Review
Takahiro Morito, Naoto Watamura, Hiroki Sasaguri, Taisuke Tomita, Makoto Higuchi, Hideyuki Okano, Erika Sasaki, Takaomi C Saido
Experimental basis for generating nonhuman primate models of frontotemporal dementia and Alzheimer's disease
Abstract: To our knowledge, no reports have described nonhuman primate (NHP) models of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) that do not depend on an overexpression paradigm. Based on our recent success in generating single human MAPT knock-in mouse models of FTDP-17, we describe the experimental basis for generating knock-in marmoset models of FTDP-17. In addition, successful generation of mutant PSEN1 knock-in marmoset models lacking exon 9 (PSEN1-Δ9) of Alzheimer's disease (AD) indicates that we will be able to reconstitute two major pathological features of AD, i.e., amyloid plaques and neurofibrillary tangles, in an accelerated manner by combining these models.
Review
Larissa Alves Barros, Debora Hashigushi, Cássio Morais Loss, Henriette van Praag, Beatriz Monteiro Longo
Vascular dysfunction in Alzheimer's disease: exploring the potential of aerobic and resistance exercises as therapeutic strategies
Abstract: Alzheimer's disease (AD) is the leading cause of morbidity and mortality worldwide, as a result of cognitive decline and neurological dysfunction. In AD, reduced cerebral blood flow and impaired vascularization result from capillary bed degeneration and decreased angiogenesis, as observed in both patients and animal models. Physical exercise is recognized as a potential intervention to delay AD progression and reduce disease risk. While most studies have focused on the benefits of aerobic exercise (AE), emerging evidence suggests that resistance exercise (RE) also exerts positive effects on overall health condition and cognitive function in aging and AD. However, a notable gap in knowledge remains regarding the effects of RE on cerebral blood flow and vascular structure. This review explores the processes by which AE and RE influence brain vascularization in aging and AD, including blood flow, endothelial function, angiogenesis and neurotrophic factor levels. Based on pre-clinical and clinical studies, we conclude that both AE and RE contribute to improved cerebral blood flow and vascular function, promoting vascular repair in the aging and AD-affected brain. By examining the relationship between exercise modalities and brain vascularization, this review expands knowledge regarding the processes underlying the neuroprotective effects of exercise in neurodegenerative and aging conditions.
Systematic Review
Mingyuan Jia, Fengting Hu, Yuxuan Hui, Jin Peng, Weiran Wang, Jia Zhang
Effects of exercise on older adults with mild cognitive impairment: A systematic review and network meta-analysis
Abstract: Background: Mild cognitive impairment (MCI) represents a transitional stage between normal aging and Alzheimer's disease (AD), with a significantly elevated risk of progressing to AD. In recent years, accumulating evidence has indicated that exercise interventions may mitigate cognitive decline in individuals with MCI and reduce the risk of conversion to AD, potentially through mechanisms such as enhancing cerebral blood flow and promoting neuroplasticity. Objective: To explore which type of exercise is most effective in improving global cognition in older adults with MCI and to investigate whether exercise can enhance their balance abilities. Methods: Randomized controlled trials were retrieved from four databases. Stata software was used for NMA and traditional meta-analysis. Results: A total of 33 studies were included, of which 28 were used to determine the best exercise modality. The results indicated that multicomponent exercise (SUCRA=76.5%) and moderate-intensity aerobic exercise (SUCRA=73.6%) are two effective modalities. The results of the traditional meta-analysis showed that exercise combined with cognitive training, moderate-intensity aerobic exercise, resistance exercise, and land-based kayaking training can improve balance ability. Conclusions: Multicomponent exercise may be the optimal exercise modality for enhancing global cognition in older adults with MCI, and various exercise modalities can improve balance abilities. However, more studies with larger sample sizes and higher quality are needed to provide further evidence.
Short Communication
Yuichiro Furuya#, Kenichiro Sato#, Yoshiki Niimi, Ryoko Ihara, Kazushi Suzuki, Atsushi Iwata, Takeshi Iwatsubo #These authors contributed equally to this work.
Cognitive Function Instrument-based anosognosia to predict amyloid status
Abstract: Anosognosia, a lack of self-awareness regarding cognitive dysfunction, often accompanies the progression of Alzheimer’s disease (AD) pathology. This study explored the relationship between AD pathology and anosognosia measured by discrepancies in Cognitive Function Instrument (CFI) scores, as rated by participants and their study partners (SP). Using mixed-effects models on non-demented participant data, the results revealed that lower self-reported CFI score compared to SP ratings was significantly associated with positive amyloid PET results (odds ratio 1.081 per-1 decrease in ΔCFI). Our findings suggest that CFI-based anosognosia could serve as a potential predictor of positive amyloid PET status.
Commentary
Michelle Shardell, Chixiang Chen
Genetic geroscience and Alzheimer’s disease: The pleiotropy is the point!
Abstract: Geroscience aims to understand how the biology of aging serves as a shared contributor to multiple age-related health conditions. Genetic variants that influence multiple traits are said to exert pleiotropic effects. The study by Pan and colleagues applied a modern statistical model to identify genetic variants with potentially pleiotropic effects by assessing their joint association with Alzheimer’s disease and related dementias and another age-related comorbidity (e.g., coronary heart disease, hyperlipidemia, cancer). Motivated by Pan and colleagues, this commentary introduces the concept of genetic geroscience as a paradigm for identifying genetic variants with potentially pleotropic effects on multiple age-related health conditions.
Meghan E Pierce, Mark Logue, Richard Sherva, Mark Miller, Bertrand R Huber, William Milberg, Jasmeet P Hayes
Association of Alzheimer’s disease genetic risk with age-dependent changes in plasma amyloid-β42:40 in veterans
Abstract: Background: Identifying biomarkers of Alzheimer’s disease (AD) is critical for early diagnosis and AD risk assessment. Objective: We examined the hypothesis that the plasma amyloid-β 42 and 40 (Aβ42:40) ratio has a curvilinear relationship with age among individuals who are at higher genetic risk for AD. Methods: This study investigated the relationship between plasma amyloid-β 42 and 40 (Aβ42:40) ratio and age in 315 men and women Veterans, including those at genetic risk for AD. Hierarchical regression models investigated linear and nonlinear relationships between age, genetic risk, and Aβ42:40. Results: We observed a curvilinear relationship between age and Aβ42:40 in individuals with higher genetic risk, characterized by an increase in the Aβ42:40 during midlife followed by a decrease in older age. Conclusions: These findings highlight distinct patterns in Aβ metabolism among genetically predisposed individuals, suggesting that early metabolic shifts may play a role in the progression of AD. Understanding these nuanced changes is essential for refining the use of Aβ42:40 ratio as a biomarker, potentially leading to more accurate risk stratification and earlier intervention strategies in AD.
Shuai Xu, Yingao Fan, Chenglu Mao, Zheqi Hu, Zhiyuan Yang, Longjie Qu, Yun Xu, Linjie Yu, Xiaolei Zhu, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Sha Liu)
Multimodal magnetic resonance imaging analysis of early mild cognitive impairment
Abstract: Background: Early mild cognitive impairment (EMCI) represents a prodromal stage of dementia, and early detection is crucial for delaying dementia progression. However, accurately identifying its neuroimaging features remains challenging. Objective: To comprehensively evaluate structural and functional neuroimaging changes in EMCI using multimodal magnetic resonance imaging (MRI) techniques. Methods: One hundred and eleven participants were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 36 with cognitively normal (CN), 30 with EMCI, 32 with late mild cognitive impairment (LMCI), and 13 with Alzheimer’s disease (AD). FreeSurfer software was employed to segment hippocampal and amygdala subregions. The amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and functional connectivity were processed using Data Processing & Analysis for Brain Imaging toolbox. Graph Theoretical Network Analysis toolbox was utilized to evaluate global functional network. Results: The volume of most hippocampal and amygdala subregions was decreased in AD group than those of EMCI group in structural MRI. Significant differences were found between EMCI and AD group in fALFF (right insula) and ReHo (bilateral caudate regions). EMCI group exhibited stronger functional connectivity between left hippocampus and right inferior temporal gyrus (compared to CN), left inferior temporal gyrus (compared to LMCI), and cerebellum crus 8 (compared to AD). EMCI group exhibited stronger connectivity between right hippocampus and left anterior cingulate gyrus compared to AD. Network metrics showed no significant differences among these groups, but all exhibited small-world properties. Conclusions: Multimodal MRI analysis revealed the neuroimaging characteristics of EMCI and promoted the understanding of the mechanisms underlying neuroimaging changes in EMCI.
Lilcelia A Williams, Lauren Terhorst, Ishan C Williams, Elizabeth Skidmore, Jennifer H Lingler
Perceived risk of Alzheimer’s disease: Insights into the Black and African American male perspective
Abstract: Background: Non-Hispanic Black and African American men are more likely to have Alzheimer’s disease (AD) than non-Hispanic White peers. Despite this, little is known about how Black and African American men perceive dementia risk, which is foundational to prevention. Objective: Acknowledging that personal vantage point influences behavior, our study examined Black and African American male perceptions about their anticipated risk for AD. Methods: We conducted a secondary analysis of Black and African American adult male responses to the Recruitment Innovations for Diversity Enhancement electronic survey study. We examined associations between perceived risk of AD and age, education, employment status, household income adequacy, marital status, living status, prior experience with AD, and subjective memory performance using generalized linear models. Results: Respondents (n=112) were age 21 to 79 years (M=51.05, SD=13.44), and 35% reported prior experience with AD through a friend or family member. Respondents’ perceived risk of developing AD ranged from 0 to 100% (M=33.46, SD=28.29). Spearman rho correlations revealed modest but significant correlations between perceived risk and age (r=21, p=0.03) and marital status (r=-0.22 p=0.02). The best fitting generalized linear model revealed low perceived risk for AD was associated with younger age, income adequacy and being married or living as married (χ2=8.76, p=0.03). Conclusion: Selected social determinants of health were associated with perceived risk. Future studies should examine additional social determinants of health (e.g., social and physical environment) and measures of cognitive and physical health to further explore relationships with perceived risk of AD in Black and African American males.
Chunhua Zhang#, Yaojun Tai#, Min Kong, Pengyuan Jia, Guozhao Ma, Maowen Ba; for Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Liyong Wu) #These authors contributed equally to this work.
Synergistic associations of amyloid-β and phosphorylated tau with tau aggregation and cognitive decline in Alzheimer’s disease
Abstract: Background: The pathological hallmarks of Alzheimer's disease (AD) include the amyloid-β (Aβ) plaques and phosphorylated tau (p-tau) forming neurofibrillary tangles. Understanding the pathophysiological cascade related to Aβ and tau process is crucial. Objective: To investigate the impact of Aβ positron emission tomography (PET) and cerebrospinal fluid (CSF) p-tau on tau pathology and cognitive decline in AD. Methods: We analyzed 319 older individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent Aβ (18F-florbetapir or 18F-florbetaben) and tau (18F-flortaucipir) PET scans, along with CSF and cognitive assessments. Aβ positivity (A+) was determined by global standardized uptake value ratio thresholds of ≥1.11 for 18F-florbetapir or ≥1.08 for 18F-florbetaben, while p-tau positivity (T+) was defined as CSF p-tau181 levels ≥23 pg/ml. Linear mixed regression models were used to assess the effects of PET Aβ and CSF p-tau181 levels on tau accumulation in predefined Braak regions and cognitive function over time. Results: Our results revealed significant differences in PET tau pathology and cognitive decline between A+ and A− individuals. We observed that interactions between Aβ and p-tau proteins were associated with tau accumulation and cognitive decline. Additionally, A−/T+ individuals exhibited higher levels of tau accumulation in all Braak regions compared to A−/T− counterparts, suggesting a potential independent role of p-tau in tau pathology in the absence of Aβ. Conclusions: Our findings suggest that Aβ positivity and elevated CSF p-tau181 levels were associated with tau accumulation and cognitive decline, highlighting the relevance of soluble p-tau as a potential biomarker for further investigation.
Fanghong Dong, Alison R Anderson, Nancy A Hodgson
Associations among diurnal cortisol, melatonin, and agitation in people living with cognitive impairment
Abstract: Background: While the underlying mechanisms of agitation are not fully understood in people with Alzheimer's disease and related disorders, research suggests that dysregulated neuroendocrine processes, including the hypothalamic-pituitary-adrenal axis, may play a role. Objective: This study aimed to explore the associations between salivary cortisol, melatonin at baseline, and agitation both at baseline and at post-intervention. Methods: This study was a secondary analysis of a two-group, randomized, parallel designed clinical trial of 210 people living with cognitive impairment. Agitation, salivary cortisol, and salivary melatonin were measured at baseline and four weeks. Salivary cortisol and melatonin indicators were generated through three timepoints of cortisol and melatonin collection across the two consecutive days. Presence of agitation was measured using the Neuropsychiatric Inventory. Logistic regressions were conducted to achieve the aim. Results: A significant association was found at baseline between diurnal cortisol slope and agitation (OR = 0.03, p = 0.029), there were no relationships between all other cortisol or melatonin indicators with agitation. Cortisol awaking response (OR = 0.16, p = 0.048), its percentage (OR = 0.27, p = 0.021) and its increase higher than 50% (OR = 0.09, p = 0.009), were significant with agitation at four weeks. Conclusions: Given the potential link between cortisol and agitation, exploring cortisol-lowering interventions like minimizing environmental stressors, smoothing transitions to different situations, stress-reduction techniques, and behavioral therapies may aid in managing agitation in older adults with cognitive impairment.
Tatiana Teresa Belfort Almeida dos Santos, Marcela Lima Nogueira, Julia Gaigher, Rogeria Rangel, Natalie de Souza, Marcia Cristina Nascimento Dourado
Comparing patterns of impairment in social cognition between young-onset and late-onset Alzheimer’s disease
Abstract: Background: Young-onset Alzheimer's disease (YOAD) is defined as when the disease starts before 65 years old. Compared with late-onset AD (LOAD), the progression is faster and more aggressive. However, the impact on social cognition deficits may not follow the same clear pattern. Objective: The present study aims to investigate the relationship between social cognition, global cognition, and other clinical variables in people with YOAD and LOAD and their caregivers. Methods: Using a cross-sectional design, we included 48 people with YOAD and 118 with LOAD, and their caregivers. We assessed social cognition, global cognition, quality of life, dementia severity, mood, functionality, neuropsychiatric symptoms, and caregiver burden. Results: The YOAD group was more impaired in general cognition (p=0.002, d=0.06), had a worse quality of life (p=0.036, d=0.36), and presented more neuropsychiatric symptoms (p=0.044, d=0.35). However, social cognition did not exhibit the same disease progression and showed no difference when compared with the reports of their caregivers or with individuals with LOAD. The multifactorial regression analyses showed that functionality was related to social cognition impairment in YOAD (p=0.035), and LOAD (p=0.001). Conclusions: Our study found that people diagnosed with YOAD showed more global cognitive impairment but maintained social and emotional functioning.
Jesus D Melgarejo, Dhrumil Patil, Sokratis Charisis, Kristina P Vatcheva, Silvia Mejia-Arango, Luis J Mena, Claudia L Satizabal, Ciro Gaona, Egle Silva, Eron Manusov, Joseph H Lee, Joseph D Terwilliger, Jose Gutierrez, Sudha Seshadri, Gladys E Maestre
Baseline associations of office and ambulatory blood pressure monitoring with cognitive function and dementia prevalence
Abstract: Background: High blood pressure has been associated with dementia prevalence and incident. However, it is unclear the relationship of office and ambulatory BP monitoring with cognitive function and dementia and in particular, it remains unknown whether ambulatory BP variability relates to dementia. Objective: To investigate the associations of office and 24-hour blood pressure (BP) with cognitive function and dementia prevalence. Methods: Cross-sectional population-based study of 1435 participants aged ≥40 years with office BP/24-hour BP, and cognitive assessments (Mini-Mental State Examination [MMSE] and Selective Reminding Test [SRT]). Dementia was diagnosed with a clinical dementia rating ≥1.0. Statistics included logistic and linear regression models. Results: The mean age was 63.8±10.3 years old and 995 (69.3%) were women. Out of the 1435 participants, 46 (3.20%) had dementia at baseline. Office and 24-hour BP levels were not associated with dementia but with one SRT. Increasing 24-hour systolic BP variability was associated with lower MMSE (adjusted mean, -0.08; 95% confidence interval [CI], -0.13, -0.03), and SRT (adjusted means ranged from -0.13 to -0.06; 95% CI ranging from -0.19 to -0.01) scores and 1.48-fold greater odds of dementia (95% CI, 1.09-2.02) regardless of BP level. Conclusions: Elevated 24-hour BP variability, not the BP level, seems to have a stronger association with lower cognitive function and dementia prevalence. Prospective studies are needed to address whether 24-hour BP variability relates to cognitive decline and dementia incidence.
Yujie Yang, Yinhu Li, Yu Chen
Changes in transcriptional regulation in the temporal lobe in patients with Alzheimer’s disease
Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder with intricate pathophysiological mechanisms. Transcriptome analysis has been used to investigate the pathogenesis of AD from the perspectives of mRNA expression, alternative splicing, and alternative polyadenylation. However, these 3 transcriptomic regulatory layers have not been comprehensively explored, limiting our understanding of the transcriptomic landscapes of AD pathogenesis. Objective: We aimed to describe the transcriptomic landscapes of AD pathogenesis, detect the contributions of different regulatory layers to the total transcriptional variance, and identify diagnostic candidates for AD prediction. Methods: We collected RNA sequencing data derived from the temporal lobes of 257 patients with AD and 97 controls, performed joint transcriptional analysis with multi-omics factor analysis (MOFA2) and weighted gene co-expression network analysis (WGCNA), and evaluated the signals with regression models. Results: We found that increasing Braak stage is associated with progressive downregulation of SYT1, CHN1, SNAP25, VSNL1, and ENC1 as well as upregulation of TNS1, SGK1, CPM, PPFIBP, and CLMN. Subsequent MOFA2 revealed that alternative splicing contributes most (R2 = 0.558) to the transcriptional variance between patients with AD and controls followed by alternative polyadenylation (R2 = 0.449) and mRNA expression (R2 = 0.438). In addition, the regression model constructed with SNAP25, VSNL1, and ENC1 expression could distinguish between patients with AD and controls (AUC = 0.752). Conclusions: We systematically detailed the transcriptional landscapes in patients with AD and report mRNA signals associated with AD, offering novel insights into AD pathogenesis and therapeutic development.
Xinru Xu#, Xian Mo#, Wen Zhang, Dongming Liu, Qian Chen, Jiaming Lu, Yajing Zhu, Jiu Chen, Xin Zhang, Zhengyang Zhu, Yingxin Chen, Qingxue Shi, Yingxin Dai, Miao Liu, Yanan Tong, Jinghua Zhang, Guoxu Zhang, ZhiguoWang, Bing Zhang #These authors contributed equally to this work.
Local and distant atrophy mediate the relationship between tau pathology and cognition in temporoparietal region in Alzheimer’s disease
Abstract: Background: Tau pathology is closely associated with brain atrophy and cognitive decline, but how it specifically influences local and distant gray matter volume (GMV) and cognitive function remains unclear. Objective: This study aims to explore the spatial relationships between tau pathology, GMV and cognition using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Methods: Twenty amyloid-β (Aβ)-positive Alzheimer’s disease (AD) patients, 14 mild cognitive impairment (MCI) patients, and 22 Aβ-negative normal controls (NC) underwent standardized neuropsychological assessments and 18F-fortaucipir PET/MRI scans. We investigated the associations between regional tau standardized uptake value ratio (SUVR) and GMV in AD signature regions. Mediation analyses were conducted to explore the potential mediating effects of local and distant GMV in the relationship between tau pathology and cognition. Results: The study indicated that increased 18F-fortaucipir SUVR and decreased GMV were related to cognitive performance in MCI and AD patients. Compared to NC group, the number of brain regions with local and distant correlations between GMV and SUVR was greater in AD/MCI group. Mediation analysis revealed that GMV served as a significant mediator between tau pathology and cognition in local regions. Furthermore, distant effects were also observed, with hippocampal atrophy partially mediated the relationship between entorhinal cortex tau pathology and cognition. Meanwhile, medial parietal lobe atrophy partially mediated the relationship between medial temporal lobe tau deposition and cognition. Conclusions: Our findings provide an anatomically detailed insight into relationships between tau, GMV and cognition, especially in entorhinal cortex-hippocampus, temporal-parietal lobe cortical circuits.
ChengBing Gong, WenTing Song, ZhengYang Zhu, Dan Yang, Xiang Zhao, Yun Xu, Hui Zhao
APOE ε4 influences the dynamic functional connectivity variability and cognitive performance in Alzheimer’s disease (Handling Associate Editor: Kristy Nielson)
Abstract: Background: Apolipoprotein E (APOE) ε4 is the most significant genetic risk factor for sporadic Alzheimer’s disease (AD). However, its impact on the dynamic changes in resting-state functional connectivity (FC), particularly concerning network formation, interaction, and dissolution over time, remains largely unexplored in AD. Objective: This study aims to explore the effect of APOE ε4 on dynamic FC (dFC) variability and cognitive performance in AD. Methods: We analyzed the dFC of AD patients, comparing APOE ε4 carriers (n = 33) with non-carriers (n = 41). The whole-brain dFC was assessed by calculating dynamic fractional amplitude of low-frequency fluctuations (dfALFF) and dynamic regional homogeneity (dReHo). To further explore the relationship between cognitive function and dFC in AD patients, we conducted a correlation analysis. Mediation analysis was also performed to determine whether dFC mediates the link between the APOE ε4 and cognitive decline in AD patients. Results: AD patients carrying the APOE ε4 exhibited more severe cognitive impairment, along with reduced dReHo and dfALFF in both the left and right posterior cerebellar lobes. In these carriers, the dFC analysis showed lower dFC between the left posterior cerebellar lobe and the left middle temporal gyrus, which was positively correlated with executive function and information processing speed. Additionally, mediation analysis indicated that APOE ε4 influences dFC in this brain region, contributing to executive dysfunction in AD. Conclusions: These findings offer preliminary evidence that APOE ε4 modulates fluctuating communication within the cerebellar lobe and the dFC between the cerebellar lobe and the temporal gyrus in AD.
Davide Quaranta, Camillo Marra, Enrico Mossello, Alessandro Pirani, Annachiara Cagnin, Federico Adinolfi, Stefano Remiddi
The management of mild neurocognitive disorder in primary care: A Delphi consensus study
Abstract: Background: Strategies to identify and treat mild neurocognitive disorder (mild NCD) are still unclear. Objective: The detection and management of mild NCD are crucial to prevent or delay its progression to major NCD, and to help those affected cope with cognitive impairment. The Cartesio Project aimed to reach a consensus on the management of mild NCD in primary care. Methods: The Advisory Board of five experts (three neurologists, one geriatrician and one general practitioner (GP)), identified four domains of mild NCD: case finding; differential diagnosis; non-pharmacological, and pharmacological intervention. A literature review was performed by consulting the PubMed, PsycNET and Scopus databases from 2017 until August 2022, and guidelines, reviews and meta-analyses on mild NCD were reviewed. A care pathway involving 18 statements was then proposed and voted on by 61 participants (39% neurologists, 31% geriatricians, 25% GPs and 5% psychiatrists). Results: Agreement was reached on 14 out of 18 statements. The practice of case finding in primary care and the need for a two-level diagnostic approach was supported, including referral to memory clinics. With regard to non-pharmacological treatments, no consensus was reached on nutritional supplementation. There was support for the use of nootropic drug treatments, but not for drugs to treat Alzheimer’s disease. Conclusions: The Cartesio Project developed a consensus to identify the best care for mild NCD. The consensus highlights educational interventions on timely detection and appropriate management of mild NCD in primary care, which may be of relevance for those patients who eventually develop Alzheimer’s disease.
Jing Liu#, Dan Liu#, Xin-Yan Xie#, Cheng Cai#, Jing-Jing Zhang, Gui-Rong Cheng, Fei-Fei Hu, Qian-Qian Nie, Juan Zhou, De-Yang Zeng, Xiao-Chang Liu, Dan Song, Jun-Yi Wang, Shi-Yue Li, Yu-Yang Cui, Chen-Lu Hu, Yi-Di Fu, Wan-Yin Cai, Yi-Qing Li, Chun-Li Li, Meng-Die Pei, Xiao-Yu Lou, Bing-Yu Zhang, Hong-Wei Ren, Jun-Li Huang, Du Wang, Zhao-Lan Huang, Gang-Bin Han, Lin-Ya Huang, Xue Yang, Yan Zeng #These authors contributed equally to this work.
Association between home dwelling situations, neighborhood social interactions, and subjective cognitive decline plus among older adults: A cross-sectional study
Abstract: Background: Home-dwelling situations (HDS) and neighborhood social interactions (NSI) significantly impact older adults’ post-retirement lives. However, their relationship with subjective cognitive decline plus (SCD-plus), a potential biomarker of preclinical Alzheimer’s disease (AD), remains uncertain. Objective: To explore the association between NSI, HDS and SCD-plus among older adults. Methods: This cross-sectional study utilized data from the Hubei Memory and Aging Cohort Study (HMACS, 2018–2022), examining the relationship between HDS, NSI, and SCD-plus status and feature scores, using logistic and linear regression models. Results: Among 3514 adults (age: ≥65 y; female: 52.44%), 1329 had SCD-plus status (37.82%). After adjusting for covariates, living with spouse only was associated with lower odds of SCD-plus (odds ratio [OR] = 0.72, 95% confidence interval [CI] [0.55, 0.95]) compared to living alone. Frequent NSI was linked to lower odds of SCD-plus (OR = 0.65, 95% CI [0.54, 0.80]) and reduced feature scores (regression coefficient [β] = -0.16, 95% CI [-0.25, -0.07]). Compared to living alone - no NSI, all other combinations showed better SCD-plus status, especially living with spouse only with frequent NSI, which demonstrated a 55% reduction in likelihood (OR = 0.45, 95% CI [0.28, 0.73]). Conclusions: Living with spouse only and frequent NSI significantly lowers the odds of SCD-plus, providing a basis for further exploration of the impact of social interactions on cognitive health.
Rong-Ji Xue#, Pei-Yang Gao#, Yan-Ming Chen, Ying Liu, Bao-Lin Han, Yi-Ming Huang, Yin-Chu Mi, Rui-Ping Cui, Yu-Jing Lin, Zuo-Teng Wang, Chen-Chen Tan, Ya-Nan Ou, Lan Tan (Handling Associate Editor: Ling-Qiang Zhu) # These authors contributed equally to this work.
Associations between plasma complement C1q and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact adults: The CABLE study
Abstract: Background: C1q is a promoter of the classical pathway of complement and its massive expression may be associated with the development of Alzheimer's disease (AD). However, the relationships between C1q and the major pathological challenges, including amyloid-β (Aβ) and tau deposition, remain undetermined in the preclinical AD phase. Objective: This study aims to investigate the connections between plasma C1q and CSF AD biomarkers. Methods: The cognitively intact participants (N = 1264) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study were categorized into four groups, including Stage 0 [normal Amyloid-β1-42 (Aβ1-42), Phosphorylated-tau (P-tau) and Total-tau (T-tau)], Stage 1 (abnormal Aβ1-42, but normal P-tau or T-tau), Stage 2 (abnormal Aβ1-42 and abnormal P-tau or T-tau), and suspected non-Alzheimer disease pathology (SNAP) (abnormal P-tau or T-tau, but normal amyloid levels). The changes in plasma C1q levels among these groups and the correlation between C1q levels and cerebrospinal fluid (CSF) AD biomarkers were performed. Results: The results demonstrated plasma C1q levels are lower in Stage 0 (p = 0.010) and SNAP (p < 0.001) compared with Stage 1. A significant association between C1q levels and CSF AD pathology, including Aβ1-42 (β = -0.143, p < 0.001), Aβ1-42/Aβ1-40 (β = -0.173, p < 0.001), P-tau/Aβ1-42 (β = 0.156, p < 0.001), and T-tau/Aβ1-42 (β = 0.130, p < 0.001) has been identified. Conclusions: The current research elucidates a positive correlation between elevated plasma C1q levels and CSF Aβ pathology, with C1q amplifying concomitantly with the pathological and clinical progression of AD.
Jian Wang#, Duo-Zi Wang#, Bing-Hu Li, Shu Yang, Fu-Qiang Guo, Bo Zheng, Jian-Hong Wang (Handling Associate Editor: Dong-Yu Fan) #These authors contributed equally to this work.
Elevated circulating cathepsin S levels are associated with cognitive decline and neurodegeneration in a cohort of patients reporting memory complaints
Abstract: Background: As a member of the cysteine protease family, cathepsin S has been implicated in the pathogenesis of various diseases, including Alzheimer’s disease (AD), primarily by promoting inflammation. Objective: Current evidence regarding the role of cathepsin S primarily comes from animal studies. This study aims to explore the clinical relevance of cathepsin S in AD. Methods: In a cohort of older adults aged 60 or above with memory complaints, we examined baseline plasma levels of cathepsin S and assessed their association with cognitive decline and biomarkers of neurodegeneration during a 36-month follow-up. Results: Plasma levels of cathepsin S were significantly higher in individuals experiencing longitudinal cognitive decline compared to those without cognitive decline. Furthermore, plasma levels of cathepsin S were associated with declines in Mini-Mental State Examination (MMSE) scores and increases in neurofilament light and pTau181 levels. Higher plasma cathepsin S levels were linked to an increased risk of longitudinal cognitive decline (decrease in MMSE scores of 3 or more), adjusting for age, sex, education, APOE genotype, alcohol consumption, smoking, and comorbidities. Conclusions: This study provides additional evidence supporting the potential role of cathepsin S in the pathogenesis of AD from a clinical perspective.
Yu Shen#, Quirui Nie#, WenWen Xiang, Shenjian Chen, Qian Cao, Daojun Hong (Handling Associate Editor: Boris-Stephan Rauchmann) #These authors contributed equally to this work.
The relationship between Alzheimer’s disease and intracerebral hemorrhage based on Mendelian randomization
Abstract: Background: Traditional epidemiologic studies suggest that Alzheimer's disease (AD) may be associated with intracerebral hemorrhage (ICH). Objective: To explore whether there is a causal relationship between AD and ICH and the underlying mechanisms involved. Methods: Mendelian randomization (MR) approach was used to explore causal relationships. The genetic instrumental variables of the candidate genetic instrumental variable AD were obtained from genome-wide association studies. The inverse variance weighted method was the primary method for MR analysis and meta-analysis. The obtained single nucleotide polymorphisms were analyzed for corresponding genes for subsequent pathway enrichment and protein-protein interaction analysis. Results: For the single AD dataset, our MR analysis of the AD datasets versus the ICH datasets revealed a genetically predicted causal relationship between AD and ICH (OR 5.947, 95%CI 1.165-30.356, pIVW = 0.032). In addition, the MR-Egger method and MR-PRESSO method revealed no horizontal pleiotropic effect of AD on the risk of ICH. Meta-analysis of each dataset using IVW revealed a final calculated OR of 1.08 (95%CI 1.02-1.15, p = 0.01). Subsequent pathway enrichment analysis revealed that the corresponding genes were involved mainly in the metabolic process of amyloid-β (Aβ) and negatively regulated Aβ formation. In the PPI network analysis, proteins such as ApoE, SROL1, CLU, ABCA7, and AβPP were found to be closely related and located in the key position of the center. Conclusions: We verified the causal relationship between AD and ICH via MR, and identified the possible pathological mechanisms involved. We also discovered that Aβ plays an important role in this process.
Anders Wimo#, Ron Handels#, Kaj Blennow, K Bjørn-Eivind Kirsebom, Per Selnes, Jaka Bon, Andreja Emersic, Fernando Gonzalez-Ortiz, Milica Gregoric Kramberger, Anders Sköldunger, Andreja Speh, Santiago Timón-Reina, Ellen Vromen, Pieter Jelle Visser, Bengt Winblad, Tormod Fladby #These authors contributed equally to this work.
Cost-effectiveness of diagnosing and treating patients with early Alzheimer’s disease with anti-amyloid treatment in a clinical setting
Abstract: Background: The introduction of anti-amyloid treatments (AAT) for Alzheimer’s disease (AD) has put the cost-effectiveness into focus. Objective: Estimate the potential cost-effectiveness of diagnostic pathways combined with AAT for early AD. Methods: Diagnostic accuracy of blood-based (BBM) and cerebrospinal fluid (CSF) biomarkers was obtained from Norwegian memory clinics using positron emission tomography (PET) as reference standard. In a health-economic model, the cost-effectiveness of three diagnostic strategies was estimated relying either on BBM (p-tau 217), CSF (Aβ42/40 ratio), and BBM with CSF confirmatory testing and compared with standard of care (SoC) and compared with CSF-AAT. The model consisted of a decision tree reflecting the diagnostic process and a subsequent Markov cohort model starting at mild cognitive impairment due to AD. All strategies except SoC were combined with AAT including costs of treatment (assumed €5,000/year), infusions and monitoring. Results: Compared with SoC all three strategies (CSF-AAT, BBM-AAT, and BBM-CSF-AAT) resulted in QALY gains at higher costs, with an incremental cost-effectiveness ratio (ICER) of 110k€, 141k€ and 110k€ respectively. Compared with CSF-AAT both BBM-AAT and BBM-CSF-AAT strategies resulted in QALYs lost at lower costs, with an ICER of 27k€ and 109k€ respectively. Results were particularly sensitive to the price of AAT and possible subcutaneous administration. Conclusions: Compared with SoC all three strategies are potentially not cost-effective as they exceeded the Swedish maximum willingness to pay threshold of €94,800 per QALY gained. BBM-CSF-AAT versus CSF-AAT is potentially cost-effective if willing to accept its QALY loss. Discussions on budget impact on different payers are needed after introducing AAT.
Tingting Ruan#, Yunxiang Ling#, Can Wu#, Yanfang Niu, Guili Liu, Chunshuang Xu, Zhongyue lv, Yalan Yuan, Xinkai Zhou, Qinwen Wang, Shujun Xu #These authors contributed equally to this work.
Abnormal epigenetic modification of lysosome and lipid regulating genes in Alzheimer’s disease
Abstract: Background: Abnormal lipid metabolism has been identified as a potential pathogenic mechanism of Alzheimer’s disease (AD), which might be epigenetically regulated. Lysosomes are critical organelles for lipid metabolism. However, the epigenetic modifications of lysosome and lipid regulating genes remain unclear in AD patients. Objective: Explore the role of abnormal epigenetic modifications, especially methylation of lysosome and lipid metabolism-related genes in AD. Methods: Methylation beadchip and MALDI-TOF mass spectrometry were used to detect genome-wide DNA methylation levels and validate key gene methylation, respectively. Clinical data were collected from all participants. Associations between clinical biochemical characteristics and altered DNA methylation in AD patients were analyzed, and a risk factor model of AD was established. Results: 41 differentially methylated positions (DMPs) corresponding to 33 genes were identified in AD patients, with 18 hypermethylated and 23 hypomethylated positions. Significant alterations were observed in lipid regulating genes (CTNNB1, DGKQ, SLC27A1) and lysosomal transmembrane gene (TMEM175). Clinical analysis revealed that TP, ALB, IB, ADA, ALP, HCY, GLU, TC, BUN, HDL-C, LDL-C, and APOA1 levels were significantly higher in AD patients, whereas A/G and DB levels were lower. TMEM175 hypermethylation was further verified and found to correlate with TC, HDL-C, LDL-C, APOA1, IB, and HCY. The AUC of the AD risk model, which integrated clinical lipid markers and TMEM175 methylation, reached 0.9519 (p < 0.0001). Conclusions: Abnormal epigenetic regulation of lysosomal gene and lipid dyshomeostasis were high-risk factors in AD. Methylation modifications of lysosome and lipid regulating genes might be key processes in AD pathogenesis.
Lubnaa Abdullah, Zhengyang Zhou, James Hall, Melissa Petersen, Fan Zhang, Sid O’Bryant
Association of Alzheimer’s disease biomarkers with low premorbid intellectual functioning in a multi-ethnic community-dwelling cohort: A cross-sectional study of HABS-HD
Abstract: Background: Individuals with intellectual disability (ID) may have a five-fold increased risk for developing Alzheimer’s disease (AD). However, studies investigating brain aging among individuals with ID without Down syndrome (DS) are lacking. To begin addressing this gap, our study utilized word reading, a widely recognized indicator of an individual's premorbid intellectual ability (pIQ), to examine the effects of ID without DS on plasma AD biomarker outcomes. Objective: To investigate the relationship between premorbid intellectual ability (pIQ) and plasma AD biomarkers in individuals with ID without DS, while considering ethnic differences in these associations. Methods: Participants from the Health & Aging Brain Study – Health Disparities (HABS-HD) were categorized into low (z ≤ -2.00) or average (z = 0.00 ± 1.00) pIQ groups based on word reading scores. Plasma biomarkers including Aβ40, Aβ42, Aβ42/40, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-tau) were assayed using Simoa technology. Results: Individuals with low pIQ exhibited significantly higher levels of p-Tau181 (p < 0.05), NfL (p < 0.05), and t-tau (p < 0.05) compared to those with average pIQ. Stratified analysis by ethnicity revealed differential associations, with Hispanic and non-Hispanic White (NHW) participants showing distinct biomarker profiles relative to non-Hispanic Black (NHB) individuals. Conclusions: The findings demonstrate that low pIQ is a reliable factor associated with plasma AD biomarker outcomes. Ethnicity appears to modulate these associations, suggesting complex interactions between factors driving cognitive resilience and AD susceptibility across diverse populations. This study highlights the importance of considering both pIQ and ethnicity in neurodegenerative processes, particularly in individuals with non-DS intellectual developmental disability.
Simona Z Vasileva-Metodiev, Drew Spargo, Eric G Klein, Frances-Catherine Quevenco, Sarah Cotton, Pascual Sanchez-Juan, Yoshiki Niimi, Nicole R. Fowler
Diagnostic journey and management of patients with mild cognitive impairment and Alzheimer’s disease dementia: A multinational, real-world survey
Abstract: Background: An Alzheimer’s disease (AD) diagnosis made in the earliest symptomatic stages substantially benefits patients and their care partners. However, little is known regarding the clinical, healthcare system-level, and patient-specific barriers that hinder timely diagnosis and treatment. Objective: To explore real-world practices surrounding the diagnostic journey and management of mild cognitive impairment (MCI)/AD dementia patients. Methods: Data were drawn from Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating MCI/AD dementia patients in France, Germany, Italy, Spain, the United Kingdom, the United States, and Japan between 2022–2024. Results: Overall, 779 physicians reported data on 5551 patients. Physicians indicated current disease severity for 5421 patients; 37.2% had MCI (87.3% with suspected prodromal AD and 12.7% undetermined etiology), 17.2% AD with mild dementia, 31.1% AD with moderate dementia, and 14.5% AD with severe dementia. When not immediately diagnosed, the median time from first consultation to initial diagnosis was 8.9 and 12.6 weeks when patients first consulted and were diagnosed by either a primary care practitioner (PCP) or a specialist, respectively, compared with 21.6 weeks when a PCP referred to a specialist for diagnosis. Diagnostic delays were predominantly due to specialist wait times. Few patients had diagnostic AD biomarker tests (cerebrospinal fluid testing 9.5%, amyloid positron emission tomography 3.7%, AD-blood tests 5.3%). Conclusions: Timely MCI and AD diagnosis is impeded by referral delays and limited use of biomarker testing. Addressing these critical care gaps requires enhanced physician training, reduced wait times and increased biomarker utilization for early management.
Yuanyuan Lu, Dan Li, Yueyi Yu, Qianqian Wang, Aonan Li, Yixin Quan, Yi Xing, for the Alzheimer’s Disease Neuroimaging Initiative
Cerebrospinal fluid VGF is associated with the onset and progression of Alzheimer’s disease
Abstract: Background: It remains unclear whether cerebrospinal fluid (CSF) VGF (non-acronymic) is associated with the onset and progression of Alzheimer’s disease (AD). Objective: To assess the levels of CSF VGF throughout the AD continuum, and its association with primary AD pathology, cognition, brain atrophy, and brain metabolism. Methods: We studied a total of 526 individuals including 377 amyloid-positive individuals (76 preclinical AD, 200 prodromal AD, and 101 AD dementia) and 149 amyloid-negative cognitively normal individuals. VGF peptide in CSF was analyzed using mass spectrometry. Results: We observed decreased CSF VGF in preclinical, prodromal, and AD dementia individuals than amyloid-negative cognitively normal individuals. Reduced CSF VGF was associated with cognitive decline, hippocampal atrophy, ventricle enlargement, and glucose hypometabolism at baseline, and it predicted a more marked deterioration over time. Conclusions: Our findings support the important contributions of VGF to disease pathogenesis and progression in the early stages of AD. Exploring the biologics modulating VGF might be a promising approach for AD prevention and early treatment.
Caroline J Zeiss, Anita Huttner, Angus C Nairn, Amy Arnsten, Dibyadeep Datta, Stephen M Strittmatter, Brent Vander Wyk, Alvaro Duque (Handling Associate Editor: Weiming Xia)
The neuropathologic basis for translational biomarker development in the macaque model of late-onset Alzheimer’s disease
Abstract: Background: Accurate placement of the macaque within the Alzheimer’s disease (AD) research framework is essential to discover early-stage predictive biomarkers. Objective: To assess utility of the aging macaque in advancing translational biomarker development for preclinical AD, we evaluated relative signal strength of comparable neuropathologic phenomena in macaques and patients. Methods: We compared pathology in patient and macaque formalin-fixed paraffin embedded (FFPE) tissues using identical criteria. We quantified expression of amyloid-β (Aβ), pTau, and inflammatory and senescence markers across species. Distribution of AD-relevant markers were compared in FFPE and perfused frozen macaque brain to assess expression of labile proteins that could inform in-life fluid biomarkers. Results: Aβ pathology in macaques closely approximated patient pathology. Complex plaque composition in macaques implied significant disruption of synaptic connectivity. In FFPE tissue, pretangle pTau immunoreactivity placed the macaque in Braak Stage 1b. In perfused frozen tissue, soluble pTau distribution approximated Braak Stage III-IV. In macaque, Aβ, pTau, and acetylcholinesterase labeling co-localized to AD-vulnerable circuits. Significant association of glial fibrillary acidic protein with Aβ occurred in humans only. The senescence marker p16 correlated positively with pTau expression and negatively with Aβ in patients only. Macaques lacked neuropathologic co-morbidities. Conclusions: AD-relevant neuropathologic signals in the macaque support biomarker discovery in the areas of Aβ plaque evolution and associated synaptic disruption as well as early-stage tau phosphorylation. Relative protection from accumulation of senescence markers, fibrillar tau and neuropathologic co-morbidities in macaque implicate species difference in rates of biological brain aging. We provide over 4000 digital slides for further study.
Zhen Zhang#, Liang Cui#, Lin Huang, Yi-Hui Guan, Fang Xie, Qi-Hao Guo #These authors contributed equally to this work.
Development and validation of the Chinese Naming Test (CNT): Diagnostic efficacy and correlation with Alzheimer’s disease biomarkers
Abstract: Background: Neuropsychological assessments are essential tools for the screening and diagnosis of patients with cognitive impairments. Cultural background differences significantly affect cognitive test performance. For China, which is rapidly aging, a culturally adaptive picture naming test is urgently needed. Objective: This study aims to develop a Chinese naming test (CNT) adapted to the cultural background of Chinese people and to explore its correlation with Alzheimer’s disease (AD) biomarkers. Methods: A total of 1459 participants were recruited, including 744 with normal cognition (NC), 492 with mild cognitive impairment (MCI), and 223 with dementia. All participants underwent a comprehensive neuropsychological assessment. The diagnostic capability of CNT was determined using Receiver Operating Characteristic curves. Part of participants underwent amyloid-β (Aβ) PET scans, tau-PET scans, and MRI scans. The relationships between CNT scores and Aβ and tau deposition, as well as brain structural changes, were analyzed. Results: The diagnostic capability of CNT for MCI showed a sensitivity of 68.7%, specificity of 75.6%, and AUC of 0.81; for dementia, the sensitivity was 72.7%, specificity was 89.5%, and AUC was 0.89. The correlation coefficient between CNT scores and brain Aβ burden was -0.11 (p=0.024). CNT scores correlated with tau burden in different Braak stages (p<0.05). The correlation coefficient between CNT scores and hippocampus atrophy was -0.15 (p=0.003). Conclusions: The CNT has good diagnostic performance in detecting MCI and dementia in Chinese population. There is a correlation between CNT scores and AD imaging markers, indicating that the CNT might has potential value in predicting cognitive changes and disease progression.
Xinghe Huang, Jie Liang, Junyu Zhang, Jiayi Fu, Yige Chen, Wuxiang Xie, Fanfan Zheng
Association of cardiovascular-kidney-metabolic health and apolipoprotein E4 genotype with risk of dementia and mortality
Abstract: Background: Poor cardiovascular-kidney-metabolic (CKM) health is becoming prevalent; however, sparse data exist regarding the association of CKM health with incident dementia and all-cause mortality. Objective: This study aimed to examine whether poor CKM health is associated with a higher risk of dementia and all-cause mortality, regardless of APOE4 carrier status. Methods: In this prospective cohort study, 352,364 participants from the UK Biobank were included. CKM syndrome was identified as a medical condition with the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease, and was classified into five stages (stage 0 to 4). Cox proportional hazards models were applied to explore the association of CKM health with incident dementia and all-cause mortality. Results: Participants in stage 2-3 and stage 4 had 1.12-fold (95% CI: 1.02-1.23, p=0.023) and 2.18-fold (95% CI: 1.96-2.43, p<0.001) increased risk of incident all-cause dementia compared with those in stage 0. Similarly, participants in stage 4 also had an increased risk of Alzheimer’s disease (HR=1.51, 95% CI: 1.28-1.78, p<0.001) and vascular dementia (HR=4.62, 95% CI: 3.54-6.03, p<0.001). Participants in later stages were at higher risk of all-cause mortality. We found an interaction between CKM health and APOE4 carrier status (p for interaction <0.001), and the relationship between CKM health and dementia was more pronounced in non-APOE4 carriers. Moreover, there were significant additive interactions between APOE4 carrier status and CKM health on the risk of dementia. Conclusions: Poor CKM health is independently associated with an increased risk of dementia, regardless of APOE4 carrier status, and all-cause mortality. These findings imply that promoting CKM health may help to reduce the risk of subsequent dementia and mortality.
Takashi Asada, Tatsuyuki Kakuma, Mieko Tanaka, Wataru Araki, Adam Jon Lebowitz, Toshimitsu Momose, Hiroshi Matsuda
A statistical method for predicting amyloid-β deposits from severity, extend, and ratio indices of the 99mTc-ECD SPECT
Abstract: Background: Amyloid-β (Aβ) deposit prediction accuracy is necessary for clinicians treating patients desiring Alzheimer’s disease (AD) modifying drugs. Aβ-PET imaging is useful for diagnosis, but high in cost compared to brain perfusion SPECT. However, SPECT displays regional cerebral blood flow (rCBF) and does not detect Aβ deposits, therefore requiring additional clinical information. Objective: This article describes a novel statistical method to predict amyloid deposits via PET images (Aβ+ or Aβ-) using the three indices of the 99mTc-ECD SPECT -- severity, extend, and ratio -- for the three ROIs. Methods: Candidate patients (N = 114 patients [55% male], 81 Aβ+ 33 Aβ-, mean age 74.2±6.6 years, mean MMSE score 23.7±2.8) underwent MRI and 99mTc-ECD SPECT scanning. After examining SPECT index, demographic, and age data, age and sex were treated as confounders in one, two, and three-index logistic additive models with severity, extend, and ratio as explanatory variables. Area under curve (AUC), sensitivity and specificity were used as statistical indices for model fitness and accuracies. Three-hold cross validation analyses were conducted to evaluate error rates. Results: According to ROC analysis, best scores for fitness and accuracy were obtained from the three-index model with patients’ age and sex for the configured ROIs including precuneus, posterior cingulate and temporal-parietal region of SPECT (AUC: 0.818, Sensitivity: 0.803, Specificity: 0.727). Conclusions: This technique using 99mTc-ECD SPECT data can predict amyloid deposits with acceptable accuracy. To confirm the reliability and validity, a multicenter SPECT study is needed.
Nils Richter, Laura Breidenbach, Maximilian HT Schmieschek, Wolf-Dieter Heiss, Gereon R Fink, Oezguer A Onur
Alzheimer-typical temporo-parietal atrophy and hypoperfusion are associated with a more significant cholinergic impairment in amnestic neurodegenerative syndromes
Abstract: Background: To date, cholinomimetics remain central in the pharmacotherapy of Alzheimer’s disease (AD) dementia. However, postmortem investigations indicate that the AD-typical progressive amnestic syndrome may also result from predominantly limbic non-AD neuropathology such as TDP-43 proteinopathy and argyrophilic grain disease. Experimental evidence links a beneficial response to cholinomimetics in early AD to reduced markers of cholinergic neurotransmission. However, the cholinergic impairment varies among patients with a clinical AD presentation, likely due to non-AD (co)-pathologies. Objective: This study examines whether AD-typical atrophy and hypoperfusion can provide information about the cholinergic system in clinically diagnosed AD. Methods: Thirty-two patients with amnestic mild cognitive impairment or mild dementia due to AD underwent positron emission tomography (PET) with the tracer N-methyl-4-piperidyl-acetate (MP4A) to estimate acetylcholinesterase (AChE) activity, neurological examinations, cerebral magnetic resonance imaging (MRI) and neuropsychological assessment. The ‘cholinergic deficit’ was computed as the deviation of AChE activity from cognitively normal controls across the cerebral cortex and correlated gray matter (GM) and perfusion of temporo-parietal cortices typically affected by AD and basal forebrain (BF) GM. Results: Temporo-parietal perfusion and GM, as well as the inferior temporal to medial temporal ratio of perfusion correlated negatively with the ‘cholinergic deficit’. A smaller Ch4p area of the BF was associated with a more significant ‘cholinergic deficit’, albeit to a lesser degree than cortical measures. Conclusions: In clinically diagnosed AD, temporo-parietal GM and perfusion are more closely associated with the ‘cholinergic deficit’ than BF volumes, making them possible markers for cholinergic treatment response in amnestic neurodegeneration.
