Atypical intrinsic neural timescale in the left angular gyrus in Alzheimer's disease.

Alzheimer's disease is characterized by cognitive impairment and progressive brain atrophy. Recent human neuroimaging studies reported atypical anatomical and functional changes in some regions in the default mode network in patients with Alzheimer's disease, but which brain area of the default mode network is the key region whose atrophy disturbs the entire network activity and consequently contributes to the symptoms of the disease remains unidentified. Here, in this case-control study, we aimed to identify crucial neural regions that mediated the phenotype of Alzheimer's disease, and as such, we examined the intrinsic neural timescales-a functional metric to evaluate the capacity to integrate diverse neural information-and grey matter volume of the regions in the default mode network using resting-state functional MRI images and structural MRI data obtained from individuals with Alzheimer's disease and cognitively typical people. After confirming the atypically short neural timescale of the entire default mode network in Alzheimer's disease and its link with the symptoms of the disease, we found that the shortened neural timescale of the default mode network was associated with the aberrantly short neural timescale of the left angular gyrus. Moreover, we revealed that the shortened neural timescale of the angular gyrus was correlated with the atypically reduced grey matter volume of this parietal region. Furthermore, we identified an association between the neural structure, brain function and symptoms and proposed a model in which the reduced grey matter volume of the left angular gyrus shortened the intrinsic neural time of the region, which then destabilized the entire neural timescale of the default mode network and resultantly contributed to cognitive decline in Alzheimer's disease. These findings highlight the key role of the left angular gyrus in the anatomical and functional aetiology of Alzheimer's disease.

Anti-neurofascin 155 Antibody-positive Neuropathy in a Human Immunodeficiency Virus-infected Patient.

Human immunodeficiency virus (HIV)-associated neuropathy is a common complication of HIV infection and has several clinical subtypes. HIV-associated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a demyelinating neuropathy whose clinical features are known to differ from those of CIDP in the HIV-uninfected population. We herein report a case of CIDP in an HIV-infected patient who was finally diagnosed with anti-neurofascin 155 (NF155) antibody-positive neuropathy. The clinical features, including clinical findings and therapeutic responses, were typical of paranodal antibody-mediated neuropathy. To our knowledge, this is the first case of anti-NF155 antibody-associated neuropathy in an HIV-infected patient.

Photo-oxygenation of histidine residue inhibits α-synuclein aggregation.

Aggregation of α-synuclein (α-syn) into amyloid is the pathological hallmark of several neurodegenerative disorders, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. It is widely accepted that α-syn aggregation is associated with neurodegeneration, although the mechanisms are not yet fully understood. Therefore, the inhibition of α-syn aggregation is a potential therapeutic approach against these diseases. This study used the photocatalyst for α-syn photo-oxygenation, which selectively adds oxygen atoms to fibrils. Our findings demonstrate that photo-oxygenation using this photocatalyst successfully inhibits α-syn aggregation, particularly by reducing its seeding ability. Notably, we also discovered that photo-oxygenation of the histidine at the 50th residue in α-syn aggregates is responsible for the inhibitory effect. These findings indicate that photo-oxygenation of the histidine residue in α-syn is a potential therapeutic strategy for synucleinopathies.

The Myocardial Accumulation of Aggregated Desmin Protein in a Case of Desminopathy with a de novo DES p.R406W Mutation.

Desminopathy is a cardiac and skeletal myopathy caused by disease-causing variants in the desmin (DES) gene and represents a subgroup of myofibrillar myopathies, where cytoplasmic desmin-postive immunoreactivity is the pathological hallmark. We herein report a 28-year-old Japanese man who was initially diagnosed with sporadic hypertrophic cardiomyopathy with atrioventricular block at 9 years old and developed weakness in the soft palate and extremities. The myocardial tissue dissected during implantation of the ventricular-assisted device showed a dilated phase of hypertrophic cardiomyopathy and intracellular accumulation of proteinase K-resistant desmin aggregates. Genetic testing confirmed a de novo mutation of DES, which has already been linked to desminopathy. As the molecular diagnosis of desminopathy is challenging, particularly if patients show predominantly cardiac signs and a routine skeletal muscle biopsy is unavailable, these characteristic pathological findings of endomyocardial proteinase K-resistant desmin aggregates might aid in clinical practice.

Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID. Targeted immunostaining studies have identified several other proteins present in these inclusions. However, the global molecular changes within nuclei with these inclusions remained unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in a NIID patient with CGG repeat expansion in NOTCH2NLC to discover candidate proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins was confirmed via immunofluorescence in autopsy brain samples from three patients with genetically confirmed NIID. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A2/B1, hnRNP A3, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than in those without, which were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. Although larger studies are needed to validate our results, these proteomic data may form the basis for understanding the pathophysiology of NIID.

Automated Evaluation of Conventional Clock-Drawing Test Using Deep Neural Network: Potential as a Mass Screening Tool to Detect Individuals With Cognitive Decline.

Introduction: The Clock-Drawing Test (CDT) is a simple cognitive tool to examine multiple domains of cognition including executive function. We aimed to build a CDT-based deep neural network (DNN) model using data from a large cohort of older adults, to automatically detect cognitive decline, and explore its potential as a mass screening tool. Methods: Over 40,000 CDT images were obtained from the National Health and Aging Trends Study (NHATS) database, which collects the annual surveys of nationally representative community-dwelling older adults in the United States. A convolutional neural network was utilized in deep learning architecture to predict the cognitive status of participants based on drawn clock images. Results: The trained DNN model achieved balanced accuracy of 90.1 ± 0.6% in identifying those with a decline in executive function compared to those without [positive likelihood ratio (PLH) = 16.3 ± 6.8, negative likelihood ratio (NLH) = 0.14 ± 0.03], and 77.2 ± 2.7 % balanced accuracy for identifying those with probable dementia from those without (PLH = 5.1 ± 0.5, NLH = 0.37 ± 0.07). Conclusions: This study demonstrated the feasibility of implementing conventional CDT to be automatically evaluated by DNN with a fair performance in a larger scale than ever, suggesting its potential as a mass screening test for ruling-in or ruling-out those with executive dysfunction or with probable dementia.

Time to onset of drug-induced parkinsonism: Analysis using a large Japanese adverse event self-reporting database.

Whether there are differences in the time to onset of drug-induced parkinsonism (DIP) depending on the type of drugs causing DIP remains uncertain, so that question was investigated here using a large real-world database. Fourteen DIP-related drug categories were defined to perform a disproportionality analysis using a large Japanese pharmacovigilance database containing more than 600,000 self-reported adverse events (AEs) recorded between April 2004 and September 2021 to identify AEs indicating "parkinsonism" in association with the defined drug categories. The time from drug administration to the onset of DIP was comparatively analyzed. Results indicated that the median time to onset was shorter than 1 month in more than half of the cases of DIP; it was shortest with peripheral dopamine antagonists (median: 0.1 weeks), followed by benzodiazepine (median: 0.5 weeks), butyrophenone (median: 0.7 weeks), novel antidepressants (median: 2.5 weeks), atypical antipsychotics (median: 3.3 weeks), other antidepressants (e.g., lithium, median: 3.7 weeks), and benzamide (median: 4.5 weeks). In contrast, anti-dementia drugs, tricyclic antidepressants, and antiepileptic drugs resulted in a relatively longer time to onset (median: 9.9, 17.2, and 28.4 weeks, respectively). In addition, a maximum delay of even longer than 2 years was reported for benzamide (846 weeks), anti-Parkinsonism drugs (382 weeks), phenothiazine (232 weeks), atypical antipsychotics (167 weeks), anti-dementia drugs (161 weeks), and benzodiazepines (120 weeks). The current results suggested that the characteristics of the time to onset of DIP may substantially differ depending on the type of drug causing that DIP. This finding may help when diagnosing patients with parkinsonism.

Stress cardiomyopathy (Takotsubo syndrome) in patients who received adrenergic agonist drugs: A pharmacovigilance study using the Japanese Adverse Drug Event Report (JADER) database.

INTRODUCTION: Stress cardiomyopathy, or Takotsubo syndrome (TTS), is an acute and reversible syndrome developing in strong association with psychological or physiological stressors. While a surge in the circulating catecholamine level is suspected as one of its pathophysiologies, the contribution of treatment with sympathomimetic drugs to the development of TTS remains uncertain. METHODS: We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing more than 500,000 patient cases recorded between April 2004 and March 2019, to detect TTS ('stress cardiomyopathy') as adverse event signals associated with adrenergic agonist drugs usage by calculating reporting odds ratio (ROR). RESULTS: Among 306 TTS cases reported to JADER, we identified 58 TTS cases with exposure to adrenergic agonist drugs, predominantly of women (52/58, 89.7%) and those in the median age-decades of the 70s. After adjusting for age in decades and sex, most of the intravenous catecholamines showed significantly higher reporting (lower 95% ROR > 1) for TTS, including adrenaline, noradrenaline, dobutamine, dopamine, phenylephrine, and ephedrine. In addition, peroral midodrine, transdermal tulobuterol, inhaled salbutamol, and inhaled procaterol also showed significantly higher ROR for TTS. We also identified a small number of TTS cases with Parkinson's disease taking midodrine or droxidopa, but not receiving other adrenergic agonists. CONCLUSION: The current pharmacovigilance study showed significantly higher RORs for TTS following the use of some of the adrenergic drugs, being mostly consistent with the TTS-related adrenergic drugs reported in earlier literature. A potential association of taking midodrine or droxidopa with the development of TTS was also suggested.

Facial nerve palsy following the administration of COVID-19 mRNA vaccines: analysis of a self-reporting database.

OBJECTIVES: Facial nerve palsy (or Bell's palsy) has occasionally been reported following the administration of coronavirus disease 2019 (COVID-19) mRNA vaccines (BNT162b2 and mRNA-1273). Our study investigated such cases using a large self-reporting database from the USA (Vaccine Adverse Event Reporting System [VAERS]). METHODS: A disproportionality analysis, adjusted for age and sex, was conducted for VAERS reports from individuals who were vaccinated at the age of 18 years or over, between January 2010 and April 2021. RESULTS: The analysis revealed that the adverse events following immunization (AEFI) of facial nerve palsy, after administration of COVID-19 mRNA vaccines, was significantly highly reported, both for BNT162b2 (reporting odds ratio [ROR] 1.84; 95% confidence interval [CI] 1.65-2.06) and mRNA-1273 (ROR 1.54; 95% CI 1.39-1.70). These levels were comparable to that following influenza vaccination reported before the COVID-19 pandemic (ROR 2.04; 95% CI 1.76-2.36). CONCLUSIONS: Our pharmacovigilance study results suggest that the incidence of facial nerve palsy as a non-serious AEFI may be lower than, or equivalent to, that for influenza vaccines. This information might be of value in the context of promoting worldwide vaccination, but needs to be validated in future observational studies.

Transcriptional downregulation of FAM3C/ILEI in the Alzheimer's brain.

Amyloid-ß (Aß) accumulation in the brain triggers the pathogenic cascade for Alzheimer's disease (AD) development. The secretory protein FAM3C (also named ILEI) is a candidate for an endogenous suppressor of Aß production. In this study, we found that FAM3C expression was transcriptionally downregulated in the AD brain. To determine the transcriptional mechanism of the human FAM3C gene, we delineated the minimal 5'-flanking sequence required for basal promoter activity. From a database search for DNA-binding motifs, expression analysis using cultured cells, and promoter DNA-binding assays, we identified SP1 and EBF1 as candidate basal transcription factors for FAM3C, and found that SMAD1 was a putative inducible transcription factor and KLF6 was a transcription repressor for FAM3C. Genomic deletion of the basal promoter sequence from HEK293 and Neuro-2a cells markedly reduced endogenous expression of FAM3C and abrogated SP1- or EBF1-mediated induction of FAM3C. Nuclear protein extracts from AD brains contained lower levels of SP1 and EBF1 than did those from control brains, although the relative mRNA levels of these factors did not differ significantly between the groups. Additionally, the ability of nuclear SP1 and EBF1 in AD brains to bind with the basal promoter sequence-containing DNA probe was reduced compared with the binding ability of these factors in control brains. Thus, the transcriptional downregulation of FAM3C in the AD brain is attributable to the reduced nuclear levels and genomic DNA binding of SP1 and EBF1. An expressional decline in FAM3C may be a risk factor for Aß accumulation and eventually AD development.

The impact of COVID-19 pandemic on the utilization of ambulatory care for patients with chronic neurological diseases in Japan: Evaluation of an administrative claims database.

The COVID-19 pandemic has affected not only the emergency medical system, but also patients' regular ambulatory care, as such decrease in the number of patients visiting outpatient clinics decreased in 2020 than in 2019, or the ban lifting of subsequent visits by telephone for outpatient clinics since March 2020 in lieu of ambulatory care for chronic diseases. In this context, we investigate the impact of the COVID-19 pandemic on ambulatory care at Japanese outpatient clinics for patients with chronic neurological diseases during 2020. We collected data from the administrative claims database (DeSC database) covering more than 1 million individuals. Serial changes in the frequency of subsequent outpatient visits to clinics or hospitals (excluding large hospitals) for chronic ambulatory care of epilepsy, migraine, Parkinson's disease (PD), and Alzheimer's disease (AD) in 2020 were measured. As a result, since April 2020, the monthly outpatient visits for epilepsy, PD, and AD decreased slightly but significantly (approximately 0.90 in relative risk [RR]) but visits for migraine increased (RR = 1.15). Telephone visit was most frequently used in April-May, in less than 5% of monthly outpatient clinic visits for the examined neurological diseases. Outpatient visits for migraine treatment were more likely to be done by telephone than in case of other diseases (adjusted Odds ratio = 2.08). These results suggest that the impact of COVID-19 pandemic on regular ambulatory care for several chronic neurological diseases yielded different effect depending on the disease, in terms of the frequency or type of outpatient visits.

Need of care in interpreting Google Trends-based COVID-19 infodemiological study results: potential risk of false-positivity.

BACKGROUND: Google Trends (GT) is being used as an epidemiological tool to study coronavirus disease (COVID-19) by identifying keywords in search trends that are predictive for the COVID-19 epidemiological burden. However, many of the earlier GT-based studies include potential statistical fallacies by measuring the correlation between non-stationary time sequences without adjusting for multiple comparisons or the confounding of media coverage, leading to concerns about the increased risk of obtaining false-positive results. In this study, we aimed to apply statistically more favorable methods to validate the earlier GT-based COVID-19 study results. METHODS: We extracted the relative GT search volume for keywords associated with COVID-19 symptoms, and evaluated their Granger-causality to weekly COVID-19 positivity in eight English-speaking countries and Japan. In addition, the impact of media coverage on keywords with significant Granger-causality was further evaluated using Japanese regional data. RESULTS: Our Granger causality-based approach largely decreased (by up to approximately one-third) the number of keywords identified as having a significant temporal relationship with the COVID-19 trend when compared to those identified by Pearson or Spearman's rank correlation-based approach. "Sense of smell" and "loss of smell" were the most reliable GT keywords across all the evaluated countries; however, when adjusted with their media coverage, these keyword trends did not Granger-cause the COVID-19 positivity trends (in Japan). CONCLUSIONS: Our results suggest that some of the search keywords reported as candidate predictive measures in earlier GT-based COVID-19 studies may potentially be unreliable; therefore, caution is necessary when interpreting published GT-based study results.

Safety of Memantine in Combination with Potentially Interactive Drugs in the Real World: A Pharmacovigilance Study Using the Japanese Adverse Drug Event Report (JADER) Database.

BACKGROUND: Memantine, an NMDA receptor antagonist, is used for the treatment of Alzheimer's disease. There is a caution to refrain from administrating memantine in combination with some specific drugs such as amantadine or dextromethorphan due to potential interactions that might augment the adverse effects of memantine. OBJECTIVE: This notification has not been validated in real-world data, which we aim to address using a large self-reporting database from Japan. METHODS: We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database reported between April 2004 and March 2019 for detecting the neuropsychiatric adverse event (AE) signals associated with memantine and other potentially interactive drugs including amantadine, dextromethorphan, cimetidine, ranitidine, procainamide, quinidine, acetazolamide, citrate, and bicarbonate. Drug-drug interactions between memantine and these drugs were assessed using multiplicative and additive models. RESULTS: There was no statistically robust evidence to support multiplicative or additive interactions between memantine and the aforementioned drugs to increase the reporting of any included neuropsychiatric AEs or AE categories. CONCLUSION: The real-world JADER data did not raise the concern about the interactive increase in the neuropsychiatric AEs in patients with dementia taking memantine in combination with amantadine or dextromethorphan, suggesting there may be no urgent need to prohibit the co-administration of these drugs presently.

Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature.

The phenotypes of patients with disease-associated variants in DNMT1 have been classified into two syndromes: hereditary sensory and autonomic neuropathy type 1E (HSAN1E, MIM614116, https://www.omim.org/ ) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN, MIM604121). The amino acid codon 511 is a hotspot, and p.Y511C is the most frequently observed disease-associated variant among those in HSAN1E patients, whereas there have been only a few reports on patients with p.Y511H. In this study, we report on the cases of a kindred carrying the DNMT1 variant NM_001130823.2:c.1531 T > C (p.Y511H) presenting with the ADCA-DN phenotype. The review of the literature further revealed that later ages at onset and the presence of cerebellar ataxia are the main characteristics of patients carrying the DNMT1 p.Y511H as compared with those carrying DNMT1 p.Y511C. Although HSAN1E and ADCA-DN are proposed to be called DNMT1-complex disorders owing to their overlapping symptoms, this finding suggests a distinct genotype-phenotype correlation regarding the DNMT1 p.Y511H and p.Y511C variants.

Autocorrelation-based method to identify disordered rhythm in Parkinson's disease tasks: A novel approach applicable to multimodal devices.

OBJECTIVE: We aim to propose a novel method of evaluating the degree of rhythmic irregularity during repetitive tasks in Parkinson's disease (PD) by using autocorrelation to extract serial perturbation in the periodicity of body part movements as recorded by objective devices. METHODS: We used publicly distributed sequential joint movement data recorded during a leg agility task or pronation-supination task. The sequences of body part trajectory were processed to extract their short-time autocorrelation (STACF) matrices; the sequences of single task conducted by participants were then divided into two clusters according to their similarity in terms of their STACF representation. The Unified Parkinson's Disease Rating Scale sub-score rated for each task was compared with cluster membership to obtain the area under the curve (AUC) to evaluate the discrimination performance of the clustering. We compared the AUC with those obtained from the clustering of the raw sequence or short-time Fourier transform (STFT). RESULTS: In classifying the pose estimator-based trajectory data of the knee during the leg agility task, the AUC was the highest when the STACF sequence was used for clustering instead of other types of sequences with up to 0.815, being comparable to the results reported in the original analysis of the data using an approach different from ours. In addition, in classifying another dataset of accelerometer-based trajectory data of the wrist during a pronation-supination task, the AUC was again highest up to 0.785 when clustering was performed using the STACF rather than other types of sequence. CONCLUSION: Our autocorrelation-based method achieved a fair performance in detecting sequences with irregular rhythm, suggesting that it might be used as another evaluation strategy that is potentially widely applicable to qualify the disordered rhythm of PD regardless of the kinds of task or the modality of devices, although further refinement is needed.

Clinical Characteristics of Neuronal Intranuclear Inclusion Disease-Related Retinopathy With CGG Repeat Expansions in the NOTCH2NLC Gene.

Purpose: To report the ocular characteristics of neuronal intranuclear inclusion disease (NIID)-related retinopathy with expansion of the CGG repeats in the NOTCH2NLC gene. Methods: Seven patients from six families (aged 66-81 years) diagnosed with adult-onset NIID were studied. Ophthalmologic examinations, including the best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and full-field electroretinography (ERGs), were performed. The expansion of the CGG repeats in the NOTCH2NLC gene was determined. Results: All patients had an expansion of the CGG repeats (length approximately from 330-520 bp) in the NOTCH2NLC gene. The most common symptoms of the five symptomatic cases were reduced BCVA and night blindness. The other two cases did not have any ocular symptoms. The decimal BCVA varied from 0.15 to 1.2. Goldmann perimetry was constricted in all four cases tested; physiological blind spot was enlarged in two of the cases. The FAF images showed an absence of autofluorescence (AF) around the optic disc in all cases and also showed mild hypo-AF or extinguished AF in the midperiphery. In all cases, the OCT images showed an absence of the ellipsoid zone of the photoreceptors in the peripapillary region, and hyperreflective dots were also present between the retinal ganglion cell layer and outer nuclear layer. The macular region was involved in the late stage of the retinopathy. The full-field ERGs showed rod-cone dysfunction. Conclusions: Patients with adult-onset NIID with CGG repeats expansions in the NOTCH2NLC gene had similar ophthalmologic features, including rod-cone dysfunction with progressive retinal degeneration in the peripapillary and midperipheral regions. The primary site is most likely the photoreceptors. Because the ocular symptoms are often overlooked due to dementia and occasionally precede the onset of dementia, detailed ophthalmological examinations are important for the early diagnosis of NIID-related retinopathy.

Attempt to Predict A/T/N-Based Alzheimer's Disease Cerebrospinal Fluid Biomarkers Using a Peripheral Blood DNA Methylation Clock.

BACKGROUND: Although aging is the strongest risk factor for the development of Alzheimer's disease (AD), it remains uncertain if the blood DNA methylation clock, which reflects the effect of biological aging on DNA methylation (DNAme) status of blood cells, may be used as a surrogate biomarker for AD pathology in the central nervous system (CNS). OBJECTIVE: We aimed to develop a practical model to predict for A/T/N-based AD biomarkers as the prediction targets using the aging acceleration of blood cells. METHODS: We obtained data of North American ADNI study participants (n = 317) whose blood DNA methylation microarray (Illumina HumanMethylation EPIC Beadchips) and cerebrospinal fluid (CSF) AD biomarkers (Aß, t-tau, and p-tau) were recorded simultaneously. Methylation clock was calculated to conduct machine learning, in order to predict binary statuses (+ or -) for A (corresponding to the lowered CSF Aß), T (the elevated CSF p-tau), or N (the elevated CSF t-tau). The predictive performance of the models was evaluated by area under curve (AUC) in the test subset within ADNI. RESULTS: Among the 317 included samples, 194 (61.2%) were A+, 247 (77.9%) were T+, and 104 (32.8%) were N+. The degree of blood aging acceleration showed weak positive correlation with the CSF Aß levels, even after adjustment with APOE genotype and other covariates. However, the contribution of aging acceleration to improve the predictive performance of models was not significant for any of A+, T+, or N+. CONCLUSION: Our exploratory attempts could not demonstrate the substantial utility of the peripheral blood cells' methylation clock as a predictor for A/T/N-based CSF biomarkers of AD, and further additional work should be conducted to determine whether the blood DNAme signatures including methylation clock have substantial utility in detecting underlying amyloid, tau or neurodegeneration pathology of AD.