Mild Alzheimer's Disease Research Articles

Mild cognitive impairment and early Alzheimer's disease eligibility for disease modification therapies in a tertiary centre for cognitive disorders: A simultaneous real-word study on aducanumab and lecanemab.

The Food and Drug Administration approved two disease-modifying treatments (DMTs) for Alzheimer's disease (AD), aducanumab and lecanemab, with limited clinical impact but significant biomarker changes. Identifying suitable candidates for these DMTs outside randomized clinical trials (RCTs) remains uncertain. This cross-sectional study, conducted in an Italian tertiary centre for cognitive disorders, aimed to evaluate how the RCT eligibility criteria for DMT treatments applies to participants with early AD. The broader Cummings etal. (Journal of Prevention of Alzheimer's Disease, 2021, 2023) criteria and the clinical differences between DMT candidates were also assessed. The study involved 408 participants (mean age 71.1 ± 8.5 years, 48% male) with a clinical diagnosis of mild cognitive impairment (161/408, 39.5%) or mild dementia (247/408, 60.5%). Amongst them, 169 individuals (41%) showed positive AD pathology biomarkers. Eligibility RCT assessment revealed 14 patients eligible for aducanumab (3.43% of 408) and 28 for lecanemab (6.86% of 408). Following Cummings' real-world criteria, aducanumab eligibility increased to 9.56%, whereas lecanemab eligibility rose to 8.33%. Applying selection criteria to only the amyloid positive (169 out of 408), the selection for DMTs was 8.3% for aducanumab and 16.5% for lecanemab. Amongst subjects diagnosed with mild AD and mild cognitive impairment in a tertiary centre for cognitive disorders, only a small percentage of patients using RCT diagnostic criteria are eligible for DMT. The application of Cummings criteria strongly increased the DMT candidates. Nevertheless, the majority of patients with cognitive disorders have been excluded from DMTs approved so far.

Quality of Life in Mild Cognitive Impairment and Mild Dementia Associated with Alzheimer's Disease: A Systematic Review.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) have a profound impact on patients' quality of life (QoL), with progressive declines occurring as the disease advances. This systematic review aims to summarize the published evidence on patient-reported outcomes (PROs) in individuals with MCI due to AD and mild AD dementia. Comprehensive searches were conducted across five major databases to identify studies reporting on utility values, disutilities, and QoL measures in these patient populations. A total of 23 studies were included that utilized various QoL assessment tools, including EQ-5D (n = 14), SF-36/SF-12 (n = 4), and QOL-AD (n = 11). Reported EQ-5D scores ranged from 0.81 to 0.92 for patients with MCI and from 0.67 to 0.85 for those with mild AD, indicating a noticeable decline in QoL as the disease progresses. QOL-AD scores ranged from 33.8 to 42.5 for MCI and from 32.4 to 38.1 for mild AD, equally reflecting the greater impairment in QoL with disease advancement. Interventions were generally associated with smaller declines in PROs compared to placebo, suggesting a positive impact of treatment in mitigating QoL deterioration. The findings underscore the significant QoL differences between MCI and mild AD, emphasizing the potential benefit of early intervention to preserve QoL and delay disease progression. This review highlights the importance of continued research to better understand QoL in patients with MCI and mild AD dementia, particularly in terms of capturing comprehensive patient-reported outcomes and evaluating the effectiveness of interventions over time. These findings can contribute to a more informed approach in clinical practice and support decision-making in the management of early-stage AD.

Costs of Care in Relation to Alzheimer's Disease Severity in Sweden: A National Registry-Based Cohort Study.

The advancement of diagnostic and therapeutic interventions in early Alzheimer's disease (AD) has demanded the economic evaluation of such interventions. Resource utilization and cost estimates in early AD and, more specifically, the amyloid-positive population are still lacking. We aimed to provide cost estimates in AD in relation to disease severity and compare these with the control population. We also aimed to provide cost estimates for a subset of the AD population with both clinical diagnosis and amyloid-positive confirmation. This was a retrospective longitudinal analysis of resource utilization using data from national registries. A cohort from the national Swedish registry for cognitive/dementia disorders (SveDem) includes all clinically diagnosed AD between 2013 and 2020. The study population included 31,951 people with AD and 63,902 age- and sex-matched controls (1:2). The population was followed until death, the end of December 2020, or 2years from the last clinic visit. Direct medical and social costs were estimated from other national registries. Direct medical costs include costs for medications and inpatient and outpatient clinical visits. Direct social costs include costs for institutionalization, home care, short-term care, support for daytime activities, and housing support. Mean annual costs and 95% confidence intervals were obtained by bootstrapping, presented in 2021 Swedish Krona (SEK) (1 SEK=0.117 USD, 1 SEK=0.0985 EUR in 2021), and disaggregated by AD severity, cost component, sex, age group, and care setting. Mean annual costs for individuals with clinically diagnosed AD were SEK 99,906, SEK 290,972, SEK 479,524, and SEK 795,617 in mild cognitive impairment (MCI), mild, moderate, and severe AD. The mean annual costs for the population with both clinical diagnosis and amyloid-positive AD confirmation (N=5610) were SEK 57,625, SEK 179,153, SEK 333,095, and SEK 668,073 in MCI, mild, moderate, and severe AD, respectively. The mean annual costs were higher in institutionalized than non-institutionalized patients, females than males, and older than younger age groups. Inpatient and drug costs were similar in all AD severity stages, but outpatient costs decreased with AD severity. Costs for institutionalization, home care, support for daytime activities, and short-term care increased with AD severity, whereas the cost of housing support decreased with AD severity. This is the first study estimating annual costs in people with AD from MCI to severe AD, including those for the amyloid-positive population. The study provides cost estimates by AD severity, cost components, care settings, sex, and age groups, allowing health economic modelers to apply the costs based on different model structures and populations.

Diagnostic Accuracy of Combined Measurement of Serum Homocysteine, C-Reactive Protein, and Serum Ferritin in Mild Cognitive Impairments and Alzheimer's Disease.

Evaluation of the diagnostic accuracy of combined detection of serum homocysteine (Hcy), C-reactive protein (CRP), and serum ferritin (SF) levels in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Descriptive study. Place and Duration of the Study: Clinical Laboratory Section, Affiliated Hospital of Hebei University, Baoding, Heibei, China, from May 2022 to June 2023. Data of 120 patients with memory decline were retrospectively collected. They were divided into an MCI group and an AD group. A further 50 healthy participants were used as a normal control (NC) group. Differences in the Hcy, CRP, and SF levels between the three groups were evaluated. The specificity, accuracy, and sensitivity of these three indices in the combined or single diagnosis of AD and MCI were compared. Their associations with the severity of AD and MCI were also compared. The AD group had the highest levels of Hcy, CRP, and SF (18.79 ± 4.50, 6.35 ± 2.04, and 355.69 ± 120.36), followed by MCI (16.75 ± 3.06, 4.58 ± 2.31, and 203.48 ± 12.76), and NC group (14.32 ± 2.06, 2.06 ± 0.76, and 98.46 ± 5.06), with statistically significant differences (all p <0.001). The diagnostic efficacy of AD for CRP was 98.50%, sensitivity was 96.00%, and specificity was 94.00%, which was higher than Hcy and SF. Tested together, the area under the ROC curve was 99.90%, specificity was 98.00%, and sensitivity was 98.00%. The diagnostic efficacy of SF for MCI had sensitivity of 100.00%, and specificity of 100.00%, which was higher than that of Hcy and CRP. When the three were combined for detection, the area under the curve of SF was 100.00%, sensitivity of 100.00%, and specificity of 100.00%. The levels of Hcy, CRP, and SF were positively correlated with the severity of AD (p <0.01), while negatively correlated with the mini-mental state examination (MMSE) score (p <0.01). The combined detection of Hcy, CRP, and SF improved the diagnostic accuracy of comorbid AD and MCI. Homocysteine, C-reactive protein, Cognitive impairment, Serum ferritin, Alzheimer's disease.

Combined Effect of tDCS and Motor or Cognitive Activity in Patients with Alzheimer’s Disease: A Proof-of-Concept Pilot Study

(1) Background: Alzheimer’s disease (AD) accounts for 70% of dementia cases and with no effective pharmacological treatments, new rehabilitation methods are needed. Motor and cognitive activities and transcranial direct current stimulation (tDCS) have shown promise in stabilizing and enhancing cognitive functions. Objective: we want to investigate the effects of tDCS combined with motor or cognitive activity on cognitive functions in AD patients. (2) Methods: Patients with mild or moderate AD were randomized between anodic tDCS groups (MotA or CogA) and sham tDCS groups (MotS or CogS). They received two weeks of treatment (45 min, five days/week), with the first 15 min using tDCS stimulation on the dorsolateral prefrontal cortex. Cognitive assessments were conducted pre-treatment (T0), post-treatment (T1), and one week after (T2). (3) Results: Twenty-three patients were included. Statistical analysis showed significant differences between anodic tDCS groups (MotA + CogA) and sham tDCS groups (MotS + CogS) with advantages for the first in improving global cognitive status (p = 0.042), selective attention (p = 0.012), and sustained attention (p = 0.012). Further analysis indicated no differences between the two anodic tDCS groups between T0 and T1. (4) Conclusions: combined anodal tDCS with motor or cognitive activity could improve global cognitive state and attention, slowing cognitive decline in AD patients. The trial was registered on Clinical Trials: NCT06619795.

The Role of Greek Olive Leaf Extract in Patients with Mild Alzheimer’s Disease (the GOLDEN Study): A Randomized Controlled Clinical Trial

Background: Olive leaves are a significant source of biophenols, which have a beneficial impact on cognitive performance. Objective: To examine, for the first time, in humans the effect of the daily consumption of a beverage containing olive leaf extract (OLE) versus a Mediterranean diet (MeDi) on patients diagnosed with mild Alzheimer’s Disease (AD), in addition to their regular treatment. Methods: A randomized clinical trial compared OLE’s effects on cognitive and functional performance in 55 mild AD patients. Each participant was randomly assigned to two groups: (1) Group 1 was given olive leaves for making a daily beverage and MeDi instructions through monthly diet programs; (2) Group 2 received only the MeDi instructions. After six months, all participants underwent a second neuropsychological evaluation. Results: Group 1 participants had statistically significantly higher MMSE scores compared to Group 2 with a p-value of 0.0135. Specifically, the mean MMSE difference in patients receiving OLE was close to 0, indicating no memory deterioration, whereas in controls it was −4.1, indicative of cognitive decline. The remaining neuropsychological assessments (FRSSD, FUCAS, ADAS-Cog, CDR, GDS, and NPI) revealed better results in the OLE group, except for GDS, which showed no change, but without statistically significant differences between the two groups.

The relationship between micronutrients and cognitive ability in an elderly population with mild cognitive impairment and Alzheimer’s disease: a cross-sectional study

BackgroundMild cognitive impairment (MCI) and Alzheimer’s disease (AD) are significant neurodegenerative disorders with increasing prevalence worldwide. Lifestyle and dietary factors, including micronutrients, have been suggested as modifiable risk factors for disease development. This study aims to investigate the association between micronutrients and cognitive ability in these diseases.MethodsA cross-sectional study involving 105 participants with MCI and AD was conducted. Dietary assessments were performed using a validated food frequency questionnaire (FFQ), and micronutrient intake was calculated based on nutrient content. Disease severity was evaluated using the Functional Assessment Staging Tool (FAST). Statistical analyses, including correlation coefficients and multiple regression models, were employed to examine the association between micronutrients and disease progression.ResultsThe results revealed significant correlations between disease severity and several micronutrients, including omega-3 fatty acids (B = -0.2, P = 0.01), carotenoids (B = -0.19, P = 0.02), dietary antioxidant compounds, including vitamins A, C, D, E (B = -0.19, P = 0.02), selenium (B = -0.17, P = 0.03), alpha-carotene (B = -0.16, P = 0.04), beta-carotene (B = -0.17, P = 0.03), and lycopene (B = -0.16, P = 0.04). Multivariate regression analysis showed that higher intake of omega-3 fatty acids was associated with slower disease progression. Furthermore, the levels of these micronutrients declined in advanced stages of the disease.ConclusionOmega-3 fatty acids and carotenoids may affect the cognitive ability and disease progression. Further longitudinal studies are warranted to establish causality and explore the therapeutic implications of these findings for the prevention and management of MCI and AD.

Longitudinal accelerated brain age in mild cognitive impairment and Alzheimer's disease.

Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. Few studies have investigated changes in brain age longitudinally in MCI and AD. We hypothesized that individuals with MCI and AD would show heightened brain age over time and across the lifespan. We also hypothesized that both MCI and AD would show faster rates of brain aging (higher slopes) over time compared to healthy controls. We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI) 1 with 3Tesla (3 T) data which totaled 677 scans from 183 participants. This constitutes a secondary data analysis on existing data. We included control participants (healthy controls or HC), individuals with MCI, and individuals with AD. We predicted brain age using a pre-trained model and tested for accuracy. We investigated cross-sectional differences in brain age by group [healthy controls or HC, mild cognitive impairment (MCI), and AD]. We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model. We predicted brain age with a mean absolute error (MAE) < 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change. We replicated past studies that showed that MCI and AD had greater brain age than HC. We additionally found that this was true over time, both groups showed higher brain age longitudinally. Contrary to our hypothesis, we found that the MCI, but not the AD group, showed faster rates of brain aging. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). Individuals with MCI may experience higher rates of brain aging than AD and controls. AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term.

Cognivue Clarity characterizes mild cognitive impairment and Alzheimer’s disease in biomarker confirmed cohorts in the Bio-Hermes Study

The Bio-Hermes Study was a cross-sectional observational study designed to develop a database of blood-based and digital biomarkers to improve detection of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We examined the ability of Cognivue Clarity to (a) detect MCI and AD in clinical diagnostics groups, (b) determine the presence of amyloid, and (c) distinguish between biomarker-confirmed groups. Bio-Hermes enrolled 887 participants who completed both Cognivue Clarity and amyloid PET scans (388 Cognitively Normal, 282 MCI, 217 Probable AD). Cognivue Clarity differentiated between Cognitively Normal, MCI, and probable AD in clinical cohorts, amyloid positive from amyloid negative individuals, and True Controls from MCI due to AD and AD in biomarker-confirmed cohorts (all p < 0.001) with large effect sizes. Cognivue Clarity correlated with amyloid PET and plasma amyloid and pTau (all p < 0.001). In biomarker confirmed groups, Cognivue Clarity had a positive likelihood ratio of 2.17, a negative likelihood ratio of 0.29, and a diagnostic odds ratio of 7.48. Cognivue Clarity detected cognitive impairment and differentiated between both clinically and biomarker defined MCI and AD groups. The use of Cognivue Clarity could assist with identification of MCI-AD or AD for inclusion into current treatment protocols or for enriching recruitment into clinical trials.Trial registration ClinicalTrials.gov (NCT04733989).

Syntactic comprehension abilities in aged people with mild cognitive impairment

ABSTRACT Background Language studies in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) have been primarily focused on lexicosemantic abilities, with a paucity of data regarding syntactic processing. Aims We aimed to verify the sentence comprehension ability of older adults with amnestic MCI (aMCI), non-amnestic MCI (naMCI), and mild AD and compare it to the performance of cognitively healthy older adults. Methods & Procedures We evaluated 32 cognitively healthy older adults, 22 with aMCI, 43 with naMCI, and 12 with mild AD using the Test for Reception of Grammar Version 2 (TROG-2). Outcomes & Results There were significant differences between the control and MCI and control and AD groups in the total number of correct answers and among the four groups’ profiles according to the type of sentence (p < 0.05). Zero anaphor, pronoun gender/number, and centre-embedded sentences discriminated at least between two groups (p < 0.05). Conclusions Poorer performance in sentences structurally more complex was in line with the severity of the cognitive decline, which may point to the effect of increased demands on working memory and executive functions on syntactic processing.

Spectris™ treatment preserves corpus callosum structure in Alzheimer's disease.

To examine the impact of 40Hz gamma stimulation on the preservation of the corpus callosum, a critical structure for interhemispheric connectivity, in people with mild cognitive impairment or Alzheimer's disease. OVERTURE (NCT03556280) participants were randomized 2:1 (Active:Sham) to receive daily, 1-h, 40Hz gamma sensory stimulation or sham treatment for 6 months. Structural magnetic resonance imaging data were analyzed to assess changes in corpus callosum area (N = 50; 33 for active, 17 for sham). Bayesian linear mixed-effects modeling was used to assess differences in longitudinal changes of corpus callosum area between the two treatment groups. All observed differences in corpus callosum area favored the active treatment group. Differences were observed in the total corpus callosum area (2.28 ± 0.87%, p < 0.02) and its subregions, including genu/rostrum (2.36 ± 0.90%, p < 0.02), anterior-body (2.64 ± 1.26%, p < 0.04), mid-body (2.79 ± 1.18%, p < 0.03), posterior-body (2.87 ± 1.41%, p < 0.05), and splenium (1.58 ± 0.73%, p < 0.04). Total corpus callosum area and some of the sub-regional differences, such as genu/rostrum and splenium, were observed as early as 3 months after commencement of treatment. The structural magnetic resonance imaging results from the OVERTURE Phase 2 study suggest that 6 months of non-invasive 40Hz stimulation reduces the rate of atrophy of the corpus callosum in individuals with Alzheimer's disease. The preservation of structural integrity in the corpus callosum, crucial for interhemispheric communication and cognitive function, may be achievable through this non-invasive approach, potentially providing a promising disease-modifying alternative in Alzheimer's disease management.

Self-Concept in Mild Cognitive Impairment and Mild Dementia due to Alzheimer's Disease Is Affected on Tests of Self-Generated Statements.

Several studies show that Alzheimer's disease (AD) and other neurocognitive disorders have a negative impact on the self and identity formation. Most studies have included persons with mild to moderate dementia, but how AD patients in the earliest phases retrieve information about themselves has only been studied scarcely. The aim of this study was to investigate if persons with mild cognitive impairment (MCI) and mild AD would generate fewer self-related statements than healthy controls. From a memory clinic, we included 17 aMCI patients, 17 patients with mild dementia (AD; MMSE ≥ 24), and 30 healthy controls. Three Events Test and Twenty Statements Test (TST) were applied to all participants. The persons with mild dementia gave significantly fewer statements compared to the controls (p < 0.001) and the aMCI patients (p < 0.01) on TST. Fewer statements were also produced by the aMCI patients compared to the control participants (p < 0.05). Persons from both patient groups produced significantly fewer contextual details compared to the controls on the Three Events Tests. There were significant associations to lexical fluency for both the TST and Three Events Test, but only a limited amount of variance was explained, and the results cannot be explained solely by a fluency effect. The results from this study are in accordance with findings from previous studies demonstrating that mild AD leads to a decline in both autobiographical memories and a diminished sense of self. Further, this study shows that changes in self-concept may occur even in the earliest clinical stages of AD.

Development and validation of an ultra-performance liquid chromatography with tandem mass spectrometry method for determination of soluble repulsive guidance molecule A in human serum and cerebrospinal fluid.

Aim: Repulsive guidance molecule A (RGMa) is upregulated in neurodegenerative diseases. To assess RGMa levels in human serum and cerebrospinal fluid (CSF), a quantification method was developed and validated according to ICH M10 guideline.Methods & results: Sample preparation consisted of immunoprecipitation (IP, only for serum), digestion and purification followed by MS.Conclusion: An UPLC-MS/MS method was established and used to assess normal range of soluble RGMa levels in serum and CSF of healthy controls, and patients with mild cognitive impairment or Alzheimer's disease. The normal range was between 13.0-44.8ng/ml (CSF) and 9.9-20.9ng/ml (serum) in healthy controls. In the CSF of patients with mild cognitive impairment and Alzheimer's disease, total soluble RGMa was twofold lower while unchanged in serum.

Annual Wellness Visits and Early Dementia Diagnosis Among Medicare Beneficiaries

Early recognition of cognitive impairment is key to optimal dementia care. No previous research has examined the probability of developing mild cognitive impairment (MCI) or Alzheimer disease and related dementias (ADRD) at 5-year follow-up among older adult Medicare beneficiaries by receipt of an annual wellness visit (AWV). To assess the association of incident AWV with the first ADRD or MCI diagnosis among older adults with Medicare fee-for-service benefits. This retrospective population-based cohort study used 100% Texas fee-for-service Medicare data from 2015 to 2022. Participants comprised 549 516 community-dwelling Medicare beneficiaries aged 68 years or older in 2018, with complete Medicare fee-for-service Parts A and B and no Medicare Advantage plan enrollment for 2015 to 2018. Medicare AWVs. The first MCI or ADRD diagnosis (reported as MCI or ADRD diagnosis, MCI diagnosis, and ADRD diagnosis) from the AWV index date in 2018 through December 31, 2022. In this cohort study of 549 516 Medicare beneficiaries with no diagnosis of MCI or ADRD in 2015 to 2017 (mean [SD] age, 76.7 [6.6] years; 289 932 women [52.8%]), 66 433 (12.1%) had an incident AWV in 2018. Annual wellness visit recipients were more likely than those who did not receive an AWV to be female, to be non-Hispanic White (followed by Hispanic, non-Hispanic Black, and other), to have more education, to reside in a metropolitan area, to have more comorbidities, and to have a primary care professional in the 12 months before the AWV index date. After propensity score matching, AWV receipt was associated with a 21% increase in MCI diagnosis (hazard ratio, 1.21 [95% CI, 1.16-1.27]) and a 4% increase in ADRD diagnosis (hazard ratio, 1.04 [95% CI, 1.02-1.06]). The increase in MCI diagnosis associated with AWV was larger when the AWV was censored or treated as a time-dependent covariate in the follow-up period. These findings indicate that AWV recipients had a timelier first MCI diagnosis than those who did not receive an AWV, but first ADRD diagnosis differed little. This study suggests that the Medicare AWV health policy may increase MCI identification, prompting more specialized care.

Cognitive processing, resilience, and family functioning as contributors to posttraumatic growth in family caregivers of patients with Alzheimer’s disease

Objectives The present study examined the existence of posttraumatic growth (PTG) and its association with cognitive processing, resilience, and family functioning in family caregivers of patients with Alzheimer’s disease (AD). Method Family caregivers (N = 114) were surveyed using measures of cognitive processing, resilience, family functioning, and PTG. Data were analyzed using descriptive statistics, Pearson correlations, and multiple regression analyses. Results The average PTG score in the sample was 48.6 (SD = 18.7; range 14–105). Race, education level, severity of the patient’s AD, cognitive processing, resilience, and family functioning explained 25.8% of the variance in PTG (F [9, 95] = 5.025, p < 0.001). Race was significantly correlated with PTG; specifically, non-White caregivers reported higher PTG than White caregivers (p < 0.05). When controlling for race and education level, mild AD, intrusive rumination, and family satisfaction were significant predictors of PTG (p < 0.05). However, deliberate rumination, resilience, and family communication were not significant predictors PTG (p > 0.05). Conclusion These findings provide insight into factors that may influence the development of PTG in family caregivers of patients with AD. Results may inform intervention strategies to mitigate the negative consequences of caregiving and promote PTG in this caregiver population.

Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum

Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOEε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/.

Disentangling normal and pathological brain atrophy for the diagnosis of mild cognitive impairment and Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Mild cognitive impairment (MCI) is the prodromal stage of AD. Accurate identification of these conditions is crucial for the early diagnosis of these diseases. Brain tissue atrophies, observable in regions such as the hippocampus and cortices, serve as an essential biomarker for MCI and AD. However, similar atrophies are also present in elderly individuals with normal cognitive function, albeit to a lesser extent, and can be found in other non-biomarker brain tissues. To address this challenge, we introduce an atrophy disentanglement network (AD-Net), designed to decouple age-related normal atrophies and disease-specific pathological atrophies in structural magnetic resonance imaging images. Specifically, we first design a dual-task prediction module, guiding the model to differentiate normal and pathological atrophies. Subsequently, we devise a feature orthogonality module for enhanced separation of the two types of atrophies. Our extensive experiments demonstrate that AD-Net outperforms existing methods, highlighting the efficiency of the devised dual-task prediction and feature orthogonality modules in disentangling normal and pathological image features and further improving the diagnosis for AD and MCI. The source code is publicly avaliable at https://github.com/CVAPPS24/ADNet.git.

A multimodal learning machine framework for Alzheimer’s disease diagnosis based on neuropsychological and neuroimaging data

Alzheimer’s disease (AD) is the most prevalent form of dementia, with no current cure. Early screening and intervention are vital. In multimodal AD data, besides neuroimaging dimensions, neuropsychological tests based on cognitive domains also provide the clinical information for diagnosing AD. However, previous multimodal methods often fuse these neuropsychological test scores with other data, losing the rich clinical details inherent in each test, including videos, speech, images, and text. To address this, we propose a novel framework with an entropy-based polynomial dimension expansion function that restores this critical information by accurately calculating the optimal polynomial degree. Additionally, the proposed framework offers a series of cognitive-based Extreme Learning Machine (ELM) models to better utilize the detailed clinical insights from neuropsychological tests, reducing diagnostic redundancy and noise. Finally, we design a boosting ensemble strategy that combines diagnostic models from various dimensions and cognitive domains, automatically optimizing weights to enhance diagnostic accuracy. Tested on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, our approach achieves over 98% accuracy and F1 scores, with no observed bias between mild cognitive impairment (MCI) and AD groups. Therefore, our framework can offer clinicians more logical recommendations for diagnosing and managing the disease.

Comparing the Effects of Transcranial Direct Current Stimulation and Cognitive Rehabilitation on Language Skills and Attention in Elderly With Mild Alzheimer's Disease

Objectives Alzheimer’s disease (AD) is one of the most common problems in the elderly, which causes a decline in their cognitive function. This study aims to compare the effects of transcranial direct current stimulation (tDCS) and short-term cognitive rehabilitation on language skills and attention in older people with mild AD. Methods &amp; Materials This is a quasi-experimental study with a pre-test/post-test/follow-up design. Participants were 60 people over 65 years of age with mild Alzheimer’s referred to a neurologist in 2022, who were selected by a convenience sampling method and were randomly assigned into two experimental groups and one control group (20 in each group). Then, the tDCS was applied in one experimental group at 10 sessions of 20 minutes once a week and the short-term cognitive rehabilitation program was provided to the second experimental group at 9 sessions of 90 minutes, once a week. No intervention was provided to the control group. Before, one week after (post-test) and one month after (follow-up) the end of the intervention, the assessments were conducted in all groups using Addenbrooke’s cognitive examination- revised (ACE-R). For data analysis, repeated measures analysis of variance test was used in SPSS software, version 23. Results Both methods improved the writing and naming domains of language skills, but they had no significant effect on the attention variable. Conclusion Both tDCS and short-term cognitive rehabilitation can be used to improve the language skills of older adults with mild AD.

Hypothalamic atrophy and structural covariance in amnestic mild cognitive impairment and Alzheimer’s dementia

BackgroundAlzheimer’s disease (AD) is characterized by progressive cognitive decline and specific brain atrophy patterns, primarily involving the medial temporal lobes. A number of studies have discussed hypothalamic involvement in AD with consecutive metabolic and/or autonomic disturbances yet only few studies have investigated hypothalamic atrophy in AD and its early stages in particular. Methods: We applied semi-automated volumetry of the hypothalamus (HTH) in 3 T MRI in a sample N = 175 participants [age 74.9 ± 7.22; gender 85 m/90f; cognitively normal controls (CN; N = 56); amnestic mild cognitive impairment (MCI; N = 78); AD (N = 41)] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In addition, we used voxel-based morphometry (VBM), cortical thickness (CTH) analyses and source-based morphometry (SBM) derived networks of structural covariance to investigate brain structural covariance patterns of the HTH under consideration of diagnostic groups, β-amyloid (AB) positivity and apolipoprotein E (APOE) ε4 status. Results: Hypothalamic atrophy was observed in both early and advanced disease stages (i.e. hypothalamic volume CN > MCI > AD). VBM, CTH analysis and SBM revealed positive associations between hypothalamic volume (HV) and AD-vulnerable regions, largely corresponding to the Papez circuit and brain regions implicated in autonomic regulation, however, group differences regarding HTH structural covariance were not observed. Similar observations were made in carriers and non-carriers of the ε4 allele, yet more pronounced in ε4 carriers. Although not reaching significance, comparisons of AB positive vs. negative subjects indicated stronger HTH atrophy in biomarker positive participants. HV was not associated with body mass index or longitudinal weight change. Conclusions: Our findings support early structural changes of the HTH in AD. HV covaries with regional volumes of AD-vulnerable regions. This could point to secondary atrophy of the HTH following atrophy of the hippocampus and other structures of the Papez circuit in AD.