrovascular diseases but also for AD. The presence of MS in individuals over 60 years of age increases the risk of developing dementia by 13% under the age of 60 and by 8% between the ages of 60 and 70. The article emphasizes the importance of oxidative stress (OS), which causes oxidation of biomolecules and tissue damage, in the pathogenesis of metabolic disorders and the development of MS. Possible mechanisms of the relationship between oxidative stress processes and metabolic disorders are described. Understanding the mechanisms of AD and MS development, as well as their interrelation, is key to developing effective methods for preventing and treating these diseases.

Prevalance of Non-Provoke Generalize Tonic-Clonic Seizure in Sporadic Alzheimer’s Disease

Background and Purpose: Alzheimer’s disease (AD) and epileptic seizure are among the most common health problems in the elderly population. This study aimed to estimate the prevalence rate and predictors of seizures in sporadic AD patients.Methods: The study was conducted by retrospectively for a period of 10 years examining the file records. Patients were selected among the patients diagnosed with probable sporadic late onset AD according to the National Institute of Neurological Communicative Disorders and Stroke AD and related disorders association criteria and the diagnostic and statistical manual of mental disorders (n=451). In our 213 sporadic AD patients who were followed up regularly and had a follow up examination in the last 6 months, the file records were examined, scanned and questioned for the presence of epileptic seizures.Results: The prevalence of non provoked generalized tonic clonic seizures in sporadic AD was found to be 6.57% (n=14). Neuroleptic use, presence of diabetes mellitus (DM) and/or treatment, presence of ischemic heart disease (IHD) and/or treatment were found to be 2.99 times, 1.91 times and 3.09 times higher in our patients who had seizures, respectively. When the factors that can affect seizures were examined, the use of neuroleptics and the presence of IHD and/or treatment were found to be statistically significant in terms of the risk of seizure in AD.Conclusions: The use of neuroleptics, the presence of IHD and DM and/or their medications could facilitate the development of unprovoked generalized tonic clonic seizures in sporadic AD. It is doubtful whether the seizures are primary or secondary generalized.

The early-onset Alzheimer's disease MRI signature: a replication and extension analysis in early-stage AD.

Early-onset Alzheimer's disease (EOAD) is less investigated than the more common late-onset Alzheimer's disease (LOAD) despite its more aggressive course. A cortical signature of EOAD was recently proposed and may facilitate EOAD investigation. Here, we aimed to validate this proposed MRI biomarker of EOAD neurodegeneration in an Appalachian clinical cohort. We also compared differences in EOAD signature atrophy in participants with biomarker-positive EOAD, LOAD, early-onset non-AD pathologies, and cognitively normal individuals. Cortical thinning was reliably detected in eight of nine signature areas of persons with EOAD relative to cognitively normal individuals despite very early disease stage. Additionally, individuals with EOAD showed thinner cortex in most signature regions relative to those with early-onset non-AD pathologies. EOAD and LOAD showed similar cortical atrophy within most EOAD signature regions. Whole-brain vertex-wise cortical analyses supported these findings. Furthermore, signature cortical atrophy showed expected relationships with measures of global and specific cognitive and functional status. This investigation further validates and expands upon the recently defined EOAD signature and suggests its robustness within a rural population, even at early disease stage. Larger scale and longitudinal studies employing this marker of EOAD neurodegeneration are needed to further understand clinical effects and appropriate management of persons with EOAD.

Targeting Aging‐Related Neuroinflammation and Autophagy as Interventions for Late Onset Alzheimer’s Disease

AbstractBackgroundThe bi‐directional autophagy and inflammation network becomes progressively dysregulated with age, with systemic inflammation as a biomarker of this dysregulation including in Alzheimer’s Disease (AD). We hypothesize that interventions which target the shared feature of systemic inflammation in the biology of aging and AD, via regulation of the autophagy‐inflammation network, will prevent the conversion to disease pathogenesis in AD as well as improve healthspan and longevity in aging populations. While previous studies report benefits of mTOR inhibition including rapamycin in transgenic mouse models of familial AD, the present studies aim to evaluate this pathway in a model of sporadic, late onset AD (LOAD) and test the contribution of AMP‐activated protein kinase (AMPK) as a critical regulator of the mTOR pathway.MethodA novel brain penetrable AMPK activator compound (BC1618) and the prototypical mTOR inhibitor rapamycin were administered chronically to male and female mice with genetic and environmental risk for LOAD. LOAD mice (APOE4/TREM2R47H/hAPP; JAX #030670) were conditioned on High Fat Diet (HFD) from 2 months of age which induced sustained inflammation. Drug exposure levels were measured by HPLC‐MS/MS for PK analysis. Subjects were evaluated through a comprehensive battery of tests longitudinally at 6‐month intervals throughout lifespan including motor, sensorimotor, cognitive behavior, frailty, blood‐based biomarkers, and PET/MR.ResultTreatment with rapamycin and BC1618 resulted in the expected appreciable exposure levels in brain and plasma. Interim analysis of LOAD+HFD mice at 22 months of age (10+ months treatment) revealed reduced survival and healthspan relative to non‐LOAD controls with no benefit of RAPA or BC1618 treatment. Ongoing studies evaluating translationally relevant PET/MR, biomarkers, pathology, and behavior throughout lifespan to evaluate effects on healthspan and lifespan are in progress.ConclusionLOAD+HFD mice model genetic x aging x environmental risk of sporadic late‐onset AD and provide a more translationally relevant model to study potential benefits of interventions that target the mTOR pathway. These studies are poised to inform influence of AMPK on autophagy and inflammation to attenuate disease progression in LOAD; which may be better predictive of effects on sporadic AD than previous studies in young transgenic early‐onset models of brain amyloid overexpression.

Multi‐ancestry genome‐wide gene × age interaction study identifies novel loci associated with late‐onset Alzheimer’s Disease

AbstractBackgroundAge is the largest risk factor for late‐onset Alzheimer’s Disease (LOAD). Although &gt;80 genetic loci have been associated with LOAD, little is known about the age dependencies of these associations except the APOE region.MethodWe performed cross‐ancestry and ancestry‐specific genome‐wide gene‐age interaction and age‐stratified association study using TOPMed‐imputed genome‐wide association study (GWAS) data from Alzheimer’s Disease Genetics Consortium (ADGC) including 34,833 non‐Hispanic Whites (NHW), 7,264 African Americans (AA), 3,232 East Asians (EA), and 2,024 Caribbean Hispanics (CH) aged 60 years and older. We chose an approximate median age‐at‐onset threshold of 75 to dichotomize participants into younger (Ncase:Ncontrol = 10, 905:11,624) and older (Ncase:Ncontrol = 9,982:14,842) groups. We first evaluated the association of LOAD with the interaction of SNP × age within each cohort using a linear mixed‐effect model including a binary term for the age group, numeric age, sex, and the first 5 principal components (PCs) of ancestry. Results from each cohort were combined using a fixed‐effect model to jointly estimate the regression coefficients of SNP and SNP × age terms, both within‐ancestry and cross‐ancestry analyses. We also performed an age‐stratified analysis that included all controls regardless of age to increase power and using the same linear model without the interaction term. Results across cohorts were combined by meta‐analysis using a fixed‐effect model within‐ancestry and a modified random‐effect model across ancestry.ResultIn cross‐ancestry joint meta‐analysis, we identified 6 genome‐wide significant (GWS) loci, 4 of which showed nominal evidence of age‐dependent association with LOAD, including CD2AP (rs5876027, PJoint = 2.33 × 10‐8, PSNP×age = 0.043), PICALM (rs583162, PJoint = 2.34 × 10‐8, PSNP×age = 7.60 × 10‐3), APOE (rs429358, PJoint = 0, PSNP×age = 1.58 × 10‐7) and LILRA5 (rs1761461, PJoint = 4.86 × 10‐8, PSNP×age = 0.032), for the first time. Within‐ancestry joint meta‐analysis identified novel associations with VXN (rs146432976, PJoint = 2.29 × 10‐8, PSNP×age = 3.08 × 10‐5) in AAs and PALM2‐AKAP2 (rs67191673, PJoint = 3.46 × 10‐9, PSNP×age = 0.013) in EAs. CR1 (rs6661489, PJoint = 3.54 × 10‐8) and TREM2 (rs75932628, PJoint = 8.61 × 10‐10) were associated with LOAD in NHWs but showed no evidence of age‐dependent effects. In cross‐ancestry age‐stratified GWAS, BIN1, PICALM, and APOE region genes reached GWS in both strata, while MS4A6A was only significant in older group (rs7232, OR = 0.88, P = 4.23 × 10‐8). A GWS association with PALM2‐AKAP2 (rs67191673, OR = 1.94, P = 3.64 × 10‐9) was identified in the EA younger group.ConclusionWe identified several ancestry‐specific age‐dependent association with previously established and novel loci.

Synapse loss in early‐ and late‐onset Alzheimer’s Disease assessed by 18F‐SynVest‐1

AbstractBackgroundWe aimed to investigate the loss of synaptic density in early‐onset and late‐onset Alzheimer’s Disease.MethodOne hundred and eighty‐two participants underwent synaptic density PET with 18F‐SynVesT‐1. Including 23 early‐onset Alzheimer‘s Disease (EOAD), 58 late‐onset Alzheimer’s Disease (LOAD), 16 EOnonAD, 28 LOnonAD, 31 younger normal control (age &lt; 65) and 26 older normal control (age ⩾ 65). We analyzed the synaptic density loss in EOAD and LOAD relative to their control group respectively. Associations between age and synaptic loss were evaluated in different groups.ResultEOAD and LOAD groups both displayed significant synaptic density across most areas of cerebrum cortex. Relative to LOAD group, EOAD group showed severer synaptic loss in Lateral Parietal lobe. In EOAD group, synaptic density in occipital lobe had positive association with age. While, in LOAD group, synaptic density in most areas of the cerebrum cortex had a negative association with age.ConclusionOur study suggested that the areas of synaptic loss were different between EOAD and LOAD.

Decision‐Making Capacity and Awareness in People with Young‐Onset Alzheimer´s Disease

AbstractBackgroundThere is a lack of research on differences between decision‐making capacity and awareness according to age at onset of dementia. We investigated the relationship between decision‐making capacity and awareness domains in people with young‐ (YOAD) and late‐onset Alzheimer´s Disease (LOAD).MethodA cross‐sectional study included 169 consecutively selected people with AD and their caregivers (124 people with LOAD and 45 people with YOAD).ResultPeople with YOAD were more cognitively impaired, but more aware of their cognitive deficits and health condition, with moderate effect sizes. All people with AD presented deficits in the domains of decision‐making capacity, with more impairment in understanding. There was a relationship between understanding and awareness domains, such that awareness was particularly important for decision‐making capacity in the YOAD group.ConclusionBetter awareness involved better understanding in the YOAD group. Clinically, our findings shed light on the need to consider the differences in the domains of awareness and their relationship with other clinical aspects such as decision‐making capacity according to age at onset of AD.