Review
Guilherme Christimann, Gabriela Rocha, José Augusto Gasparotto Sattler
Bioactive compounds and dietary patterns in Alzheimer’s disease
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly, leading to severe cognitive decline and loss of autonomy. The accumulation of amyloid-β peptides and tau proteins in the brain is considered the central pathogenic mechanism, which results in neuronal dysfunction and cell death. Various metabolic disruptions, such as chronic oxidative stress and inflammatory processes, further exacerbate the progression of AD. This review, based on literature from PubMed, SciELO, MDPI, and ScienceDirect, evaluates the role of bioactive compounds and dietary patterns, specifically the Mediterranean and MIND diets, in mitigating the progression of AD. These diets, rich in vitamins, flavonoids, carotenoids, and omega-3 fatty acids, have shown potential in reducing oxidative damage and inflammation in the brain, offering neuroprotective benefits. The findings suggest that bioactive compounds such as vitamin E isomers and polyphenols may delay cognitive decline, presenting a promising avenue for future dietary interventions aimed at optimizing the consumption of these compounds to prevent or slow the onset of AD. Further research is needed to determine the optimal doses and combinations of these bioactive compounds to maximize their protective effects.
Review
Catarina Xavier, Nádia Pinto
Navigating the blurred boundary: Neuropathologic changes versus clinical symptoms in Alzheimer’s disease, and its consequences for research in genetics
Abstract: During decades scientists tried to unveil the genetic architecture of Alzheimer’s disease (AD), recurring to increasingly larger sample numbers for genome-wide association studies (GWAS) in hope for higher statistical gains. Here, a retrospective look on the most prominent GWAS was performed, focusing on the quality of the diagnosis associated with the used data and databases. Different methods for AD diagnosis (or absence) carry different levels of accuracy and certainty applied to both subsets of cases and controls. Furthermore, the different phenotypes included in these databases were explored, as several incorporate other ageing comorbidities and might be encompassing many confounding agents as well. Age of the samples’ donors and origin populations were also investigated as these could be biasing factors in posterior analyses. A tendency for looser diagnostic methods in more recent GWAS was observed, where greater datasets of individuals are analyzed, which may have been hampering the discovery of associated genetic variants. Specifically for AD, a diagnostic method conveying a clinical outcome may be distinct from the disease neuropathological assessment, since the first has a practical perspective that not necessarily needs a confirmation. Due to its properties and complex diagnosis, this work highlights the importance of the neuropathological confirmation of AD (or its absence) in the subjects considered for research purposes to avoid reaching statistically weak and/or misleading conclusions that may trigger further studies with powerless groundwork.
Systematic Review
Esther K Hui, Naaheed Muakdam, Gianna Kohl, Gill Livingston
Effect of diabetes medications on the risk of developing dementia, mild cognitive impairment, or cognitive decline: A systematic review and meta-analysis
Abstract: Background: Diabetes is a risk factor for dementia, but we do not know whether specific diabetes medications ameliorate this risk. Objective: To systematically review and meta-analyze such medication’s effect on the risk of developing dementia, mild cognitive impairment (MCI), or cognitive decline. Methods: We searched three databases until 21 November 2023. We included randomized controlled trials (RCT), cohort, and case-control studies assessing association between antidiabetic medication and future dementia, MCI, or cognitive decline. We meta-analyzed studies separately for individual drug classes and their comparators (no medication, placebo, or another drug). We appraised study quality using the Newcastle-Ottawa Scale and Physiotherapy Evidence Database Scale. Results: 42 studies fulfilled inclusion criteria. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus placebo reduced dementia risk by 53% in 3 RCTs (n=15,820, RR=0.47[0.25,0.86]) and 27% in 3 case-control studies (n=312,856, RR=0.73[0.54,0.99], I2=96%). Repaglinide was superior to glibenclamide by 0.8 points on the Mini-Mental State Examination scale in another RCT. Meta-analysis of 7 longitudinal studies showed glitazones (n=1,081,519, RR=0.78[0.76,0.81], I2=0%) were associated with reduced dementia risk. Metformin (n=999,349, RR=0.94[0.79,1.13], I2=98.4%), sulfonylureas (RR=0.98[0.78,1.22], I2=83.3%), dipeptidyl peptidase-IV inhibitors (DPP-1V) (n=192,802, RR=0.86[0.65,1.15], I2=92.9%) and insulin (n=571,274, RR=1.09[0.95,1.25], I2=94.8%) were not. Most studies were observational and limited by confounding by indication. Conclusions: In people with diabetes, RCTs consistently showed GLP-RAs reduce future dementia risk. Glitazones consistently showed protective effects, without heterogeneity, suggesting potential generalizability of these results. Metformin, sulfonylureas, insulin, and DPP-1V studies had inconsistent findings. If information is available future studies should consider dosage, severity, and duration.
Short Communication
Jeffrey N Weiss and Daryl Eber
Earlier diagnosis of Alzheimer’s disease by dynamic light scattering spectroscopy
Abstract: Dynamic light scattering (DLS) spectroscopy measures changes in the Brownian movement of particles at the molecular level. Since the retina of the eye is a neural tissue and an outgrowth of the brain, a clinical instrument was developed capable of making DLS measurements from the retina in patients with mild cognitive impairment undergoing positron emission tomography nuclide imaging for the presence of cerebral amyloid.
Commentary
Avinash Chandra, Kaviya Senthilvel, Rifah Anjum, Ijeoma Uchegbu, Laura J Smith, Helen Beaumont, Reshma Punjabi, Samina Begum, Charles R Marshall
Cultural variation in trust and acceptability of artificial intelligence diagnostics for dementia
Abstract: Digital health innovations hold diagnostic and therapeutic promise but may be subject to biases for underrepresented groups. We explored perceptions of using artificial intelligence (AI) diagnostics for dementia through a focus group as part of the Automated Brain Image Analysis for Timely and Equitable Dementia Diagnosis (ABATED) study. Qualitative feedback from a diverse public engagement group indicated that cultural variations in trust and acceptability of AI diagnostics may be an unrecognised source of real-world inequity. Efforts focused on the adoption of AI diagnostics in memory clinic pathways should aim to recognise and account for this issue.
Vassiliki Rentoumi, Evangelos Vassiliou, Nikiforos Pittaras, Admir Demiraj, Manolis Papageorgiou, Dimitra Sali, Athina Papatriantafyllou, Panagiotis Griziotis, Artemis Chardouveli, Konstantinos Pattakos, George Paliouras (Handling Associate Editor: Qiang Cheng)
Linguistic cues for automatic assessment of Alzheimer’s disease across languages
Abstract: Background: Most common forms of dementia, including Alzheimer's disease, are associated with alterations in spoken language. Objective: This study explores the potential of a speech-based machine learning (ML) approach in estimating cognitive impairment, using inputs of speech audio recordings. Methods: We develop an automatic ML pipeline that ingests multimodal inputs of audio and transcribed text, mapping speech and language to domain-specific biomarkers optimized for high explainability and predictive ability. The resulting features are fed through a multi-stage pipeline to determine efficient classification configurations. Results: We evaluated the system on large real-world datasets, achieving above 90% and 70% weighted average F1 scores for two-class (AD versus normal controls) and three-class (AD versus mild cognitive impairment versus normal controls) classification tasks, respectively. Model performance remains stable across different population characteristics. Conclusions: The study introduces a robust, non-invasive method for gauging the cognitive status of AD and MCI patients from speech samples, with the potential of generalizing effectively to multiple types of diseases/disorders which may burden language.
Han Tong, Vladislav A Petyuk, Michael Sendtner, Ajay Sood, David A Bennett, Ana W Capuano, Zoe Arvanitakis (Handling Associate Editor: Ramit Ravona-Springer)
Alzheimer’s disease-related cortical proteins modify the association of brain insulin signaling with cognitive decline
Abstract: Background: Brain insulin signaling has been associated with both Alzheimer’s disease (AD) pathology and cognitive decline, but the mechanisms remain unclear. Objective: To examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline. Methods: Participants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) and had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function. Results: Higher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT308AKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities. Conclusions: AD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.
Paige N Braden-Kuhle, Vivienne A Lacy, Kelly N Brice, Morgan E Bertrand, Hatice Buse Uras, Catherine Shoffner, Bridgette E Fischer, Ashish Rana, Jada L Willis, Gary W Boehm, Michael J Chumley (Handling Associate Editor: Helen Macpherson)
A Mediterranean-style diet protects against cognitive and behavioral deficits, adiposity, and Alzheimer’s disease-related markers, compared to a macronutrient-matched typical American diet in C57BL/6J mice
Abstract: Background: Research suggests that modifying risk factors may prevent or delay up to 40% of dementia cases, including Alzheimer’s disease (AD). Thus, understanding the potential of healthful dietary patterns, like the Mediterranean diet (MD), in AD prevention is crucial. While supplementation of individual Mediterranean foods has demonstrated efficacy in reducing AD biomarkers and cognitive impairment in rodents, the effects of a comprehensive MD warrant further investigation. Additionally, while rodent studies often use a “Western diet” as a model for the typical American diet (TAD), these diets generally exceed the macronutrient densities of typical American consumption, particularly in fats and carbohydrates. Objective: To better reflect human diets, we developed two diets for mice that more closely mirrored the macronutrient composition of the traditional MD or the TAD, each with matched macronutrient profiles (50% kcal from carbohydrates, 35% kcal from fat, 15% kcal from protein), and distinct food sources from Mediterranean regions or the U.S., respectively. Methods: Male C57BL/6J mice were randomly assigned to one diet (MD or TAD) at weaning (21 days of age), which they consumed for six months. Results: Compared to the TAD, MD animals had lower body weight, abdominal and hepatic fat, serum TNF-α, and central Aβ1–42, while also exhibiting enhanced exploratory behavior, reduced anxiety-like behavior, and preserved spatial memory. The MD also protected against LPS-induced central inflammation and BDNF loss. Conclusions: These findings suggest that a comprehensive MD provides protection against metabolic and AD-related markers in wildtype mice, despite matched caloric availability to the TAD.
Cornelia Becker#, Lucas Herschung#, Willy Gomm, Britta Haenisch #These authors contributed equally to this work.
Dementia diagnosis and prescription of antidementia drugs: An analysis of German claims data (2006-2016)
Abstract: Background: Use of claims data allows to analyze health service characteristics of dementia, which is one of the most frequent cognitive disorders in Germany and worldwide. Objective: The study aimed at describing the variability in dementia diagnoses and in antidementia drug prescription pattern. Methods: We analyzed data from a population-based sample of one of the largest German statutory health insurances. The cohort included 30,403 patients with incident dementia diagnosis from 2006-2016. We described frequencies, patterns, and interrelations of diagnoses (Alzheimer’s disease (AD), vascular dementia, other specific dementia, unspecified dementia (UD), antidementia drugs (ADD), and professional groups. We described switches in diagnostic and medication patterns between index quarter and following quarters, and evaluated the prescriptions in relation to national guidelines. Results: A total of 87% of patients received a diagnosis of UD in at least one quarter of insurance. In the quarter of incident diagnosis, 13.9% of patients received more than one diagnostic code of dementia (14%), whereas over the course of observation, the majority of patients received more than one diagnostic code (61%). Most patients were diagnosed by a general practitioner without involving a specialist. All professional groups primarily made UD diagnoses except specialists who mainly diagnosed AD. Thirty-five percent of all patients and 67% of AD patients were prescribed an ADD at least once. Conclusions: Specialists made the most specific diagnoses and prescribed most ADDs. A specialist consultation may be advisable, but only 34% of patients visited one. Many AD patients might be left untreated due to underdiagnosis or -treatment.
Kazuko Ishikawa-Takata, Kazuki Fujiwara, Takayuki Tanaka, Keiji Nakamura, Hisamine Kobayashi, Shinobu Okada
Associations of dietary protein and amino acid intakes with disability-adjusted life years for Alzheimer’s disease in Japanese people
Abstract: Background: The number of patients with dementia is increasing worldwide. In Japan, dementia is the most significant reason recognized for people requiring nursing care. Protein is one of the possible preventive nutrients for dementia; however, adequate intake levels can differ according to usual protein intakes and protein sources. Objective: This study examined the relationships between disability-adjusted life years (DALYs) for Alzheimer’s disease and protein or amino acid intakes. Methods: Global Burden of Disease Study data (DALYs for each sex and age group in each year) and de-identified individual records from the National Health and Nutrition Survey Japan (data from 46,831 subjects) from 2001 to 2019 were used. Multiple regression analyses were conducted to assess the relationships between DALYs and protein or amino acid intakes with lifestyle factors and sociodemographic index as confounding factors. Results: Higher protein-to-energy ratios were correlated with lower DALYs in women in their 70s (partial regression coefficient [Coeff.] = −349.488, p=0.034), in men in their 60s (Coeff.= −51.484), and in both sexes combined in their 60s (Coeff.= −26.696, p=0.015) even after adjusting for other possible nutrient intakes. Additionally, elevated isoleucine, lysine, tyrosine, histidine, arginine, alanine, asparagine, and glycine levels were correlated with lower DALYs in women in their 70s (Coeff. = −2.752 to −0.141). Conclusions: Adequate protein and specific amino acid intakes may be associated with DALYs for Alzheimer’s disease.
Béatrice Raymond-Lessard, Claude Bélanger, Carol Hudon, Sébastien Grenier, CIMA-Q Group
Characterization of subclinical depressive and anxiety symptoms in older adults with subjective cognitive decline progressing to objective cognitive impairment: A prospective 4-year follow-up study
Abstract: Background: Subjective cognitive decline (SCD) is linked to a more rapid progression to the development of mild cognitive impairment (MCI) or Alzheimer's disease (AD). SCD has been correlated with affective symptoms such as depression and anxiety. Recent research aimed to shed light on the relationship between these affective symptoms and how they might correlate to a more rapid progression to objective cognitive impairment. No studies have assessed the presence, type, and intensity of depressive and anxiety symptoms between SCD individuals who progressed versus those who did not. Objective: This study aimed to establish whether there are differences between subclinical depressive and anxiety symptoms in terms of presence, type, and intensity of symptoms presented by individuals with SCD who progressed to an objective cognitive decline. Methods: The recruited participants originated from the Consortium for the Early Identification of Alzheimer’s Disease - Québec (CIMA-Q) cohort. They were assessed twice, with an interval of 4 years separating the evaluations. Anxiety symptoms were assessed using the Geriatric Anxiety Inventory (GAI) and depression symptoms using the Geriatric Depression Scale (GDS-30). Results: The presence, type and intensity of anxiety symptoms did not significantly distinguish the two groups. Only one type of hopelessness-related depressive symptom was significantly higher in SCD participants who had progressed to objective cognitive decline compared with those who had not. Conclusions: Our results suggest that it may be beneficial to target hopelessness in non-pharmacological interventions aimed at preventing the progression of people with SCD to MCI or AD.
Linzy Bohn, Yao Zheng, G Peggy McFall, Melissa K Andrew, Roger A Dixon
Frailty in motion: Amnestic mild cognitive impairment and Alzheimer’s disease cohorts display heterogeneity in multimorbidity classification and longitudinal transitions
Abstract: Background: Data-driven examination of multiple morbidities and deficits are informative for clinical and research applications in aging and dementia. Resulting profiles may change longitudinally according to dynamic alterations in extent, duration, and pattern of risk accumulation. Do such frailty-related changes include not only progression but also stability and reversion? Objective: With cognitively impaired and dementia cohorts, we employed data-driven analytics to (a) detect the extent of heterogeneity in frailty-related multimorbidity and deficit burden subgroups and (b) identify key person characteristics predicting differential transition patterns. Methods: We assembled baseline and 2-year follow-up data from the National Alzheimer’s Coordinating Center for amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) cohorts. We applied factor analyses to 43 multimorbidity and deficit indicators. Latent Transition Analysis (LTA) was applied to the resulting domains in order to detect subgroups differing in transition patterns for multimorbidity and deficit burden. We characterized heterogeneity in change patterns by evaluating key person characteristics as differential predictors. Results: Factor analyses revealed five domains at two time points. LTA showed that two latent burden subgroups at Time 1 (Low, Moderate) differentiated into an additional two subgroups at Time 2 (adding Mild, Severe). Transition analyses detected heterogeneous changes, including progression, stability, and reversion. Baseline classifications and transitions varied according to clinical cohort, global cognition, sex, age, and education. Conclusions: Heterogeneous frailty-related subgroup transitions can be (a) detected in aging adults living with aMCI and AD, (b) characterized as not only progression but also stability and reversion, and (c) predicted by precision characteristics.
Wanlin Lai#, Debo Li#, Junqi Wang#, Qian Geng, Yilin Xia, Yutong Fu, Wanling Li, Yong Feng, Ling Jin, Ruiqi Yang, Zijie Huang, Yuhang Lin, Han Zhang, Sitong Chen, Lei Chen (Handling Associate Editor: Tahera Ahmed) #These authors contributed equally to this work.
Exhaled breath is feasible for mild cognitive impairment detection: A diagnostic study with portable micro-gas chromatography
Abstract: Background: Mild cognitive impairment (MCI) is an important prodromal stage of Alzheimer's disease (AD), affecting 69 million individuals globally. At present, there is a lack of a community-applicable tool for MCI screening. Exhaled breath volatile organic compounds (VOCs) have been used to distinguish MCI from cognitively normal (CN) individuals only in small sample size studies and the efficacy has not been compared with blood biomarkers. Objective: This diagnostic study aimed to assess the feasibility of exhaled breath VOCs detection by a portable micro-gas chromatography (μGC) device as a screening tool to discriminate MCI from CN individuals in a community population. Methods: A detection model was developed and optimized from five distinct machine learning algorithms based on the differential VOCs between 240 MCI and 241 CN individuals. Among these 481 participants, five plasma biomarkers were measured in 397 individuals (166 MCI and 231 CN). Results: The final model (481 individuals) incorporating eight differential VOCs showed good performance with an area under the receiver-operating characteristic curve (AUC) of 0.84 (95% confidence interval (95%CI) 0.83-0.85). The AUC of the VOC model (0.80, 95% CI 0.69-0.90) was higher than that of the plasma model (0.77, 95% CI 0.65-0.88) (397 individuals). Conclusions: The detection of exhaled breath VOCs by a portable μGC device is feasible for MCI screening in community populations, potentially facilitating early detection and intervention strategies for individuals at high risk.
Kai-Jing Yeh#, Meng-Jie Sun#, Shin-Joe Yeh, Sung-Chun Tang, Jeng-Min Chiou, Yen-Ching Chen, Jen-Hau Chen #These authors contributed equally to this work.
Cognition and vascular factors: Insights from carotid intima-media thickness and ankle-brachial index in a cohort
Abstract: Background: Limited research has explored the intercorrelation between peripheral and central vascular factors on cognition incorporated longitudinal cognitive measures. Objective: Explore associations between central and peripheral vascular factors and cognition. Methods: This prospective cohort study recruited 516 older adults at baseline (2011–2013) with three follow-ups until 2019. Global and domain-specific cognition (memory, executive function, verbal fluency) were assessed biennially. The ankle-brachial index (ABI) and carotid intima-media thickness (CIMT) were the peripheral and central vascular markers. Generalized linear mixed models were utilized to explore the relationship between vascular factors and cognition adjusting for relevant covariates. Results. Over time, one unit increment in the ABI was associated with decreased attention performance ("β" ̂=-1.26). At baseline, one unit increase in CIMT (1 mm) was associated with better attention performance ("β" ̂=0.93) while the association decreased over time ("β" ̂=-0.23). Over time, a unit increase in CIMT was associated with poor performance in global cognition ("β" ̂=-0.52), memory ("β" ̂=-0.21), executive function ("β" ̂=-0.16), and verbal fluency ("β" ̂=-0.15). These associations were particularly evident in APOE ε4 non-carriers, participants without lacunar infarct, and participants with hyperintensities. A significant interaction was found between lacunar infarct and CIMT on attention performance over time. Participants with both abnormal ABI (either low or high) and elevated CIMT showed the most pronounced decline in attention and memory domains, suggesting that the joint effect of these vascular markers affects cognitive performance. Conclusions: Peripheral and central vascular factors differentially and jointly affect cognitive performance, emphasizing the importance of promoting vascular health to prevent dementia in the preclinical phase.
Andrea D Olmstead, Shengjie Zhang, Larry Shaver, Fernanda Ewerling, Bonnie Henry, Xibiao Ye (Handling Associate Editor: Michael Waller)
Effect of long-term care and pandemic wave on relative risk of COVID-19-related infection, hospitalization and mortality in people living with dementia: A population-based cohort study
Abstract: Background: People living with dementia (PLWD) are vulnerable to serious COVID-19 illness and death but the contribution of various factors including long-term care (LTC), pandemic wave, hospitalization, comorbidities, and underlying neurological health remains unclear. Objective: To investigate the relative risk of SARS-CoV-2 infection, hospitalization, and mortality (COVID-19 and non-COVID-19) in PLWD compared to those without dementia, by living circumstance and pandemic wave, while controlling for additional risk factors. Methods: A cohort of people 65 and up with dementia, including Alzheimer’s disease, was propensity score matched to a control cohort using linked population-level health records. Relative risk of outcomes was estimated using adjusted Cox proportional hazards modelling. The modifying effects of LTC residence and pandemic wave on all outcomes, and of COVID-19-related hospitalization on COVID-19 mortality were investigated. Results: Compared to controls without dementia, PLWD had higher risk of infection and COVID-19 mortality whether they lived in LTC or not. For PLWD in LTC, relative risk was often reduced or not significantly different when stratified by wave but remained higher for PLWD not in LTC (32-93%). In LTC, likelihood of hospitalization was 53-64% lower for PLWD compared to those without dementia. PLWD not hospitalized for COVID-19 had higher COVID-19 mortality than non-hospitalized, non-dementia controls both in and not in LTC (32% and 477%, respectively). Conclusions: PLWD repeatedly had higher risk of COVID-19 infection and mortality, but risk varied with changing pandemic circumstances and living environment. Higher mortality may have been associated with reduced hospital transfers, complex care needs and neurological health.
Dan Hu, Mei Chen, Xuyang Li, Sarah Daley, Peter Morin, Yuyang Han, Martin Hemberg, Howard L Weiner, Weiming Xia
ApoE ε4-dependent Alteration of CXCR3+CD127+ CD4+ T cells associates with elevated plasma neurofilament light chain in Alzheimer’s disease
Abstract: Background: Recent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimer's disease (AD). Objective: To characterize the composition of adaptive immune cells in the peripheral blood of AD patients. Methods: We utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects. Results: We found that the abundance of proinflammatory CXCR3+CD127+ Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain protein. This correlation is apolipoprotein E (ApoE) ε4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3+CD127+ Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+CD127+ Th1 cells in the CSF of AD patients was further increased compared to HCs. Conclusions: These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3+CD127+ Th1 cells, may potentially be mediated by factors such as ApoE ε4 genotype.
Xian Shi, Wen-Ao Zheng, Xin-Le Hou, Ya Chen, Hai-Feng Chen, Wei-Na Yao, Ting-Yu Lv, Feng Bai
Differential effects of 2 and 4 weeks repetitive transcranial magnetic stimulation inducing neuroplasticity on cognitive improvement
Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is an efficient intervention for alleviating cognitive symptoms in Alzheimer's disease (AD), but the optimal treatment duration for high efficacy remains unclear. Objective: This study investigates the effects of 2-week and 4-week rTMS on neural network plasticity and cognitive improvement, aiming to identify the optimal treatment duration for cognitive impairment. Methods: rTMS was administered to cognitively impaired patients over 2-week and 4-week periods, exploring its effects on cognitive improvement and induced neural circuits. The study also examines the predictive value of these neural circuits for individual treatment responses. Results: The 4-week rTMS treatment significantly outperformed the 2-week course in improving cognitive function. Neural activity analysis identified the precuneus as a key region for episodic memory. Changes in brain regions, particularly within the default mode network (DMN), visual network (VN), and motor network (MN), were associated with cognitive improvements. Baseline functional connectivity in these regions predicted changes in general cognition (r=0.724, p<0.001) and episodic memory (r=0.447, p=0.022) after rTMS. Conclusions: Extended rTMS treatment enhances cognitive performance in cognitive impairment patients, with the 4-week course showing superior effects. Reduced connectivity in the DMN following rTMS was linked to cognitive improvements. The neural network baseline can predict patients' treatment responses.
T Rune Nielsen, Kasper Jørgensen, Marco Canevelli, Simone Pomati, Alfonso Delgado-Álvarez, Sanne Franzen, Alvaro Lozano-Ruiz, Maria Özden, Juliette Palisson, Naaheed Mukadam, Gunhild Waldemar
Validation of the Brief Assessment of Impaired Cognition and Brief Assessment of Impaired Cognition Questionnaire in a multicultural memory clinic sample across six European countries
Abstract: Background: With the changing demographic landscape in most countries worldwide, accurate and brief culture-sensitive case-finding instruments are needed to identify patients with possible cognitive disorders. Objective: To investigate the discriminative validity of the Brief Assessment of Impaired Cognition (BASIC) and BASIC Questionnaire (BASIC-Q) in a multicultural memory clinic sample across six European countries. Methods: The study was a European cross-sectional multi-center study. Receiver operating characteristic curve analysis was used to examine discriminative validity of BASIC and BASIC-Q in identifying cognitive impairment (mild cognitive impairment (MCI) or dementia) as compared to specialist diagnosis. Regression analysis was used to assess the influence of sociodemographic variables and assessment in a second language on scores. Results: The study included a total of 479 participants of which 169 (36%) had immigrant background. BASIC and BASIC-Q had high diagnostic accuracy for cognitive impairment (MCI or dementia) with areas under the curve (AUC) of 0.93 and 0.92, respectively. Age had a significant, but small effect on BASIC, while both BASIC and BASIC-Q were unaffected by sex, education, immigrant status, and assessment in a second language. Among patients with affective/anxiety disorder, 80% scored below cutoff for cognitive impairment on BASIC and 94% on BASIC-Q. However, applying an Objective Performance vs. Subjective Complaints ratio to differentiate between patients with cognitive impairment and affective/anxiety disorder resulted in high overall classification accuracies, with AUC values of 0.80 and 0.74, respectively. Conclusions: The present study suggests that BASIC and BASIC-Q are valid brief case‐finding instruments for cognitive impairment in a multicultural setting.
Sydney Y Schaefer, Alexandra M Reed, Kevin Duff
Validating a brief performance-based measure of cognition and daily functioning in amnestic mild cognitive impairment and mild Alzheimer’s disease
Abstract: Background: The Clinical Dementia Rating (CDR) scale is widely used as a cognitive and functional measure in Alzheimer’s disease (AD) clinical trials. Given its time and personnel burden, there is a need to more efficiently identify patients who warrant further evaluation or clinical trial qualification. To potentially address this need, a novel performance-based test of cognition and daily functioning has been developed for use in AD research and clinical care. Objective: To test whether this novel performance-based test is associated with levels of daily functioning in both impaired and unimpaired individuals. Methods: One-hundred-seventy-one participants (72 cognitively unimpaired; 53 amnestic mild cognitive impairment; 46 mild AD) completed the novel performance-based test of cognition and daily functioning, as well as the Quick Dementia Rating System (QDRS) for estimating global CDR. Results: The novel test was significantly associated with the QDRS Total, as well as the Behavioral and Cognitive subdomains, and differentiated between estimated global CDR scores of 0 versus ≥0.5. No significant effect of age, sex, or education on the performance-based test was observed. Conclusions: The performance-based test used in this study can be considered a measure of cognition and daily functioning. As such, it may be a quick, objective method for identifying impaired individuals who may qualify for clinical trial enrollment or may warrant further evaluation without the need for informant input.
Dongyu Wang#, Alexandra Scalici#, Yanbing Wang, Honghuang Lin, Achilleas Pitsillides, Nancy Heard-Costa, Carlos Cruchaga, Ellen Ziegemeier, Joshua C Bis, Myriam Fornage, Eric Boerwinkle, Philip L De Jager, Ellen Wijsman, Josée Dupuis, Alan E Renton, Sudha Seshadri, Alison M Goate, Alzheimer's Disease Neuroimaging Initiative (ADNI), The Alzheimer’s Disease Sequencing Project, Anita L DeStefano#, Gina M Peloso# #These authors contributed equally to this work.
Frequency of variants in Mendelian Alzheimer’s disease genes within the Alzheimer’s Disease Sequencing Project
Abstract: Background: Prior studies examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer’s Disease Sequencing Project (ADSP). Objective: To characterize previously-reported clinically-relevant variants and DM variants in PSEN2, PSEN1, APP within the participants from the ADSP. Methods: We identified rare variants (MAF<1%) in PSEN2, PSEN1, and APP in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (Ntotal = 31,490). We additionally curated variants from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes. Results: We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in PSEN2, 25 in PSEN1, and 2 in APP. The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with noncarriers (p=7.8×10-57). Additionally, we identified 197 rare variants (MAF < 1%) within ADSP participants not reported in known clinical databases. Conclusions: A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to noncarriers.
Yu-Jing Lin, Ying Liu, Ze-Hu Sheng, Yan Fu, Ling-Zhi Ma, Zi-Hao Zhang, Lan-Yang Wang, Liang-Yu Huang, Min Liu, Zuo-Teng Wang, Lan Tan for the Alzheimer’s Disease Neuroimaging Initiative
The associations of cerebrospinal fluid ApoE and C1q with Alzheimer’s disease biomarkers
Abstract: Background: The roles of complement 1q (C1q) and Apolipoprotein E (ApoE) in driving Alzheimer's disease (AD) progression might be explained by their associations with neuroinflammation and AD pathology which were previously reported. Objective: We examined the associations of cerebrospinal fluid (CSF) C1q and ApoE with CSF neuroinflammatory biomarkers and AD core biomarkers, as well as explored whether C1q mediated the associations of CSF ApoE with these biomarkers. Methods: Here, we analyzed CSF proteomics data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) using two different ADNI proteomics datasets—SomaScan (n=579)and multiple reaction monitoring (MRM[n=207]). Linear regression analyses were conducted to explore the association of CSF ApoE and C1q. The mediation model and structural equation model (SEM) were conducted to explore the associations of ApoE and C1q with AD biomarkers. Results: Multiple linear regression showed that CSF ApoE was positively associated with CSF C1q in total participants and Alzheimer’s continuum participants. Mediation analyses indicated that C1q mediated the associations of CSF ApoE with CSF T-tau, P-tau, sTREM2 and GFAP (mediation proportions range from 15.06 to 44.64%; all the p values<0.05) but not with CSF amyloid-β and progranulin (PGRN). The SEM yielded similar results. Conclusions: Our findings suggest that C1q is linked to ApoE, and it mediates the associations of ApoE with T-tau, P-tau, sTREM2, GFAP, indicating C1q association with ApoE might be involved in AD progression.
Edna N Bosire, Karen Blackmon, Lucy W Kamau, Chinedu Udeh-Momoh, Dilraj Sokhi, Jasmit Shah, Sylvia Mbugua, Kendi Muchungi, Irene Meier, Vaibhav Narayan, Olivera Nesic, Zul Merali
Healthcare providers perspectives and perceptions of dementia diagnosis and management at the Aga Khan University Hospital, Nairobi, Kenya
Abstract: Background: The rising number of older people, including those living with Alzheimer’s disease and related dementias (AD/ADRD) in sub-Saharan Africa (SSA) highlights the need for an improved clinical diagnosis and management of the diseases. Objective: To understand and describe healthcare providers’ perceptions and practices regarding AD/ADRD diagnosis and care in Kenya, not previously reported Methods: This was an ethnographic study involving observations and semi-structured interviews with healthcare providers working at Aga Khan University Hospital, Nairobi (AKUHN) Kenya. Twenty-one healthcare providers were purposively recruited and interviewed in English, with the data transcribed verbatim and thematically analysed using Nvivo version 14. Results: Our findings reveal that AKUHN’s dementia diagnostic pathway aligns with universal best practice models and involves multidisciplinary care. Yet, healthcare providers noted that this level of care is not representative of most public hospitals in Kenya, where a lack of diagnostic equipment and trained staff severely limits patient access to timely dementia care. In addition, new medications that can slow AD/ADRD progression, are not readily available in Africa, including Kenya. We also identified barriers to timely diagnosis and care such as: lack of dementia policy and guidelines, limited expertise of healthcare providers, high cost of care, and sociocultural factors, including stigma. Conclusions: We emphasize the need for the Kenyan government and relevant stakeholders to develop social and healthcare policies and allocate resources to raise awareness about dementia and combat stigma, train healthcare providers, improve early detection and service delivery through access to diagnostic tools, and establish clear guidelines/protocols for AD/ADRD care.
Shi-Yao Wang#, Zhi-Hang Huang#, Rui Duan, Xin-Xin Fu, Jing-Wen Qi, Zi-Jian Luo, Ying-Dong Zhang, Teng Jiang #These authors contributed equally to this work.
IL-34/TREM2 modulates microglia-mediated inflammation and provides neuroprotection in a mouse model of sporadic Alzheimer’s disease
Abstract: Background: As a recently identified cytokine, interleukin-34 (IL-34) is predominantly produced by neurons and functions as a modulator for glial functions. Emerging evidence indicates that IL-34 exerted neuroprotective effects in Alzheimer’s disease (AD), but the underlying mechanism remained elusive. Objective: To uncover the mechanisms by which IL-34 provides neuroprotection in AD. Methods: Using senescence-accelerated mouse prone substrain 8 (SAMP8) mice, a well-established model for sporadic AD, we investigated the dynamic changes in brain IL-34 concentrations during AD progression. Afterwards, SAMP8 mice received a 4-week continuous intracerebroventricular infusion of IL-34. Morris water maze test was employed to assess the spatial cognitive functions. Neuronal and synaptic markers, oxidative stress makers, pro-inflammatory cytokines and glial activation markers in the brains of SAMP8 mice were measured. Finally, amyloid-β (Aβ)42-stimulated primary microglia, lentivirus-mediated gene knockdown strategy and co-immunoprecipitation assay were utilized to uncover the possible mechanisms by which IL-34 exerted neuroprotection in AD. Results: In SAMP8 mice, we revealed that brain IL-34 concentrations gradually decreased during AD progression. A 4-week continuous intracerebroventricular infusion of IL-34 rescued spatial cognitive impairments, ameliorated neuronal and synaptic damage, and suppressed oxidative stress and microglia-mediated inflammation in the brains of SAMP8 mice. Using Aβ42-stimulated primary microglia, we demonstrated for the first time that IL-34 suppressed microglial NLRP3 inflammasome activation and pro-inflammatory cytokines release by interacting with triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial functions. Conclusions: These findings uncover the mechanisms by which IL-34 provides neuroprotection in AD, indicating that IL-34/TREM2 signaling may represent a novel therapeutic strategy for this devastating disease.
Mingzhou Fu, Herong Wang, Erin B Ware#, Kelly M Bakulski# #These authors contributed equally to this work.
Understanding causal estimates of smoking behaviors for cognitive impairment: A Mendelian randomization study
Abstract: Background: Smoking has been linked to dementia, but the causal relationship has not been well established. Objective: Our study used a Mendelian randomization (MR) framework to examine the impact of different stages and kinds of smoking behavior on cognitive status. Methods: We analyzed a Health and Retirement Study sample, categorizing cognitive status into three levels (normal, cognitive impairment-non dementia, dementia) and using self-reported smoking behaviors. We used multivariable logistic regressions to examine associations and MR to examine potential causality. We used smoking polygenic scores as instruments for one-sample MR and validated through two-sample MR with genome-wide association study summary statistics. Results: Current smoking was associated with 1.33 times higher odds of cognitive impairment non-dementia (95% CI: 1.06, 1.65) in European ancestry participants (N=7708). Among participants who had ever smoked, each 10-additional year of smoking was associated with 1.11 times higher odds of cognitive impairment-non dementia (95% CI: 1.10, 1.22). Using ever smoking polygenic score as a validated instrumental variable, we detected strong causal effects of ever smoking, current smoking, and total smoking years on cognitive impairment (all p<0.001). Two-sample MR showed no evidence of causality between smoking behaviors and Alzheimer’s disease. No causality was observed in the African ancestry sample (N=1928). Conclusions: Smoking behavior was cross-sectionally associated with and potentially on the causal pathway of cognitive impairment non-dementia in the larger European ancestry sample. However, no associations were observed with dementia, and the findings did not replicate across ancestry groups. The causal relationship between smoking and cognitive health remains suggestive but not conclusive. Promoting smoking cessation remains a prudent public health strategy to prevent numerous health conditions, and its potential impact on cognitive health warrants further investigation.
Srijan Konwar, Riccardo Manca, Matteo De Marco, Hilkka Soininen, Annalena Venneri
Interactive effects of APOE ɛ4 status and vascular burden on white matter microstructural integrity in aging with and without neurocognitive decline
Abstract: Background: Carrying the Apolipoprotein (APOE) ε4 allele lowers age of onset and increases Alzheimer’s disease (AD) risk. Neuropathological findings suggest a mixed etiology in many AD patients and vascular pathology is common. Objective: This study tested the interactive effect of APOE status and multiple vascular comorbidities on white matter (WM) microstructure in aging and early AD. Methods: 195 participants from the VPH-DARE@IT dataset were stratified in low/high vascular burden based on the Framingham Risk Score (BMI version). Tract-based spatial statistics was used for WM analyses. Results: There was a main effect of APOE, with APOE ɛ4 carriers having higher fractional anisotropy (FA) and lower axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD) than non-carriers. There was a main effect of vascular burden with lower FA and higher AxD, MD, and RD in the higher-burden than the low-burden group. A significant interaction between APOE genotype and vascular burden was also found for all diffusion indices. Post hoc comparisons revealed lower left hemisphere WM integrity when comparing the low-risk group (i.e., non-carriers low burden) to intermediate risk groups (i.e., non-carriers high burden or ɛ4 carriers low burden). The contrasts between the two intermediate risk groups showed altered WM integrity bilaterally. Only the non-carriers high burden showed greater alterations in WM integrity when compared with the high-risk group (i.e., ɛ4 carriers high burden) mainly in right hemisphere tracts. Conclusions: These findings indicate an interactive effect of a risk gene and vascular comorbidities on WM integrity in aging and early AD.
Momoyo Shimosaka, Hiroyuki Nishimoto, Sayaka Okahashi, Derong Zeng, Kayoko Fukui, Teruaki Kawasaki, Ichiro Akiguchi, Ayae Kinoshita
Assessment of instrumental activities of daily living in patients with cognitive impairment based on their ability to use household appliances
Abstract: Background: Detecting life disability is crucial in diagnosing dementia; however, early detection has proven challenging with previous assessment scales. This study focused on an individual’s ability to use household appliances as a means of detecting life disability. Objective: The objectives of this study are threefold: (1) to compare the ability to use household appliances between the non-dementia and dementia groups, (2) to determine whether the level of life disability based on the ability to use appliances is at the level of diagnosed dementia or non-dementia, and (3) to explore the impact of age and gender on the ability to use appliances. Methods: We selected 13 essential household appliances for elderly individuals and proposed an instrumental activities of daily living (IADL) assessment tool to evaluate their usage. Our sample consisted of 98 patients with cognitive impairment, divided into a non-dementia group (N = 34) and a dementia group (N = 64). Most participants in the dementia group had Alzheimer’s disease or related conditions. Through multiple logistic regression, the model equation aimed to determine whether a subject’s functional disability indicated a potential dementia diagnosis. Results: The optimal model equation identified the microwave oven and air conditioner as key factors, achieving an area under the curve (AUC) of 0.78. Additionally, analysis by age and gender enhanced the discriminative power of the results. Conclusions: Our proposed scoring system can efficiently determine the degree of life disability by assessing appliance usage, demonstrating comparable discriminatory ability to existing scales.
Cecilia Tremblay#, Neha Shakir#, Nan Zhang, Charles H Adler, Holly A Shill, Shyamal Mehta, Erika Driver-Dunckley, Christine M Belden, Alireza Atri, Thomas G Beach, Geidy E Serrano, Parichita Choudhury #These authors contributed equally to this work.
Associations between neuropsychiatric symptoms and pathology in clinicopathologically defined Alzheimer’s disease, Alzheimer’s disease with Lewy bodies, and dementia with Lewy bodies
Abstract: Background: Neuropsychiatric symptoms (NPS) are frequent in Alzheimer’s disease (AD) dementia, but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co-occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). NPS trajectories over disease course in these subgroups is not well understood. Objective: We investigated changes in NPS severity over time, at two time points, comparing clinicopathologically defined cohorts of AD (without LB), ADLB, DLB, and controls. Methods: Cases with two available Neuropsychiatric Inventory-Questionnaire (NPIQ), at the time of enrollment and within 2.5 years of death, were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Differences and rate of change in NPIQ scores were compared between AD (n=75), ADLB (n=48) DLB (n=65), and controls (n=32) with covariates for age, sex, and cognition. Results: First NPIQ scores were highest in ADLB when compared to AD (p=0.04) and controls (p=0.01) but not different from DLB. A significant increase in NPS severity was observed in DLB and AD (p<0.001) over a mean follow up time of 4.9 ± 3.0 years, and the rate of change was significantly greater in DLB when compared to other groups. Final NPIQ scores were highest in DLB when compared to AD (p=0.03) but not ADLB, and in DLB, ADLB, and AD than controls (all p<0.001). Conclusions: Early NPS burden as well as NPS severity progression rate, independently of cognitive status, might be useful clinical metrics and may help predict underlying pathological diagnoses.
Kelly RB Parker, Ryan McGrath, Yeong Rhee, Jeremy Hamm
Western Mediterranean diet predicts 9-year changes in episodic memory in an adult lifespan sample of Americans
Abstract: Background: The Mediterranean Diet (MD) is well-studied for slowing cognitive declines. Few studies have examined how a Western MD (wMD) may impact cognitive function. Objective: This study examined whether a wMD predicted less cognitive decline over 9 years in a national sample of American adults. The measures were episodic memory (EM) and executive functioning (EF) at baseline and 9 years follow-up. Methods: This is a secondary analysis of the Midlife in the United States Study (MIDUS), using a longitudinal cohort design with cross-sectional dietary data. Participants in this study had data from Waves 2 and 3 of MIDUS (n=833, 46±12 years; 45% male). Regression analyses tested whether wMD adherence predicted 9-year changes in EM and EF. Moderator analyses determined whether the relationship between wMD, EM, and EF differed across sociodemographic characteristics. Results: wMD score at Wave 2 predicted attenuated declines in EM 9 years later (β=0.06, p=0.04). The association between wMD and EM was not moderated by age, sex, race, education, or income and thus consistent across sociodemographic subpopulations. wMD did not predict EF (fully adjusted wMD β=0.00, p=0.86). Contextualized effect sizes showed that individuals who strongly adhered to the wMD (+1 SD) experienced ~50-60% less decline in 9-year EM when compared to those with average adherence. Conclusions: A wMD was related to slowed EM declines across sociodemographic populations in a national U.S. sample. Education is needed about healthful dietary habits, including increased fruit and vegetable intake.