Alzheimer's Disease In Population Research Articles

Blood Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-Analysis.

Neuroinflammation, particularly early astrocyte reactivity, is a significant driver of Alzheimer disease (AD) pathogenesis. It is unclear how the levels of astrocyte biomarkers change in patients across the AD continuum and which best reflect AD-related change. We performed a systematic review and meta-analysis of 3 blood astrocyte biomarkers (glial fibrillary acidic protein [GFAP], chitinase-3-like protein 1 [YKL-40], and S100B) in patients clinically diagnosed with AD. MEDLINE and Web of Science were searched on March 23, 2023, without restrictions on language, time, or study design, for studies reporting blood levels of the astrocyte biomarkers GFAP, YKL-40, or S100B in patients on the AD continuum (including those with mild cognitive impairment [MCI] and dementia) and a cognitively unimpaired (CU) control population. AD diagnosis was based on established diagnostic criteria and/or comprehensive multidisciplinary clinical consensus. Studies reporting indirect biomarker measures (e.g., levels of biomarker autoantibodies) were excluded. Risk of bias assessment was performed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. Pooled effect sizes were determined using the Hedge g method with a random-effects model. The review was prospectively registered on PROSPERO (registration number CRD42023458305). The search identified 1,186 studies; 36 met inclusion criteria (AD continuum n = 3,366, CU n = 4,115). No study was assessed to have a high risk of bias. Compared with CU individuals, patients on the AD continuum had higher GFAP and YKL-40 levels (GFAP effect size 1.15, 95% CI 0.94-1.36, p < 0.0001; YKL-40 effect size 0.38, 95% CI 0.28-0.49, p < 0.0001). Both biomarkers were elevated in more advanced clinical stages of the disease (i.e., in AD dementia compared with MCI due to AD: GFAP effect size 0.48, 95% CI 0.19-0.76, p = 0.0009; YKL-40 effect size 0.34, 95% CI 0.10-0.57, p = 0.0048). No significant differences in blood S100B levels were identified. We demonstrated significant elevations in blood GFAP and YKL-40 levels in patients on the AD continuum compared with CU individuals. Furthermore, within the AD clinical spectrum, significant elevation correlated with more advanced disease stage. Our findings suggest that both biomarkers reflect AD-related pathology. Our findings are limited by the lack of cultural and linguistic diversity in the study populations meta-analyzed. Future meta-analyses using a biomarker-defined AD population are warranted.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD. The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ42/Aβ40) and tau pathology (p-tau181) were enrolled, with serial CSF and plasma levels of Aβ42 and Aβ40 measured over 104 weeks. Longitudinal changes of CSF Aβ42, plasma Aβ42/Aβ40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex. A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ42 level and plasma Aβ42/Aβ40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26). In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD. https://clinicaltrials.gov/study/NCT04693520.

Alzheimer's diseases in America, Europe, and Asian regions: a global genetic variation.

Alzheimer's disease (AD) is one of the multifaceted neurodegenerative diseases influenced by many genetic and epigenetic factors. Genetic factors are merely not responsible for developing AD in the whole population. The studies of genetic variants can provide significant insights into the molecular basis of Alzheimer's disease. Our research aimed to show how genetic variants interact with environmental influences in different parts of the world. We searched PubMed and Google Scholar for articles exploring the relationship between genetic variations and global regions such as America, Europe, and Asia. We aimed to identify common genetic variations susceptible to AD and have no significant heterogeneity. To achieve this, we analyzed 35 single-nucleotide polymorphisms (SNPs) from 17 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, TOMM40, MS4A6A, ARID5B, SORL1, APOC1, MTHFD1L, BDNF, TFAM, and PICALM) from different regions based on previous genomic studies of AD. It has been reported that rs3865444, CD33, is the most common polymorphism in the American and European populations. From TOMM40 and APOE rs2075650, rs429358, and rs6656401, CR1 is the common investigational polymorphism in the Asian population. The results of all the research conducted on AD have consistently shown a correlation between genetic variations and the incidence of AD in the populations of each region. This review is expected to be of immense value in future genetic research and precision medicine on AD, as it provides a comprehensive understanding of the genetic factors contributing to the development of this debilitating disease.

Three major effects of APOEε4 on Aβ immunotherapy induced ARIA.

The targeting of amyloid-beta (Aβ) plaques therapeutically as one of the primary causes of Alzheimer's disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (micro- and macro-). From preclinical and clinical trials, it has been observed that the greatest genetic risk factor for AD, APOEε4, is also a major risk factor for anti-Aβ immunotherapy-induced ARIA. APOEε4 carriers represent a large population of AD patients, and, therefore, limits the broad adoption of these therapies across the AD population. In this review we detail three hypothesized mechanisms by which APOEε4 influences ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of CAA. The effects of APOEε4 on ARIA risk is clear, however, the underlying mechanisms require more research.

Alzheimer’s disease classification algorithm based on fusion of channel attention and densely connected networks

Mild cognitive impairment (MCI) is a syndrome that occurs in the preclinical stage of Alzheimer’s disease (AD) and is also an early signal of the onset of AD. Early detection and accurate differentiation between MCI and AD populations, and providing them with effective intervention and treatment, are of great significance for preventing or delaying the onset of AD. In this paper, we propose a deep learning model, SE-DenseNet, that combines channel attention and dense connectivity networks and apply it to the field of magnetic resonance imaging (MRI) data recognition for the diagnosis of AD and MCI. First, to extract MRI features with high quality, a slicing algorithm based on two-dimensional image information entropy is proposed to obtain AD brain lesion features with stronger representation ability. Second, in terms of model structure, SENet is introduced as a channel attention module and redistribute the weight of image features in the channel dimension; use DenseNet as the main architecture to maximize information flow, and each layer is directly interconnected with subsequent layers. It enables the network to learn and extract relevant features from the input data and improve the classification ability of the network. Finally, our proposed model is validated on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, the results have shown that the accuracy for the four classification tasks of AD-NC, AD-MCI, NC-MCI, and AD-NC-MCI can reach 98.12%, 97.42%, 97.42%, and 95.24%, respectively. At the same time, the sensitivity and specificity have also achieved satisfactory results, exhibited a high performance in comparison with the classic machine learning algorithm and several existing state-of-the-art deep learning methods, demonstrating the proposed method is a powerful tool for the early diagnosis and detection of AD.

Impact of serum leptin and adiponectin levels on brain infarcts in patients with mild cognitive impairment and Alzheimer's disease: a longitudinal analysis.

The adipokines leptin and adiponectin have been associated with atherosclerosis and the risk of cerebral infarcts. Pre-clinical studies, however, suggest a protective role against ischemic brain damage. In this study we analyzed the relationship between serum leptin and adiponectin levels and the onset or progression of brain infarcts in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). All data were extracted from the ADNI database. The final population included 566 subjects, with 58 healthy controls, 396 MCI and 112 AD. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographics, neuropsychological test results, CSF biomarkers, regional brain metabolism with FDG-PET data and the number of brain infarcts on longitudinal MRI scans were extracted. Leptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the groups. Multivariate logistic regression analysis at baseline for the presence of brain infarcts showed a predictive value for leptin but not for adiponectin. Multivariate longitudinal analysis showed that age was the only significant predictor of brain infarcts development at 15-year follow-up, while serum leptin and adiponectin levels did not play a role in this population. The evidence on the pathogenetic or protective role of adipokines on ischemic brain damage is mixed. In this MCI and AD population, serum leptin and adiponectin were not associated with the development of brain infarcts; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.

Application of a Novel Endpoint Staging Framework: Proof of Concept in the AMBAR Study.

A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer's disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized 'target' stages of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (-4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS. Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework.

The Associations of Phosphorylated Tau 181 and Tau 231 Levels in Plasma and Cerebrospinal Fluid with Cognitive Function in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Cerebrospinal fluid (CSF) or blood biomarkers like phosphorylated tau proteins (p-tau) are used to detect Alzheimer's disease (AD) early. Increasing studies on cognitive function and blood or CSF p-tau levels are controversial. Our study examined the potential of p-tau as a biomarker of cognitive status in normal control (NC), mild cognitive impairment (MCI), and AD patients. We searched PubMed, Cochrane, Embase, and Web of Science for relevant material through 12 January 2023. 5,017 participants from 20 studies-1,033 AD, 2,077 MCI, and 1,907 NC-were evaluated. Quantitative analysis provided continuous outcomes as SMDs with 95% CIs. Begg tested publication bias. MCI patients had lower CSF p-tau181 levels than AD patients (SMD =-0.60, 95% CI (-0.85, -0.36)) but higher than healthy controls (SMD = 0.67). AD/MCI patients had greater plasma p-tau181 levels than healthy people (SMD =-0.73, 95% CI (-1.04, -0.43)). MCI patients had significantly lower p-tau231 levels than AD patients in plasma and CSF (SMD =-0.90, 95% CI (-0.82, -0.45)). MCI patients showed greater CSF and plasma p-tau231 than healthy controls (SMD = 1.34, 95% CI (0.89, 1.79) and 0.43, (0.23, 0.64)). Plasma p-tau181/231 levels also distinguished the three categories. MCI patients had higher levels than healthy people, while AD patients had higher levels than MCI patients. CSF p-tau181 and p-tau231 biomarkers distinguished AD, MCI, and healthy populations. Plasma-based p-tau181 and p-tau231 biomarkers for AD and MCI need further study.

Efficacy and safety of repetitive Transcranial Magnetic Stimulation and transcranial Direct Current Stimulation in memory deficits in patients with Alzheimer's disease: Meta-analysis and systematic review

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are two of the most used non-pharmacological interventions for Alzheimer's Disease (AD). However, most of the clinical trials have focused on evaluating the effects on global cognition and not on specific cognitive functions. Therefore, considering that memory loss is one of the hallmark symptoms of AD, we aim to assess the efficacy and safety of tDCS and rTMS in memory deficits. For that, multilevel random effect models were performed considering the standardized mean difference (SMD) between active and sham stimulation. A total of 19 studies with 411 participants demonstrated positive effects in memory after tDCS (SMD=0.20, p = 0.04) and rTMS (SMD=0.44, p = 0.001). Subgroup analysis revealed that tDCS had greater efficacy when administered in temporal regions (SMD=0.32, p = 0.04), whereas rTMS was superior when applied in frontal regions (SMD=0.61, p < 0.001). Therefore, depending on the brain region of stimulation, both interventions produced a positive effect on memory symptoms in AD patients. Finally, the safety of both techniques was observed in the AD population after the reporting of almost no serious events.

Vortioxetine Treatment for Depression in Patients with Prodromal vs Mild Alzheimer’s Disease: A Six-Month, Open-Label, Observational Study

BackgroundDepressive symptoms are common in Alzheimer disease (AD) from the prodromal stage. The benefits of antidepressants have been investigated in patients with AD dementia with mixed results.ObjectivesThis study aimed to compare the efficacy of vortioxetine in prodromal and mild-to-moderate AD patients with depression, and to assess the comparative effect on secondary measures, including behavioral disturbances, cognitive function, and activities of daily living.ParticipantsAll subjects with AD at a single-center dementia center underwent a standard evaluation with mini-mental state examination (MMSE), basic and instrumental activities of daily living (BADL and IADL), geriatric depression scale (CDS), neuropsychiatrie inventory (NPI), and clinical evaluation every six months.MeasurementsThe study specifically assessed patients on vortioxetine with available six-month follow-up data. The changes in CDS, NPI, MMSE, BADL/IADL at six months in the entire AD population and mild-to-moderate AD vs prodromal population were analyzed using repeated measure multivariate analyses. Linear regression analyses were implemented to evaluate baseline demographics and clinical characteristics associated with depressive and cognitive improvements at six months.ResultsOut of 680 AD patients, 115 were treated with vortioxetine, and 89 with six-month follow-up data were included in the analyses. A significant improvement at follow-up was observed for CDS, NPI total and sub score items (mood, anxiety, apathy, sleep disturbances, eating abnormalities). Both mild-to-moderate and prodromal AD showed a positive CDS response, whereas mild-to-moderate AD showed a better improvement on total NPI and apathy/nighttime behaviors subitems compared to prodromal AD. Higher baseline CDS score was the only variable associated with higher responses in linear regression analyses. MMSE showed a significant improvement at six months in the entire cohort, with a greater effect in prodromal vs mild-to-moderate AD. Cognitive improvement (i.e., MMSE changes) was associated with cognitive status at baseline but independent of the antidepressant/behavioral changes (i.e., GDS/NPI).ConclusionsOur results suggest that vortioxetine is highly tolerable and clinically effective in both prodromal and mild-to-moderate AD with depression. Patients with mild-to-moderate AD benefited more from a wide range of behavioral disturbances. The study also showed significant improvement in global cognitive measures, especially in prodromal AD subjects. Further studies are needed to investigate the independent beneficial effect of vortioxetine on depression and cognition in AD.

Connected speech features in non-English speakers with Alzheimer’s disease: protocol for scoping review

BackgroundA large body of literature indicates that connected speech profiles in patients with Alzheimer’s disease (AD) can be utilized for diagnosis, disease monitoring, and for developing communication strategies for patients. Most connected speech research has been conducted in English, with little work in some European languages. Therefore, significant drawback remains with respect to the diversity of languages studied, and how the fragmentation of linguistic features differs across languages in AD. Accordingly, existing reviews on connected speech in AD have focused on findings from English-speaking patients; none have specifically focused on the linguistic diversity of AD populations. This scoping review is undertaken to provide the currently reported characteristics of connected speech in AD in languages other than English. It also seeks to identify the type of assessments, methods to elicit speech samples, type of analysis and linguistic frameworks used, and micro- and macro-linguistic features of speech reported in non-English speakers with AD.MethodWe will conduct a scoping review of published studies that have quantitively assessed connected speech in AD in languages other than English. The inclusion criteria for the studies would be subject/s with a clinical diagnosis of AD. The search will include the electronic databases PubMed, Ovid-Embase, PsycINFO, Linguistic and Language Behaviour s (LLBA), and Web of Science up until March 2023. Findings will be mapped and described according to the languages studied, the methodology employed (e.g., patient characteristics, tasks used, linguistic analysis framework utilized), and connected speech profiles derived (e.g., micro- and macro-linguistic reported).DiscussionThe scoping review will provide an overview of languages studied in connected speech research in AD with variation in linguistic features across languages, thus allowing comparison with the established key features that distinguish AD patients from healthy controls. The findings will inform future research in connected speech in different languages to facilitate robust connected speech research in linguistically and ethnically diverse populations.

Exploring Spoken Discourse and Its Neural Correlates in Women With Alzheimer's Disease With Low Levels of Education and Socioeconomic Status.

Early impairments in spoken discourse abilities have been identified in Alzheimer's disease (AD). However, the impact of AD on spoken discourse and the associated neuroanatomical correlates have mainly been studied in populations with higher levels of education, although preliminary evidence seems to indicate that socioeconomic status (SES) and level of education have an impact on spoken discourse. The purpose of this study was to analyze microstructural variables in spoken discourse in people with AD with low-to-middle SES and low level of education and to study their association with gray matter (GM) density. Nine women with AD and 10 matched (age, SES, and education) women without brain injury (WWBI) underwent a neuropsychological assessment, which included two spoken discourse tasks, and structural magnetic resonance imaging. Microstructural variables were extracted from the discourse samples using NILC-Metrix software. Brain density, measured by voxel-based morphometry, was compared between groups and then correlated with the differentiating microstructural variables. The AD group produced a lower diversity of verbal time moods and fewer words and sentences than WWBI but a greater diversity of pronouns, prepositions, and lexical richness. At the neural level, the AD group presented a lower GM density bilaterally in the hippocampus, the inferior temporal gyrus, and the anterior cingulate gyrus. Number of words and sentences produced were associated with GM density in the left parahippocampal gyrus, whereas the diversity of verbal moods was associated with the basal ganglia and the anterior cingulate gyrus bilaterally. The present findings are mainly consistent with previous studies conducted in groups with higher levels of SES and education, but they suggest that atrophy in the left inferior temporal gyrus could be critical in AD in populations with lower levels of SES and education. This research provides evidence on the importance of pursuing further studies including people with various SES and education levels. Spoken discourse has been shown to be affected in Alzheimer disease, but most studies have been conducted on individuals with middle-to-high SES and high educational levels. The study reports on microstructural measures of spoken discourse in groups of women in the early stage of AD and healthy women, with low-to-middle SES and lower levels of education. This study highlights the importance of taking into consideration the SES and education level in spoken discourse analysis and in investigating the neural correlates of AD. https://doi.org/10.23641/asha.24905046.

Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study.

Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. The goal of this study was to study human GE180 from the perspective of the previous animal observations. With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

PP125 Why Understanding The Burden Of The Population Is Fundamental

IntroductionDespite intense efforts in development of new treatments over the last two decades, symptomatic treatments remain the only option for the vast majority patients diagnosed with dementia due to Alzheimer’s disease (AD). There remains a significant unmet need for disease modifying therapies (DMTs) to slow or stop AD progression. DMTs in development are targeting early stages of AD (pre-clinical, mild cognitive impairment and mild dementia stages), thereby creating an entirely new treatment paradigm for patients, clinicians, and payers. A key challenge will be in identifying the appropriate patient for treatment in a very heterogenous population. We have performed a literature review to better understand and define the AD population, with a view to enabling more targeted treatment in future.MethodsEmbase, MEDLINE and the Cochrane Library were searched to identify publications between 2010-2021 on observational studies reporting evidence on prevalence and subgroup identification, including clinical feasibility of identification. The search was restricted to English language.ResultsWe identified 45 studies, mostly from Europe, USA and Asia. Populations were primarily grouped based on generic demographic factors (e.g., age, sex, gender), AD staging, comorbidities or biomarkers. Prevalence data was available for six subpopulations: pre-dementia stage, mild dementia, age, Apolipoprotein E (APOE) genotype, comorbid obesity and hypertension. Across these, data on prevalence were heterogenous depending on study design and country of origin, and ranging between 66 million to 102 million for people with mild AD dementia, or as another example, ranging between 46 million to 92 million for APOE genotype carriers worldwide.ConclusionsThe heterogeneity and the uncertainty in prevalence of the AD population represent big challenges to clinicians and payers. Future discussions on target patient identification for new treatments should be aligned and integrated with current clinical practice e.g. leveraging validated biomarkers as diagnostic tools. Additional research on an integrated approach to identify patients who would benefit the most from DMTs will be needed.

Nutrition in Alzheimer’s Disease: A Review of an Underappreciated Pathophysiological Mechanism

AbstractBackgroundPharmacy therapy of Alzheimer’s disease (AD) is one of the areas that are well funded, but where little progress has been made due to the complex pathogenesis. The gut‐microbiota‐brain axis has gained tremendous traction in the pathogenesis of AD through bidirectional communication with multiple neural, immune, and metabolic pathways, providing new insights into novel therapeutic strategies. Dietary nutrition is an important and profound environmental factor that influences the composition and function of the microbiota. The Nutrition for Dementia Prevention Working group recently found that dietary nutrition can affect the cognition of AD‐related dementia directly or indirectly through complex interactions of behavioral, genetic, systemic, and brain factors. This review aimed to emphasize the knowledge gaps to provide direction for future research and to establish optimal nutrition‐based intervention strategies for AD.MethodThis review discusses the associated evidence between malnutrition and the onset and development of AD for modifying the potentially reversible nutrition‐related risk factors of AD, describe the potential pathogenesis underlying the role of nutrition in the progression of AD and emphasize the current knowledge gaps for further research.ResultThe role and effects that nutrition and diet have on AD are more pervasive than previously believed. We identified and highlighted a novel vicious cycle comprising malnutrition, development of AD, and heavy caregiver burden (Figure 1). As pharmacological approaches demonstrate limited benefits for improving the symptoms of AD, early nutritional intervention for preventing or delaying the progression of AD are worth attempting. The mechanisms underlying the effect of nutrition on the development of AD remain uncertain, including genetics and epigenetics, AD‐specific biomarkers, metabolic pathways, the gut‐microbiota‐inflammation‐brain axis, and their complex interactions (Figure 2).ConclusionThese potential nutrition‐related pathogenic pathways can be exploited as an important environmental factor and could be the focus of targeted AD interventions. Future research is needed to fill in the discussed gaps in knowledge, including prospective studies to identify nutritional biomarkers that can predict AD, multi‐omics studies to elucidate the exact mechanisms by which nutrition influences AD, and clinical trials to identify the best nutritional intervention strategies to prevent and improve cognitive and behavioral disturbances in the AD population.

18F]AV45 standardized uptake value ratio harmonization using ComBat in multi‐center cross‐sectional Alzheimer’s studies

AbstractBackground[18F]AV45 (florbetapir) based Positron emission tomography (PET) imaging of brain amyloid load is one of the core biomarkers for Alzheimer’s disease (AD). However, with the rise in the trend of combining data from multicenter studies, the need to correct substantial technical variability associated with image intensity scale due to multi‐center effect continues to rise. While smoothing methods remove small variability, data‐driven feature harmonization methods can adjust for scanner settings and patient motion without over‐blurring the scans. Here we aimed to investigate the effect of ComBat harmonization on multi‐site florbetapir studies to reduce variance across diagnosis groups.MethodWe assessed 163 scans from the Alzheimer’s disease Neuroimaging Initiative (ADNI3) database. These scans were acquired from 14 different sites. T1‐weighted MRI images were processed using the ADNI pipeline. PET images had 20 min (4×5min frames) acquisition at 50‐70 min post‐injection of 370 MBq (10.0 mCi) ± 10% florbetapir. Raw PET images from all sites were downloaded for quality control at the University of Michigan where the rest of the preprocessing took place using ADNI guidelines. These preprocessed scans were then used to extract SUVR maps using the cerebellar gray matter as the reference region. Based on the literature, the global SUVR for each subject was estimated from the averaged frontal, parietal, temporal, and cingulate cortices. ComBat harmonization was then performed using multicenter data, preserving diagnosis group as the covariate. A paired t‐test and logistic regression were performed to analyze the effect of the harmonization method on the SUVR.ResultA paired t‐test confirms the significant difference between the pre‐and post‐ComBat SUVR, especially for AD samples. Although the variance only decreases by 7.1% for CN as opposed to 26.9% (MCI) and 55.4% (AD), this may be explained by the large variance in the age in the sample as well as the possibility of amyloid positive individuals in the CN population. The logistic regression shows an accuracy of 87.9% for AD.ConclusionEven though ComBat harmonization significantly reduces the variance in AD and MCI population, more studies need to be performed to check its use across all PET derived features.

Associations of GFAP, NfL, Aβ42/40, and pTau231 with global cognition in LEADS

AbstractBackgroundHistorically, Alzheimer’s disease (AD) biomarkers have been used to identify the presence of pathology and have been shown to change well ahead of symptom onset. While previous research has evaluated plasma pTau231 and its associations with cognition, little to none of this research has focused on early‐onset AD (EOAD) populations. Here we investigate how select plasma biomarkers are associated with global cognitive measures in early‐onset cognitive impairment.MethodThe current sample included 367 Longitudinal Early‐Onset AD Study (LEADS) participants (aged 41 to 65) categorized as amyloid PET‐positive EOAD, amyloid PET‐negative EOnonAD, or cognitively normal (CN). Each participant had baseline global cognitive (Mini‐Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA], Clinical Dementia Rating Scale sum of boxes [CDR‐SB], and ADAS‐Cog13) and plasma biomarker assessments (Simoa‐HDx N4PE kit: Aβ42/40, phosphorylated Tau [pTau231], Neurofilament light protein [NfL], and glial fibrillary acidic protein [GFAP]). Partial correlations were used to check for associations with cognitive performance controlling for age, sex, and years of education. Fisher r‐to‐z transformations were conducted to compare the performance across diagnostic groups.ResultPartial correlations in the pooled sample showed moderate associations between cognition and plasma pTau231, GFAP and NfL (r = .42‐.50, p&lt;.001) and weaker associations with Aβ42/40 (r = .25‐.33, p&lt;.001). When split into diagnostic groups, the NfL and GFAP correlations were significant in both EOAD and EOnonAD, but not CN. The pTau231 correlations were significant only in EOAD. Aβ42/40 correlations were non‐significant within specific diagnostic groups. No differences were observed in the magnitude of the cognitive and biomarker associations between EOAD and EOnonAD samples (ps&gt;.05).ConclusionAs expected, the neurodegenerative biomarkers pTau231 and NfL showed stronger association with cognition compared to the marker for brain amyloidosis (Aβ42/40). The nonspecific markers for neurodegeneration (NfL) and brain astrogliosis (GFAP) showed associations in both EOAD and EOnonAD while the markers specific to AD were only significant in EOAD. Plasma biomarkers show great promise for AD diagnosis and monitoring.

Preclinical Alzheimer’s disease is associated with distinct gut microbial metagenomic profiles

AbstractBackgroundAlterations in gut microbiome in individuals with Alzheimer’s disease (AD) may contribute to development or exacerbation of AD pathology via the microbiota‐gut‐brain axis. Composition and diversity of gut microbiota have been studied previously in AD dementia; here we investigate the gut microbial genes involved and their association with AD pathology prior to development of dementia.MethodCerebrospinal fluid (CSF; N = 98) and fecal samples (N = 333) were collected from participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center studies. CSF biomarkers of AD, β‐amyloid (Aβ)42/Aβ40 and phosphorylated‐tau‐181 (phospho‐tau [181P]), were quantified using robust prototype assays from the Roche NeuroToolKit (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Fecal samples were analyzed by whole genome sequencing. Sequences were filtered, quality controlled, and profiled for taxonomy and functional classification at species level using MetaPhlAn 4.0/HUMAnN 3.0 software. Compositional/functional differential abundance, alpha‐/beta‐diversity, correlation between feature abundance and sample metadata, gene‐set enrichment (GSE), and network analyses were performed using R packages (phyloseq/vegan/DESeq2/NetCoMi/rstatix/clusterProfiler). Analyses compared clinical status and biomarker groups.ResultThe relative abundance of phylum Firmicutes and Bacteroidetes decreased and increased, respectively, in individuals with AD versus cognitively unimpaired (CU) individuals. In CU individuals, functional profiles differed in Aβ‐positive (A+) and phospho‐tau [181P]‐positive (T+) groups versus Aβ‐ and phospho‐tau [181P]‐negative (A−T−) individuals. In the microbial metagenome, 64 genes were significantly increased (p &lt; 0.05) in the A+T+ group versus the A−T− group; 21/64 genes had ≥1 significant correlation with the AD biomarkers (e.g., toxic protein SymE positively correlated with phospho‐tau [181P] and negatively correlated with Aβ42/Aβ40 in CU individuals, suggesting that it may be a contributor to pathophysiological metabolic pathways in AD). Three KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in GSE analyses, including fatty acid metabolism/degradation and cationic antimicrobial peptide resistance, were significantly associated (p &lt; 0.05) with genes that were enriched in the AD population versus CU individuals.ConclusionIndividuals with AD have distinct differential abundance in microbiota composition, in addition to an increase and enrichment of genes associated with AD pathogenesis pathways. These genes were associated with AD biomarkers prior to development of AD dementia.

Real‐world use and cost of health and social care services of 18,116 patients living with Alzheimer’s disease

AbstractBackgroundThe increasing prevalence of Alzheimer’s disease (AD) will substantially impact health and social care systems worldwide. In this study, we aimed to estimate the real‐world use and cost of health and social care services in a large cohort of AD patients in the United Kingdom.MethodWe conducted a retrospective cohort study using Discover‐NOW, a real‐world database containing linked primary and secondary care electronic health records of people living in North‐West London, England. A total of 18,116 patients diagnosed with AD were followed from first observed AD diagnosis to end of patient follow up, within the time window from 1 January 2010 to 31 December 2021. The baseline prevalence of 33 comorbidities, survival duration, health and social care resource utilisation and total direct health and social care costs (in 2019 terms) were estimated.ResultOf 18,116 patients with AD, 8,970 (50%) used social care after diagnosis. Most patients using social care were female (65% vs 62% in the general AD population) and were a similar age at diagnosis (median 82 years) compared to those who did not. Of the patients with social care utilisation, 5,248 (59%) resided in care homes and 2,636 (29%) received domiciliary care at home. Annual direct social and health care costs for each patient receiving social care were £25,664 and £6,248 respectively, constituting an annual total cost of £31,912. Median survival from time of AD diagnosis was 4.9 years in the general AD population and 1.9 years after care home admission. Patients who entered care homes, entered at a median age of 85 years and had higher baseline prevalence of stroke (11% vs 7%), chronic kidney disease (40% vs 35%), and atrial fibrillation (17% vs 13%) than the general AD population.ConclusionIn AD patients who used social care, social care costs were &gt;4 times other healthcare costs. Slowing or delaying the requirement for social care would have a major impact on reducing the societal and economic burden of AD on patients and society.