Review
Xinmao Yang#, Jie Wang#, Xiaotao Jia#, Yaqian Yang, Yan Fang, Xiaoping Ying, Hong Li, Meiqian Zhang, Jing Wei, Yanfang Pan #These authors contributed equally to this work.
Microglial polarization in Alzheimer’s disease: Mechanisms, implications, and therapeutic opportunities
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Microglial cells, the resident immune cells in the central nervous system, play a crucial role in the pathogenesis of AD. Microglia can undergo polarization, shifting between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in response to different stimuli. Dysregulation of microglial polarization towards the pro-inflammatory phenotype leads to the release of inflammatory cytokines, oxidative stress, and synaptic dysfunction. These processes contribute to neuronal damage and cognitive decline in AD. However, several challenges remain in this field. The complex molecular mechanisms governing microglial polarization in AD need to be further elucidated. In this review, we discuss the mechanisms underlying microglial polarization in AD and its implications in disease progression.
Review
Jaime Ramirez Gomez, Sarthak Dalal, Davin Devara, Bhupender Sharma, Daniela Rodarte, Subodh Kumar
MicroRNA-based recent research developments in Alzheimer’s disease
Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by memory and physical impairment in aged individuals. microRNAs (miRNAs) are small, single-stranded noncoding RNAs that induce translational repression by binding to the 3’ UTR of a target mRNA. miRNAs play a crucial role in neurological activity by mediating cellular proliferation, synaptic plasticity, apoptosis and more. Ongoing research in patents and clinical trials have called attention to promising miRNAs as biomarkers and therapeutics in AD. Recent research has shown that miRNAs are aberrantly expressed in AD brain, blood, cerebrospinal fluid and serum. Attenuated miRNA expressions have diagnostic potential in AD by interacting with amyloid-β synthesis, phosphorylated tau, and neurofibrillary tangles. In this study, miRNA-29a, miRNA-125b, miRNA-34a, miRNA-146a, and miRNA-155 have shown promise as potential biomarker candidates for AD. Improving cognitive symptoms can be traced to restoring the endogenous miRNA activity by synthesizing miRNA mimics and miRNA antisense oligonucleotides. miRNA-483-5p, miRNA-188-5p, miRNA-219, miRNA135a/5p, miRNA-23/23b-3p, miRNA-124, and miRNA-455-3p are growing therapeutics for AD. However, miRNA-based therapeutics struggle outside of preclinical testing. miRNA-107, miRNA-206, miRNA-30/7, and miRNA-142-3p face bottlenecks in clinical trials due to a lack of experimental design, transparency and volunteer size. Patenting recent miRNA-based developments demonstrates the commitment in identifying a new biomarker and/or therapeutic for AD.
Commentary
J Wesson AshfordThe VA Million Veteran Program, Alzheimer’s disease, and genetics: Important steps forward but many steps still to go on the march to control dementia and Alzheimer’s disease
Abstract: The VA Million Veteran Program (MVP) is a nationwide initiative that seeks to examine how genes influence health and behaviors in military veterans. An article by Merritt et al. analyzing data from the MVP, developing and testing algorithms to query dementia and Alzheimer’s disease (AD) diagnoses from the VA’s electronic health record system and examining genetic factors, provides an extraordinarily important contribution to the dementia and AD fields. The analyses presented in the article show how large databases can be used to further understand dementia and AD, pointing the way for many more important advances for this field.
Commentary
Timothy Daly, Andi Olluri (Handling Editor: Allyson Rosen)
Is provision of substantial dietary interventions for brain health ethical?
Abstract: We argue that the provision of substantial dietary modifications to individuals who wish to maximize their brain health is ethically permitted, despite evidence for such an intervention being not yet fully conclusive. However, we argue that for a burdensome therapy with weak evidence and potential harms, balanced communication, informed consent and follow-up are necessary components of the ethical provision of such lifestyle changes. Moreover, health should be discussed as a value with individuals alongside non-health priorities to achieve balance and avoid brain healthism.
Commentary
Claudio Liguori
Obstructive sleep apnea is a common diagnosis in patients admitted at the memory clinic: Please screen for it!
Abstract: Obstructive sleep apnea (OSA) affects a large portion of middle-aged and older adults. It has been linked to increased risk of cognitive decline and Alzheimer’s disease. OSA can impair cognitive performance and patients with cognitive complaints can frequently present with this sleep disorder. Although instruments able for correctly screening patients with cognitive impairment and OSA exist, there is no evidence about utility and feasibility of their use in the memory clinics. The study by Lam et al. showed that, in case of impossibility of performing polysomnography–that is the gold standard for OSA diagnosis, pulse oximetry can represent a good instrument for screening patients with cognitive impairment for OSA, and they do not suggest using sleep interview or STOP-Bang questionnaire for screening this sleep disorder.
Fernando Mijares Diaz, Alessandro Orlando, Andrea LC Schneider, James R Pike, Clifford R Jack, Jennifer A Deal, A Richey Sharrett
Differences in brain volume in individuals with mild cognitive impairment and normal cognition across different anatomical regions: The Atherosclerosis Risk in Communities (ARIC) study
Abstract: Background: Mild cognitive impairment (MCI) represents a stage between cognitively normal and Alzheimer’s disease. Despite much published research on MCI, there continues to be a knowledge gap of volumetric brain changes in MCI versus cognitively normal (CN) in racially diverse, community-based samples. Objective: The study aimed to understand differences in volume of selected brain regions in individuals with MCI versus those who are cognitively normal. Methods: This was a cross-sectional study with 1835 participants, which sampled all cognitively impaired participants (n=667) and a subsample of cognitively normal participants from the ARIC neurocognitive study (ARIC-NCS). All individuals underwent a brain MRI. Two models (5 versus 22 regions of interest [ROI]) were built to analyze differences in brain volume between cognitively normal and MCI, and among 3 cognitive domains (memory, language, executive function). Using previous visits data, we estimated the standard deviations of 20-year cognitive decline equivalent to the difference in brain volume between MCI and CN. Results: Every lobe was significantly smaller in individuals with MCI, with the largest difference observed in the temporal lobe. Moreover, there was a significant difference between MCI and CN in every subregion within the temporal lobe. The difference in volume between CN and MCI was equivalent to the total brain volume difference associated with a 1.24 standard deviation greater long-term cognitive decline. Conclusions: Loss of volume in all cortical lobes, but particularly in the temporal lobe, was associated with MCI. Additionally, significant volume differences were observed in the temporal lobe in all three cognitive domains.
Rong Guo, Deyu Li, Fang Li, Linna Ji, Hongying Liu, Huiting Qiao, Zeping Lv, Yi Tang, Daifa Wang
Effects of whole-head 810 nm near-infrared therapy on cognitive and neuropsychiatric symptoms in Alzheimer’s disease: A pilot study
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by significant cognitive and behavioral impairments. Near-infrared (NIR) light treatment has shown potential in cognitive improvement in previous studies. However, clinical trials of NIR for AD remain limited. Objective: This study investigated the safety and effects of whole-head 810 nm NIR therapy in AD patients, including long-term efficacy. Methods: An open-label pilot study on whole-head NIR treatment for AD patients was conducted. Nine AD patients completed 4-month treatment (810 nm, 100 mW/cm², 30 min/session, 6 sessions weekly). Safety and efficacy were evaluated at baseline, months 2 and 4, and 2-month post-treatment. Results: After four months of whole-head NIR treatment, mean changes from baseline on the Mini-Mental State Examination were 3.2 (p=0.02). Mean changes from baseline on the Alzheimer's Disease Assessment Scale-Cognitive were -5.0 (p=0.05), mean changes from baseline on the Montreal Cognitive Assessment were 1.9 (p=0.12). Mean changes from baseline on the Neuropsychiatric Inventory were -4.2 (p=0.47). These benefits were sustained two months at least. With no device-related adverse effects were reported. Conclusions: Whole-head 810 nm NIR light is safety and offers promising benefits for AD patients. To fully confirm its efficacy, durability, and underlying mechanisms, further large-scale randomized controlled trials are necessary.
Yu-Ting Dong#, Xiao Luo#, Li-Li Zhang, Yi-Meng Gong, Dan Wang, Dong-Ling Zhong, Yu-Xi Li, Xiao-Min Ma, Rong-Jiang Jin, Juan Li #These authors contributed equally to this work.
Genetic colocalization of cathepsins H, D, and L1 with Alzheimer’s disease: Implications for biomarker and therapeutic target discovery
Abstract: Background: Cathepsins, a family of lysosomal proteases, have been implicated in Alzheimer's disease (AD) pathogenesis through their involvement in amyloid-β protein precursor processing and neuroinflammation. However, the specific roles of different cathepsins in AD remain unclear. Objective: This study aimed to investigate the genetic associations and potential causal relationships between cathepsins and AD, using Mendelian randomization (MR) to explore their roles as biomarkers and therapeutic targets. Methods: A two-sample MR analysis was conducted using genome-wide association study data for AD and cathepsins. Genetic variants associated with cathepsin expression were used as instrumental variables. Forward MR assessed the causal effect of cathepsins on AD, while reverse MR explored the impact of AD on cathepsin levels. Colocalization analysis was performed to identify shared genetic variants between cathepsins and AD. Results: Cathepsin H was significantly associated with an increased risk of AD (p = 0.0034, OR = 1.04), with consistent results across multiple MR methods. Colocalization analysis revealed a significant genetic overlap between Cathepsin L1 and AD (PP.H4 = 100%), suggesting a shared genetic basis. Conclusions: Cathepsin H may be a potential risk factor for AD, while Cathepsin L1 shows promise as a therapeutic target and biomarker due to its genetic overlap with AD. Further research is needed to explore the mechanisms by which these cathepsins influence AD progression and to assess their therapeutic potential in diverse populations.
Anne Keefer, Nikolas Dietzel, Peter L Kolominsky-Rabas, Elmar Graessel
The use of outpatient support services: Differences between people with mild cognitive impairment and people with mild to moderate dementia
Abstract: Background: Little is known about the utilization of outpatient support services by people with mild cognitive impairment (MCI). Objective: This study aimed to analyze the use of support services by people with MCI compared to people with mild to moderate dementia. Methods: The data basis is the multicenter, prospective register study 'Digital Dementia Register Bavaria - digiDEM Bayern'. The sample consists of 913 people with cognitive impairment, including 389 with MCI and 524 with mild to moderate dementia. Classification into 'MCI' and 'mild to moderate dementia' is based on the Mini-Mental State Examination and Montreal Cognitive Assessment. The use of support services was surveyed using the Dementia Assessment of Service Needs. Fisher's exact test and multiple linear regression were conducted to analyze for group differences. Results: Four out of thirteen support services are used less frequently by people with MCI than by people with mild to moderate dementia: 'Outpatient care' (p < 0.001, φ = -0.199), 'Acquisition of aids' (p = 0.004, φ = -0.096), 'Adult daycare' (p < 0.001, φ = -0.290), and 'Respite care' (p = 0.029, φ = -0.095). Even the overall utilization rate is lower for people with MCI (b = -0.18, p = 0.027), although other factors such as a care level (b = 1.01, p < 0.001) are more strongly related. Conclusions: There are differences in utilization between people with MCI and people with mild to moderate dementia, but these are small. Therefore, access to support services should be provided at the first signs of cognitive impairment.
James E Galvin, Michael J Kleiman, Paul W Estes, Heather M Harris, Ernest Fung
Cognivue Clarity® characterizes amyloid status and preclinical Alzheimer’s disease in biomarker confirmed cohorts in the Bio-Hermes Study
Abstract: Background: Cognivue Clarity® is an FDA-cleared computerized cognitive test to screen for cognitive impairment included in the Bio-Hermes Study to test blood-based and digital biomarkers’ ability to screen for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). A subset of cognitively normal individuals have amyloid deposition (Preclinical AD) but no current assessment can identify these individuals in the absence of expensive biomarkers. Objective: We examined differences in Cognivue Clarity performance between amyloid positive and amyloid negative individuals and whether Cognivue Clarity could differentiate True Controls (cognitively normal/amyloid negative), Preclinical AD (cognitively normal/amyloid positive), and MCI due to AD (MCI-AD, cognitively impaired/amyloid positive). Methods: Cognivue Clarity was administered to all participants in the Bio-Hermes Study who also had amyloid PET and blood-based biomarkers. Performance was compared between biomarker-defined groups: True Controls (n=297), Preclinical AD (n=95), and MCI-AD (n=113). Results: Cognivue Clarity global scores distinguished amyloid positive individuals from amyloid negative individuals (p<0.001) and differentiated True Controls versus Preclinical AD (p=0.014) and Preclinical AD versus MCI-AD (p<0.001). Three subtests [Shape Discrimination (p=0.004), Visual Salience (p=0.008), Adaptive Motor Control (p=0.004)] and the 3-test mean (p<0.001) differentiated True Controls from Preclinical AD. The 3-test composite correlated with Amyloid PET (r=-0.433) and pTau217 (r=-0.400). The 3-test mean identified Preclinical AD in both White and Black participants. Conclusions: Cognivue Clarity, a 10-minute computerized battery, screens for individuals with cognitive impairment, characterizes amyloid positive individuals, and identifies Preclinical AD. This has great potential as a cost- and time-effective strategy to screen and enroll in AD prevention trials.
Milan Fiala, Bruce D Hammock, Sung Hee Hwang, Julian Whitelegge, Ketema Paul, Karolina Elżbieta Kaczor-Urbanowicz, Andrzej Urbanowicz, Santosh Kesari
Inhibitors of soluble epoxide hydrolase and cGAS/STING repair defects in amyloid-β clearance underlying vascular complications of Alzheimer’s disease
Abstract: Background: Alzheimer’s disease (AD) and its monoclonal antibody therapies are associated with brain vasculitis and amyloid-related imaging abnormalities. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFAs), such as 11,12-epoxyeicosatetraenoic acid (EEQ), are anti-inflammatory and pro-resolution mediators, which are increased by dietary supplements with ω-3 PUFAs. EpFAs are, however, enzymatically hydrolyzed by soluble epoxide hydrolase (sEH) in macrophages in vivo and in vitro. Objective: To repair the inflammatory transcriptome and amyloid-β (Aβ) degradation in macrophages of AD patients using the inhibitors of a) soluble epoxide hydrolase (sEHIs), termed TPPU and EC5026, together with EpFAs, or b) STING pathway termed H-151. Methods: Immunobiology, immunochemistry, RNA sequencing, and confocal microscopy was used. Results: In the AD brain (examined postmortem), monocyte/macrophages upload Aβ in plaques and transfer it without degradation into brain vessels, and, after apoptosis, release Aβ causing vasculitis. AD patients’ macrophages are inflammatory. The epoxides of docosahexaenoic acid termed EDP and the inhibitors TPPU and H-151 decrease inflammatory cytokines and markers of endoplasmic reticulum stress and regulate macrophage unfolded protein response through increase of transcripts of activating transcription factor 4 (ATF4) and ATF6. Treatment of AD macrophages by TPPU with epoxyeicosatetraenoic acid (EEQ) or H-151 increased uploading of Aβ at 2 hours and increased degradation of Aβ after 24 hours. Conclusions: The sEHIs, EC5026 and TPPU, and the inhibitor of STING path H-151 increased uptake and degradation of Aβ in macrophages and should be tested together with ω-3 PUFA supplementation in a clinical trial of AD patients.
Mervin Tee, Beatriz E Padrela, Margaux Dupeyron, Jiannan Huang, Marcus Low, Simon Konstandin, Klaus Eickel, Matthias Günther, Karolina Minta, Victor R Schinazi, Giorgio Colombo, Jan Petr, Henk JMM Mutsaerts, Saima Hilal
Associations between potential risk factors and blood-brain barrier water permeability in middle-aged and older adults
Abstract: Background: Blood-brain barrier (BBB) dysfunction is suggested to be a potential mediator between vascular risk factors and cognitive impairment, leading to vascular cognitive impairment. Objective: To investigate the relationships between age, sex, and vascular risk factors and BBB water permeability as well as their relationship with cognition. Methods: To measure BBB permeability, a novel arterial spin labelling MRI technique (ME-ASL) was applied to derive the time of exchange (Tex), arterial time transit (ATT), and cerebral blood flow (CBF). The association of potential risk factors, such as age, sex, body mass index (BMI), blood pressure (BP), and medical history, with these BBB parameters were assessed in 144 community-dwelling adults (median age 59 years, 57% females). The relationship between BBB permeability and cognitive performance measured by the Montreal Cognitive Assessment (MoCA) was also assessed. Results: We found that increased BMI was significantly associated with decreased CBF (β=-0.06). Systolic BP and diastolic BP showed significant associations with all ASL parameters; systolic BP was negatively correlated with Tex (β=-0.02) and CBF (β=-0.01) but positively with ATT (β=0.02). Diastolic BP was negatively associated with Tex (β=-0.03) and CBF (β=-0.03) but positively with ATT (β=0.03). MoCA scores had a borderline significant association with Tex (OR=1.51) and a significant association with CBF (OR=1.84), which became non-significant after adjusting for confounders. Conclusions: These outcomes underscore the potential of using ME-ASL, warranting further research to strengthen these findings.
Shu-Wen Lin, Yen-Hsuan Hsu, Jir-Jei Yang, Min-Chien Tu
A higher vertebrobasilar pulsatility index is associated with lower parietal perfusion in Alzheimer’s disease
Abstract: Background: While cerebrovascular hemodynamics exhibits critical interplay with the pathogenesis of dementia, limited articles have examined the impact of vertebrobasilar (VB) hemodynamics on cerebral blood flow (CBF), and to what extent it varies by dementia subtypes. Objective: To explore the associations between VB hemodynamics and CBF by dementia subtypes. Methods: This research recruited a total of 120 dementia patients [43 subcortical ischemic vascular dementia (SIVD); 59 Alzheimer’s disease (AD); 18 mixed dementia] and 40 older adults with normal cognition and compared their transcranial doppler (TCD) flow parameters and arterial spin labeling-measured CBF. Using the partial correlation analysis, the associations between TCD parameters and CBF values were explored among the defined subgroups. Results: A higher VB pulsatility index (PI) was related to lower parietal CBF and lower VB end-diastolic velocity (EDV). Moreover, the significance of flow parameters in the basilar artery (BA) to parietal CBF was identified: peak-systolic velocity (PSV) unanimously showed positive correlations among all subgroups except SIVD, and both PSV and EDV showed positive correlations in AD. Of note, there were more noticeable “BA flow-frontoparietal CBF” associations among the high than low VB PI group, and AD than SIVD group. Conclusions: The findings indicate that VB-resistance-related parietal vulnerability and topological CBF associations vary by dementia subtypes. Given VB hemodynamics-CBF relationships, the current research extends our understanding of the vasocognopathic effects among dementia patients.
Chathura Siriwardhana, Enrique Carrazana, Kore Liow
Survival disparities among Alzheimer’s disease patients in HawaiiAbstract: Background: Survival after an Alzheimer's disease (AD) diagnosis is vital for patients, their families, caregivers, and healthcare providers. Hawaii, known for its diverse ethnic population, exhibits significant racial health disparities. Objective: This study examined racial/ethnic and socioeconomic disparities in AD survival in Hawaii and developed machine learning models to predict overall survival using Hawaii Medicare data. Methods: Nine years of Hawaii Medicare data were utilized to gather information on AD development after age 65, following patients to capture all-cause survival or until censoring. The study examined the effects of race/ethnicity and socioeconomic status (SES) on mortality risk. Cox regression analysis was conducted on overall survival, accounting for covariates. A Survival Random Forest was employed to model survival, incorporating K years of longitudinal health profiles. Results: The study included 9393 AD subjects. Analysis revealed that Asian Americans (AA) had a later age at AD diagnosis (p<0.001), with an average age of 85.9, compared to 82.7 and 83.3 years for whites and Native Hawaiians and Pacific Islanders (NHPI), respectively. Low SES showed a marginal increase in hazard (Hazard Ratio [HR]=1.36, p<0.001). After covariate adjustment, compared to AAs with better SES, increased hazards were found for their white counterpart (HR=1.18, p<0.001) and groups with low SES: AA (HR=1.28, p<0.001), white (HR=1.51, p<0.001), and NHPI (HR=1.39, p<0.001). The predictive model had a Concordance-Index of 0.82, showing reasonable predictability. Conclusions: Racial/ethnic and SES disparities significantly influence AD onset and survival. Combined with longitudinal health status data, machine learning demonstrates reasonable predictability of survival.
Atsuhito Nakamichi, Noriyuki Kimura, Takuya Hanaoka, Teruaki Masuda, Takuya Ataka, Etsuro Matsubara
Association between plasma cytokine levels and multiple neuroimaging modalities in mild cognitive impairment
Abstract: Background: The relationship between peripheral cytokines and neuroimaging biomarkers for Alzheimer’s disease (AD) is not yet well established. Objective: To determine the association of cytokine plasma levels with brain amyloid deposition, cortical glucose metabolism, hippocampal volume, and white matter lesions (WMLs) in older adults with mild cognitive impairment (MCI). Methods: We recruited 50 older individuals with amnestic MCI (25 men and 25 women; median age, 75 years) and performed plasma analysis, 11C-Pittsburgh compound-B positron-emission tomography (PiB-PET), 18F-fluorodeoxyglucose positron-emission tomography, and magnetic resonance imaging. Global PiB and FDG uptake were assessed by the ratio of the voxel number-weighted average of the mean uptake in the frontal, temporoparietal, and posterior cingulate, in reference to the cerebellum. The Fazekas scale was used to evaluate WMLs. Plasma levels of 48 cytokines were simultaneously measured with bead-based multiplex assays. Results: The plasma levels of IL-2R, IL-3, IL-5, IL-7, IL-9, IL-16, IL-18, FGF-basic, G-CSF, GM-CSF, MIP-1α, RANTES, TNF-α, CTACK, GROα, HGF, IFN-α2, LIF, MCP-3, β-NGF, SCF, SCGF-β, and TRAIL were significantly associated with global PiB uptake, whereas those of IL-7 and GROα were significantly associated with hippocampal volume after covariate adjustment and false discovery rate correction. Conclusions: Plasma cytokines are associated with brain amyloid deposition rather than brain dysfunction or hippocampal atrophy. Moreover, cytokines may play important roles in early-stage AD pathophysiology.
Jee Wook Kim, Min Soo Byun, Dahyun Yi, Joon Hyung Jung, Nayeong Kong, Yoon Young Chang, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Koung Mi Kang, Chul-Ho Sohn, Yun Sang Lee, Yu Kyeong Kim, Dong Young Lee, for the KBASE Research Group
Daily fluid intake and brain amyloid deposition: A cohort study
Abstract: Background: Little information is yet available for the association between daily water intake, a modifiable lifestyle factor, and Alzheimer’s disease (AD) pathology and cerebrovascular injury in the living human brain. Objective: Our aim was to explore the correlation between daily fluid intake and in vivo AD pathologies (i.e., amyloid-β (Aβ) and tau) and cerebrovascular injury. Methods: 287 cognitively normal (CN) older adults completed extensive clinical assessments, daily fluid intake evaluations, and multimodal brain imaging at both the initial baseline and the subsequent 2-year follow-up. Results: Low daily fluid intake was significantly associated with a higher level or a more rapid increase of Aβ deposition, especially in apolipoprotein E4 negative individuals. Meanwhile, low daily fluid intake was cross-sectionally related with cerebrovascular injury. Conclusions: Our findings suggest that high daily fluid intake is associated with decreased brain amyloid deposition, indicating that sufficient daily fluid intake may be helpful for prevention of AD.
Yasmine Salman#, Lara Huyghe#, Lisa Quenon, Olivia Ghysens, Vincent Malotaux, Sandra O Tomé, Dietmar Rudolf Thal, Bernard J Hanseeuw #These authors contributed equally to this work.
Autopsy-proven patient with corticobasal degeneration presenting with visuo-constructive disorders as initial symptoms: How advanced MRI sequences can help clinical practice
Abstract: Background: Cortico-basal degeneration (CBD) is a neurodegenerative disease typically responsible for cortico-basal syndrome (CBS) or progressive limb apraxia. Half of CBD patients, however, present atypical symptoms, making the diagnosis difficult. Objective: We reported the case of a woman in her late sixties (BM208), an unusual case of autopsy-proven CBD, showing early signs of Benson’s syndrome or posterior cortical atrophy. In addition, we compared cognitive performance and atrophy in different brain regions of BM208 with other neurodegenerative diseases patients to highlight clinical signs that could have guided the diagnosis earlier. Methods: We retrospectively compared BM208 to patients with typical amnestic Alzheimer’s disease (AD) (n=18, Mini-Mental State Exam (MMSE) scores between 18 and 24), Benson’s syndrome due to AD (n=3), CBS/progressive supranuclear palsy (PSP) syndrome (n=5), and Lewy body dementia (LBD) patients (n=3) and a control group (n=24). All these participants underwent an MMSE, a complete neuropsychological examination and 3DT1 MRI. Results: Although BM208 was more severely cognitively impaired overall, her cognitive performance was more similar to Benson’s syndrome patients’ cognitive profile compared to CBS patients or any other degenerative pathology (typical AD/LBD). Consistently, although BM208 was more atrophic than all other groups, she showed cortical atrophy that matched a Benson’s syndrome pattern more than typical AD or CBS. However, the analysis of subcortical atrophy revealed atrophy of the basal ganglia corresponding CBS cases. Furthermore, visual analyses on sagittal T1 images showed atrophy of the midbrain, characteristic of CBS/PSP syndrome. Conclusions: These results highlight the additive value of fine-grained MRI subcortical quantification to diagnose non-AD rare neurodegenerative disorders.
Kelechi Ndukwe, Peter A Serrano, Patricia Rockwell, Lei Xie, Maria E Figueiredo-Pereira
Brain-penetrant histone deacetylase inhibitor RG2833 improves spatial memory in females of an Alzheimer’s disease rat model
Abstract: Background: Nearly two-thirds of Alzheimer’s disease (AD) patients are women. Therapeutics for women are critical to lowering their elevated risk of developing this major cause of adult dementia. Moreover, targeting epigenetic processes such as histone acetylation that regulate multiple cellular pathways is advantageous given the multifactorial nature of AD. Histone acetylation takes part in memory consolidation, and its disruption is linked to AD. Objective: Determine whether the investigational drug RG2833 has repurposing potential for AD. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier. Methods: RG2833 effects were determined on cognition, transcriptome, and AD-like pathology in 11-month TgF344-AD female and male rats. Treatment started early in the course of pathology when therapeutic intervention is predicted to be most effective. Results: RG2833-treatment of 11-month TgF344-AD rats: (1) Significantly improved hippocampal-dependent spatial memory in females but not males. (2) Upregulated expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation in females. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at p < 0.05, false discovery rate < 0.05, and fold-change equal or > 1.5. (3) Failed to improve amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. Conclusions: Our study highlights the potential of histone-modifying therapeutics such as RG2833 to improve cognitive behavior and drive the expression of immediate early, synaptic plasticity and memory consolidation genes, especially in female AD patients.
Ningning Pan, Shujuan Liu, Xinting Ge, Yuanjie Zheng, for Alzheimer’s Disease Neuroimaging Initiative
Association of hippocampal atrophy with tau pathology of temporal regions in preclinical Alzheimer’s disease
Abstract: Background: Hippocampal atrophy is linked to memory and cognitive deficits, preceding clinical diagnosis of mild cognitive impairment (MCI) by decades. Morphometry changes in the hippocampal formation (HF) and their relationship to tau deposition in non-demented individuals remains unclear. Objective: To investigate morphometry changes in the HF and their association with tau deposition in a non-demented cohort. Methods: Eighty-three subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent T1-weighted MRI and Tau-PET scans at baseline and longitudinal follow-up. Participants were divided into amyloid-negative (Aβ-) and amyloid-positive (Aβ+) groups. Hippocampal volume/thickness were measured, and associations with tau deposition in temporal regions were examined using multivariable linear regression. Results: No significant association was found between the hippocampal volume/thickness and tau deposition of temporal regions for the Aβ- group. For the Aβ+ group, the hippocampal thickness was significantly associated with tau deposition of entorhinal cortex (ERC) for both hemispheres, and temporal pole, inferior temporal, and middle temporal regions for right hippocampi with the longitudinal follow up scans, while no significant association with the baseline scans. It was interesting that there was strong association between the baseline tau deposition of ERC and temporal pole and the longitudinal follow up thickness of left hippocampi, while the associated regions for the right hemisphere were ERC, temporal pole, and inferior temporal regions. Conclusions: Hippocampal atrophy may precede cognitive symptoms, with tau deposition in adjacent temporal regions contributing to hippocampal changes. The right HF appears more vulnerable than the left, indicating hemispheric differences in pathology.
Qian Yang#, Hao Yang#, Wei Long, Sheng Zuo, Defa Zhu, Qihao Guo #These authors contributed equally to this work.
Rapid cognitive assessment: Accuracy and discriminant validity of Mini-Cog and process-based Clock Drawing Test
Abstract: Background: The Mini-Cog is a brief cognitive examination comprising a three-item memory recall and a simplified Clock Drawing Test (CDT). There is limited research on the effects of detailed scoring criteria for the Mini-Cog on cognitive screening. Objective: To assess the diagnostic effectiveness of three Mini-Cog versions and a new process-based CDT test in identifying mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to cognitively normal controls (NC). Methods: We prospectively enrolled 950 subjects who underwent standardized neuropsychological assessments and the Mini-Cog test. The CDT was scored using an adapted 10-point scale. The accuracy of three Mini-Cog versions (Mini-Cog1: 3-word delayed recall + 2-point CDT; Mini-Cog2: 3-word immediate recall + 3-word delayed recall + 3-point CDT; Mini-Cog3: 3-word immediate recall + 3-word delayed recall + 10-point CDT) was assessed through the receiver operating characteristic analysis. Sensitivity and specificity were determined for each diagnostic threshold. Results: The optimal cut-off point for Mini-Cog3 is 12/16 for MCI and 10/16 for AD. Mini-Cog3 demonstrated the highest diagnostic efficacy, with AUCs of 0.82 (95% CI: 0.78-0.85) for MCI and 0.95 (95% CI: 0.94-0.97) for AD, with sensitivity of 85% for both MCI and AD. The CDT's AUCs were 0.77 (95% CI: 0.73-0.81) for MCI, and 0.87 (95% CI: 0.84-0.90) for AD, with sensitivity of 89% for MCI, and 82% for AD. Conclusions: A more elaborate scoring system, such as Mini-Cog3, may serve as an effective screening method for the rapid and accurate detection of cognitive dysfunction in patients with MCI and AD.
Xin-Xin Fu#, Bin Wei#, Zhi-Hang Huang#, Rui Duan, Yang Deng, Yan E, Shi-Yao Wang, Shuai-Yu Chen, Ying-Dong Zhang, Teng Jiang #These authors contributed equally to this work.
Modulation of mitochondrial functions contributes to the protection of lamotrigine against Alzheimer’s disease
Abstract: Background: Our previous studies have established that the broad-spectrum anti-epileptic drug lamotrigine (LTG) confers protection against cognitive impairments, synapse and nerve cell damage, as well as characteristic neuropathologies in APP/PS1 mice, a mouse model of Alzheimer's disease (AD). However, the precise molecular mechanisms responsible for this protective effect induced by LTG remain largely elusive. Objective: In this study, we aimed to investigate the mechanisms underlying the beneficial effects of LTG against AD. Methods: Five-month-old APP/PS1 mice were treated with 30 mg/kg of LTG daily for three consecutive months. Subsequently, high-throughput ribosome profiling sequencing was conducted to identify differentially translated genes (DTGs) rescued by LTG in the brains of these mice. To gain further insights into the potential functions and pathways of these LTG-rescued DTGs, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. RNA expression, protein levels, and translational efficiency were assessed to explore how LTG regulated gene expression processes in AD-related DTGs. Additionally, Aβ42 peptide-stimulated primary neurons were used to uncover the potential mechanisms and signaling pathway by which LTG mitigated oxidative stress under AD context. Results: For the first time, we reveal that LTG inactivates mitochondrial complexes in the brains of APP/PS1 mice by suppressing the translational efficiency of mitochondrial complexes-related genes. More importantly, we demonstrate that LTG mitigates mitochondrial-mediated oxidative stress in neurons within the context of AD by activation of SIRT6/PGC-1α pathway. Conclusions: These findings provide further insights into the mechanisms underlying the protective effects of LTG against AD.
Wupadrasta Santosh Kumar, Sayali Rajendra Bhutare, Neelam Sinha, Thomas Gregor Issac for the Alzheimer's Disease Neuroimaging Initiative
Bayesian network modeling of statistical dependency within cognitive domains and clinical dementia severity ratings for Western and Indian cohorts
Abstract: Background: Dementia is studied rigorously in the current times, to assess the potential factors that contribute towards its progression, such as demographic factors, geographical background as well as to understand its impact on essential life skills. Alzheimer’s disease, the most common form of dementia, is a major focus due to its prevalence and lack of curative treatments. Objective: We aim to study dementia progression across two geographically distinct populations, by analyzing Clinical Dementia Rating (CDR) scores and its domain-specific components, which reflect the decline in essential life skills. This analysis may support clinicians in designing targeted interventions. Methods: This study investigates the statistical dependencies between the CDR and its six defining domain scores across two distinct aging datasets: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Longitudinal Aging Study of India (LASI). We analyzed the dependencies among domain scores and their influence on the global CDR in both datasets using data-driven directed acyclic graphs, within Bayesian network models. Results: Distinct notable similarities and differences in the associations and the edge strengths between the Western and Indian populations were identified. Memory showed similar prominence in contributing towards global CDR, while the incoming edges on memory domain reduced in LASI over ADNI, specifically from the domains, Home and hobbies, and Community affairs. Conclusions: The analysis highlights a stronger dependency of CDR scores on memory functions in both datasets. The results overall elucidate population-specific differences and similarities in dementia progression across diverse demographic contexts.
Sun Ah Park, Young-Sil An, Yong-Jin Park, Ji-Yeong Lee, Hyuna Jeon, Yoon Seob Kim, Keun Lee, Kyunghwa Sun, Sun Min Lee, So Young Moon (Handling Associate Editor: Inga Zerr)
Comparative analysis of Elecsys and ELISA for differentiating amyloid-PET status in a Korean memory clinic based on cerebrospinal fluid biomarkers
Abstract: Background: The adoption of Alzheimer’s disease (AD) biomarkers in clinical practice is expected to increase following recent approval of disease-modifying therapies. Fully automated immunoassays, Elecsys platform, offer convenience and enhanced reliability. Objective: This study was performed to evaluate the performance of the Elecsys assay in a Korean clinical setting, comparing its effectiveness to ELISA for detecting amyloid-PET positivity. Methods: Cerebrospinal fluid (CSF) Aβ42, pTau181, tTau, pTau181/Aβ42, and tTau/Aβ42 were evaluated using Elecsys kits on a Cobas e 411 analyzer and manual Innotest ELISA with paired frozen samples (n = 118) from subjects with cognitive status ranging from unimpaired to mild cognitive impairment and dementia. Results: Strong linear correlations were observed between Elecsys- and ELISA-measured Aβ42, pTau181, and tTau levels. Receiver operating characteristic-based cutoff points for pTau181/Aβ42 (0.0252) and tTau/Aβ42 (0.258) in Elecsys demonstrated the highest areas under the curve (0.97 and 0.96) and predictive values (96.6% for both) for detecting amyloid-PET abnormalities. No cases of abnormal amyloid PET status were found without concurrent abnormal CSF biomarkers when considering Elecsys Aβ42 and the pTau181/Aβ42 ratio simultaneously. In addition, previously established cutoffs for combined ratios effectively differentiated amyloid PET status in our samples. Conclusions: This study demonstrated the utility of Elecsys-measured CSF AD biomarkers in agreement with amyloid-PET classification in the Korean population. The pTau181/Aβ42 and tTau/Aβ42 ratios were the most accurate in detecting amyloid-PET (+), with Elecsys showing higher accuracy than ELISA. The study also supported the applicability of common cutoffs from Western countries for these biomarkers in our samples.
Felix G Wittmann, Alexander Pabst, Andrea Zülke, Melanie Luppa, Maria I Cardona, Melanie Boekholt, Thomas Fankhänel, Solveig Weise, Robert Philipp Kosilek, Linda Sanftenberg, Christian Brettschneider, Juliane Döhring, Martin Williamson, Birgitt Wiese, Jochen René Thyrian, Wolfgang Hoffmann, Jochen Gensichen, Hans-Helmut König, Hanna Kaduszkiewicz, Thomas Frese, Steffi G Riedel-Heller
Adherence to intervention components: The key to success? Analysis on health-related outcomes of the AgeWell.de intervention to preserve cognition
Abstract: Background: The aim of the study was to analyze the impact of adherence to the intervention components on the effectiveness of AgeWell.de, a multi-domain lifestyle intervention against cognitive decline, on function in everyday activities, quality of life, depressiveness and social isolation. Objective: Studying the effect of adherence on health-related outcomes. Methods: Participants were aged 60-77 years at baseline and at risk (Cardiovascular Risk Factors, Ageing and Dementia Score (CAIDE) ≥9). Adherence to the components nutrition, enhancement of physical and social activities and cognitive training was analyzed in two ways, first continual within the intervention group (n=378, mean age=69.1 years, 52.7% female) and second as dichotomous split (75% adherence) and in reference to the control group (received infomaterial and regular health advice; n=441, mean age=69 years, 53% female). Generalized linear regression models were then run on the health outcomes functioning in everyday activities, quality of life, depressive symptoms, and social inclusion. Results: Health-related quality of life and depressiveness were improved in participants with better adherence to nutritional counselling and enhancement of physical and social activities. Better adherence to social activities was relevant for function in everyday activities. Effects of high adherence to cognitive training was found for improvements in depressiveness when comparing it to the control group. No effect was found on social inclusion when considering the particular components. Conclusions: The extent of adherence to most components influenced health-related outcomes such as health-related quality of life and depressiveness. With this study, the effectiveness of AgeWell.de can be understood in greater depth.
Qing Tian#, Qing Dong#, Zhumin Su, Yingying Liu, Lili Ma, Huimin Dong, Yiru Xu, Zhan Ma, Xiaohong Chen, Xiaomeng Ma #These authors contributed equally to this work.
Association of body weight and serum uric acid with Alzheimer’s disease biomarkers and cognitive impairment
Abstract: Background: Given the limited effective treatments for Alzheimer’s disease (AD), obesity and serum uric acid (SUA) levels which are considered modifiable risk factors for dementia are of interest. However, research indicates conflicting results. Objective: We aimed to further investigate the association of body weight (BW) and SUA with AD biomarkers and cognitive impairment. Methods: Clinical data were collected from 139 adults (mean age 66.9 years) with chronic cognitive impairment. Cerebrospinal fluid (CSF) biomarkers and PET imaging were used to assess amyloid-β (A) and Tau (T) tangles load, classifying participants into AT profiles based on the results. The association of BW and SUA with AT profiles was evaluated using multivariable logistic regression, and their relationship with cognitive function (Mini-Mental State Examination (MMSE) scores) were analyzed using multivariable linear regression. Results: Lower BW levels significantly influenced the presence of Aβ positive state (A+) (p=0.007), while SUA levels did not (p=0.263). Higher dementia proportion (p=0.021), lighter BW (p=0.019), and lower mean arterial pressure (MAP) levels (p=0.025) were associated with AD pathological progress (A-T-→A+T-→A+T+), but SUA was not observed statistically significant. Among all participants regardless of Aβ state, high education levels (p<0.001), high BW (p=0.010), and high SUA (p=0.036) were associated with high MMSE scores, and high serum creatinine (p=0.003) was associated with low MMSE scores. Conclusions: Lower BW may accelerate AD pathology and cause cognitive impairment, while SUA is not linked to AD pathological progression but protects cognitive function.
Yujiro Kuroda, Kosuke Fujita, Taiki Sugimoto, Kazuaki Uchida, Yoko Yokoyama, Taichi Shimazu, Junko Saito, Hidenori Arai, Takashi Sakurai
Evaluating the feasibility of a community-adapted multi-domain intervention for dementia prevention in older adults
Abstract: Background: Dementia impacts individuals, families, and society, necessitating effective prevention strategies. Objective: To evaluate the feasibility of a community-adapted multi-domain intervention for dementia prevention among older adults in Obu City, Japan and how uncertainties in implementing definitive trials can be reduced. Methods: A 12-month one-arm intervention trial was conducted with 60 community-dwelling older adults aged 65–86 years from two district regions. The multi-domain intervention included physical exercise, nutrition guidance, cognitive training, social participation, and vascular risk management. The primary outcome was the continuation rate, defined as the proportion of participants attending >60% of classes from the initial assessment to 6 months. Secondary outcomes, such as fidelity, acceptability, and appropriateness, were assessed through qualitative and quantitative evaluations. Additionally, health outcomes, including cognitive function and overall lifestyle, were evaluated. Results: The study achieved continuation rates of 75% and 76% at 6 and 12 months, respectively, indicating high feasibility. Participants showed high program acceptability (average acceptance score, 4.4 of 5). Fidelity was high regarding content coverage and duration, although the frequency and coverage varied between study sites. Cognitive function remained stable; food-diversity status improved significantly over the study period, though the absence of a control group limits causal interpretation of these changes. Conclusions: The community-adapted multi-domain intervention for dementia prevention demonstrated high feasibility and acceptability among older adults. Our findings can help reduce uncertainties and support planning future definitive trials to evaluate the effectiveness of community-based dementia-prevention programs.
Alessandra Giannella Samelli, Natalia Gomes Gonçalves, Fernanda Yasmin Odila Maestri Miguel Padilha, Vitor Martins Guesser, Carla Gentile Matas, Camila Maia Rabelo, Renata Rodrigues Moreira, Itamar S Santos, Paulo Andrade Lotufo, Isabela J Bensenõr, Paola Gilsanz, Claudia Kimie Suemoto
Hearing loss and cognitive decline in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) during eight years of follow-up
Abstract: Background: Hearing loss (HL) of moderate or higher grades is common in older adults with increasing prevalence as people age, rising from 12% at the age of 60 years to over 58% at 90 years. HL in midlife is one of the main potentially modifiable risk factors for dementia. It is estimated that 7% of dementia cases globally could be avoided if this risk factor was eliminated. However, much of the research conducted has been in high-income countries even though low- and middle-income countries have the highest prevalence of dementia. Objective: To study the association between HL and cognitive decline during eight years of follow-up in a Brazilian sample. Methods: Participants from the São Paulo center of the Brazilian Longitudinal Study of Adult Health were evaluated in three study waves (2008-10, 2012-14, and 2017-19). HL was defined as pure-tone audiometry above 25 dB in the better ear. Cognitive performance was evaluated with six tests related to memory, verbal fluency, and trail-making tests. A global cognitive z-score was derived from these tests. The association between HL and cognitive decline was evaluated with linear mixed-effects models adjusted for sociodemographic, lifestyle, and clinical factors. Results: Of 805 participants (mean age 51±9 years, 52% women, 60% White), 62 had HL. During follow-up, HL was associated with faster global cognitive decline (β=-0.012, 95% CI=-0.023; 0.000, p=0.039). Conclusions: HL was significantly associated with a faster rate of global cognitive decline after a median follow-up of eight years in a sample of middle-income country.
