Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

Focusing on Earlier Management of Alzheimer Disease: Expert Opinion Based on a Modified Nominal Group Technique.

BACKGROUND: Despite the number of people living with Alzheimer disease (AD), awareness of the early stages of this condition, including mild cognitive impairment due to AD-which poses management challenges-continues to be low. To identify areas for improvement in early AD management, dementia specialists convened in a virtual roundtable meeting. METHODOLOGY: A modified version of the nominal group technique was followed to prioritize specific topics and allow experts to provide their opinions. The overarching topics prioritized and discussed were (1) education and support for primary care physicians on cognitive assessment, detection of mild cognitive impairment, and patient monitoring; (2) nonpharmacological interventions; (3) and the introduction of disease-modifying therapies. CONCLUSIONS: Consensus was achieved regarding the need for educating primary care physicians on identifying people with cognitive impairment and for better diagnostic tools for its detection and early management. Management of mild cognitive impairment due to AD should encompass an adequate follow-up schedule aiming to maintain function for as long as possible, and primary care physicians and patients should be aware of the benefits of nonpharmacological interventions.

Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots-A new collection method for remote settings.

BACKGROUND: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSv enous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings. METHODS: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aß) 40, Aß42; and phosphorylated tau (p-tau181 and p-tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single-molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS: All DPSvenous and plasma analytes correlated significantly, except for Aß42. In the validation cohort, DPSvenous GFAP, NfL, p-tau181, and p-tau217 differed between CSF Aß-positive and -negative individuals and were associated with worsening cognition. DISCUSSION: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood-based biomarkers to remote settings with simplified sampling conditions, storage, and logistics. HIGHLIGHTS: A wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPSvenous). DPSvenous biomarkers correlated with standard procedures and cognitive status. DPSvenous biomarkers had a good diagnostic accuracy discriminating amyloid status. Our findings show the potential interchangeability of DPSvenous and plasma sampling. DPSvenous may facilitate remote and temperature-independent sampling for AD biomarker measurement. Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

[Teleconsultation in a coloproctology unit during the COVID-19 pandemic. Preliminary results]. / Teleconsulta en una unidad de coloproctología durante la pandemia de COVID-19. Resultados preliminares.

Introduction: During the state of alarm established in Spain due to the COVID-19 pandemic, most of the face-to-face outpatient consultations were cancelled and a telephone consultation was established to follow up coloproctological patients. The objective of this study was to analyse the efficacy of telemedicine (by telephone) in monitoring patients in a coloproctology unit, in the context of the COVID-19 pandemic. Method: Prospective descriptive study of consecutive patients in a single centre. The result of the teleconsultation was classified as discharge, resolved visit or reprogramming and was analysed by different diagnostic groups. Results: From March 19th to April 17th, 2020, the teleconsultation of 190 patients was carried out. The response rate was 94.2% (179). The diagnostic categories of the patients attended were: 51 (26.9%) colorectal neoplasia, 48 (25.3%) proctological pathology, 72 (37.9%) pelvic floor dysfunctions and 19 (10%) other benign pathologies. 105 (55.26%) could be recited as if they had come in person. Eleven (5.8%) patients were discharged. No significant differences were found between the different diagnostic categories and the resolution of the teleconsultation. The reasons for reprogramming are analyzed in the study. Conclusion: In the context of a pandemic, teleconsultation has allowed 61% of follow-up visits to be definitively solved, avoiding the reprogramming of 116 patients. The new social and health paradigm after the pandemic will require a rethinking of our healthcare model, and in many aspects, telemedicine can offer tools for this.

Unraveling the Tau Puzzle: A Brief Discussion on Biomarkers in Alzheimer's Disease.

This commentary provides an in-depth analysis of a recently published systematic review on 'Biomarkers of Tau Pathology in Alzheimer's Disease', elucidating insights into its implications for the field. This meta-analysis highlights the potential of plasma and CSF p-tau 181/231 as promising, non-invasive, and cost-effective diagnostic tools for patients suffering from AD continuum. The study comprehensively reviews the diagnostic potential of these p-tau isoforms, shedding light on their role in the precision diagnosis of Alzheimer's disease. Here we discuss the significance of these findings and the methodological nuances, emphasizing broader implications for advancing personalized medicine in neurodegenerative disorders.

FACEmemory®, an Innovative Online Platform for Episodic Memory Pre-Screening: Findings from the First 3,000 Participants.

BACKGROUND: The FACEmemory® online platform comprises a complex memory test and sociodemographic, medical, and family questions. This is the first study of a completely self-administered memory test with voice recognition, pre-tested in a memory clinic, sensitive to Alzheimer's disease, using information and communication technologies, and offered freely worldwide. OBJECTIVE: To investigate the demographic and clinical variables associated with the total FACEmemory score, and to identify distinct patterns of memory performance on FACEmemory. METHODS: Data from the first 3,000 subjects who completed the FACEmemory test were analyzed. Descriptive analyses were applied to demographic, FACEmemory, and medical and family variables; t-test and chi-square analyses were used to compare participants with preserved versus impaired performance on FACEmemory (cut-off = 32); multiple linear regression was used to identify variables that modulate FACEmemory performance; and machine learning techniques were applied to identify different memory patterns. RESULTS: Participants had a mean age of 50.57 years and 13.65 years of schooling; 64.07% were women, and 82.10% reported memory complaints with worries. The group with impaired FACEmemory performance (20.40%) was older, had less schooling, and had a higher prevalence of hypertension, diabetes, dyslipidemia, and family history of neurodegenerative disease than the group with preserved performance. Age, schooling, sex, country, and completion of the medical and family history questionnaire were associated with the FACEmemory score. Finally, machine learning techniques identified four patterns of FACEmemory performance: normal, dysexecutive, storage, and completely impaired. CONCLUSIONS: FACEmemory is a promising tool for assessing memory in people with subjective memory complaints and for raising awareness about cognitive decline in the community.

CSF proteomic profiling with amyloid/tau positivity identifies distinctive sex-different alteration of multiple proteins involved in Alzheimer's disease.

In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162 proteins in cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.05). These sex-specific proteins strongly predicted amyloid/tau positivity (AUC=0.98 in males; 0.99 in females), significantly higher than those with age, sex, and APOE-ε4 (AUC=0.85). The identified sex-specific proteins were well validated (r≥0.5) in the Stanford study (N=108) and Emory study (N=148). Biological follow-up of these proteins led to sex differences in cell-type specificity, pathways, interaction networks, and drug targets. Male-specific proteins, enriched in astrocytes and oligodendrocytes, were involved in postsynaptic and axon-genesis. The male network exhibited direct connections among 152 proteins and highlighted PTEN, NOTCH1, FYN, and MAPK8 as hubs. Drug target suggested melatonin (used for sleep-wake cycle regulation), nabumetone (used for pain), daunorubicin, and verteporfin for treating AD males. In contrast, female-specific proteins, enriched in neurons, were involved in phosphoserine residue binding including cytokine activities. The female network exhibits strong connections among 51 proteins and highlighted JUN and 14-3-3 proteins (YWHAG and YWHAZ) as hubs. Drug target suggested biperiden (for muscle control of Parkinson's disease), nimodipine (for cerebral vasospasm), quinostatin and ethaverine for treating AD females. Together, our findings provide mechanistic understanding of sex differences for AD risk and insights into clinically translatable interventions.

Relationships of change in Clinical Dementia Rating (CDR) on patient outcomes and probability of progression: observational analysis.

BACKGROUND: Understanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer's disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD. METHODS: The study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models. RESULTS: The estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period. CONCLUSIONS: The findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling.

Sex and aging signatures of proteomics in human cerebrospinal fluid identify distinct clusters linked to neurodegeneration.

Sex and age are major risk factors for chronic diseases. Recent studies examining age-related molecular changes in plasma provided insights into age-related disease biology. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and neurodegeneration. By comprehensively examining 7,006 aptamers targeting 6,139 proteins in CSF obtained from 660 healthy individuals aged from 43 to 91 years old, we subsequently identified significant sex and aging effects on 5,097 aptamers in CSF. Many of these effects on CSF proteins had different magnitude or even opposite direction as those on plasma proteins, indicating distinctive CSF-specific signatures. Network analysis of these CSF proteins revealed not only modules associated with healthy aging but also modules showing sex differences. Through subsequent analyses, several modules were highlighted for their proteins implicated in specific diseases. Module 2 and 6 were enriched for many aging diseases including those in the circulatory systems, immune mechanisms, and neurodegeneration. Together, our findings fill a gap of current aging research and provide mechanistic understanding of proteomic changes in CSF during a healthy lifespan and insights for brain aging and diseases.

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

INTRODUCTION: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. Highlights: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Exploring small non-coding RNAs as blood-based biomarkers to predict Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) diagnosis relies on clinical symptoms complemented with biological biomarkers, the Amyloid Tau Neurodegeneration (ATN) framework. Small non-coding RNA (sncRNA) in the blood have emerged as potential predictors of AD. We identified sncRNA signatures specific to ATN and AD, and evaluated both their contribution to improving AD conversion prediction beyond ATN alone. METHODS: This nested case-control study was conducted within the ACE cohort and included MCI patients matched by sex. Patients free of type 2 diabetes underwent cerebrospinal fluid (CSF) and plasma collection and were followed-up for a median of 2.45-years. Plasma sncRNAs were profiled using small RNA-sequencing. Conditional logistic and Cox regression analyses with elastic net penalties were performed to identify sncRNA signatures for A+(T|N)+ and AD. Weighted scores were computed using cross-validation, and the association of these scores with AD risk was assessed using multivariable Cox regression models. Gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) enrichment analysis of the identified signatures were performed. RESULTS: The study sample consisted of 192 patients, including 96 A+(T|N)+ and 96 A-T-N- patients. We constructed a classification model based on a 6-miRNAs signature for ATN. The model could classify MCI patients into A-T-N- and A+(T|N)+ groups with an area under the curve of 0.7335 (95% CI, 0.7327 to 0.7342). However, the addition of the model to conventional risk factors did not improve the prediction of AD beyond the conventional model plus ATN status (C-statistic: 0.805 [95% CI, 0.758 to 0.852] compared to 0.829 [95% CI, 0.786, 0.872]). The AD-related 15-sncRNAs signature exhibited better predictive performance than the conventional model plus ATN status (C-statistic: 0.849 [95% CI, 0.808 to 0.890]). When ATN was included in this model, the prediction further improved to 0.875 (95% CI, 0.840 to 0.910). The miRNA-target interaction network and functional analysis, including GO and KEGG pathway enrichment analysis, suggested that the miRNAs in both signatures are involved in neuronal pathways associated with AD. CONCLUSIONS: The AD-related sncRNA signature holds promise in predicting AD conversion, providing insights into early AD development and potential targets for prevention.

Association between clinical dementia rating and clinical outcomes in Alzheimer's disease.

INTRODUCTION: We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI-Q]), and cognitive impairment in Alzheimer's disease (AD). METHODS: We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR-global. RESULTS: Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI-Q scores increased steeply with MCI (NPI-Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI-Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). DISCUSSION: CDR-global staged AD by capturing differences in relevant outcomes along AD progression. Highlights: There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages.

Unveiling the sound of the cognitive status: Machine Learning-based speech analysis in the Alzheimer's disease spectrum.

BACKGROUND: Advancement in screening tools accessible to the general population for the early detection of Alzheimer's disease (AD) and prediction of its progression is essential for achieving timely therapeutic interventions and conducting decentralized clinical trials. This study delves into the application of Machine Learning (ML) techniques by leveraging paralinguistic features extracted directly from a brief spontaneous speech (SS) protocol. We aimed to explore the capability of ML techniques to discriminate between different degrees of cognitive impairment based on SS. Furthermore, for the first time, this study investigates the relationship between paralinguistic features from SS and cognitive function within the AD spectrum. METHODS: Physical-acoustic features were extracted from voice recordings of patients evaluated in a memory unit who underwent a SS protocol. We implemented several ML models evaluated via cross-validation to identify individuals without cognitive impairment (subjective cognitive decline, SCD), with mild cognitive impairment (MCI), and with dementia due to AD (ADD). In addition, we established models capable of predicting cognitive domain performance based on a comprehensive neuropsychological battery from Fundació Ace (NBACE) using SS-derived information. RESULTS: The results of this study showed that, based on a paralinguistic analysis of sound, it is possible to identify individuals with ADD (F1 = 0.92) and MCI (F1 = 0.84). Furthermore, our models, based on physical acoustic information, exhibited correlations greater than 0.5 for predicting the cognitive domains of attention, memory, executive functions, language, and visuospatial ability. CONCLUSIONS: In this study, we show the potential of a brief and cost-effective SS protocol in distinguishing between different degrees of cognitive impairment and forecasting performance in cognitive domains commonly affected within the AD spectrum. Our results demonstrate a high correspondence with protocols traditionally used to assess cognitive function. Overall, it opens up novel prospects for developing screening tools and remote disease monitoring.

Association of oxidative stress and inflammatory metabolites with Alzheimer's disease cerebrospinal fluid biomarkers in mild cognitive impairment.

BACKGROUND: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aß-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. METHODS: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aß-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. RESULTS: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression. CONCLUSIONS: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.

Genome-wide association study and polygenic risk scores of retinal thickness across the cognitive continuum: data from the NORFACE cohort.

BACKGROUND: Several studies have reported a relationship between retinal thickness and dementia. Therefore, optical coherence tomography (OCT) has been proposed as an early diagnosis method for Alzheimer's disease (AD). In this study, we performed a genome-wide association study (GWAS) aimed at identifying genes associated with retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness assessed by OCT and exploring the relationships between the spectrum of cognitive decline (including AD and non-AD cases) and retinal thickness. METHODS: RNFL and GCIPL thickness at the macula were determined using two different OCT devices (Triton and Maestro). These determinations were tested for association with common single nucleotide polymorphism (SNPs) using adjusted linear regression models and combined using meta-analysis methods. Polygenic risk scores (PRSs) for retinal thickness and AD were generated. RESULTS: Several genetic loci affecting retinal thickness were identified across the genome in accordance with previous reports. The genetic overlap between retinal thickness and dementia, however, was weak and limited to the GCIPL layer; only those observable with all-type dementia cases were considered. CONCLUSIONS: Our study does not support the existence of a genetic link between dementia and retinal thickness.

Macular vessel density in the superficial plexus is not a proxy of cerebrovascular damage in non-demented individuals: data from the NORFACE cohort.

INTRODUCTION: Optical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with measures of cerebrovascular pathology and atrophy quantified by brain magnetic resonance imaging (MRI) in non-demented individuals. METHODS: Clinical, demographical, OCT-A, and brain MRI data from non-demented research participants were included. We analyzed the association of regional macular VD with brain vascular burden using the Fazekas scale assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) assessed in a multiple linear regression analysis. We also explored the associations of macular VD with hippocampal volume, ventricle volume and Alzheimer disease cortical signature (ADCS) thickness assessed in multiple linear regression analyses. All analyses were adjusted for age, sex, syndromic diagnosis and cardiovascular variables. RESULTS: The study cohort comprised 188 participants: 89 with subjective cognitive decline and 99 with mild cognitive impairment. No significant association of regional macular VD with the Fazekas categories (all, p > 0.111) and WMH volume (all, p > 0.051) were detected. VD in the nasal quadrant was associated to hippocampal volume (p = 0.007), but no other associations of macular VD with brain atrophy measures were detected (all, p > 0.05). DISCUSSION: Retinal vascular measures were not a proxy of cerebrovascular damage in non-demented individuals, while VD in the nasal quadrant was associated with hippocampal atrophy independently of the amyloid status.

Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.

The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n = 719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.