Journal of Alzheimer's Disease - Volume 98, issue 3

Authors: Shen, Zhiwei | Yang, Xinyi | Lan, Yulong | Chen, Gao

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no “curative” drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory …can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα , CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ , CSF1 R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD. Show more

Keywords: Alzheimer’s disease, microenvironment, microglia, neuro-inflammation, stem cell

DOI: 10.3233/JAD-231159

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 741-754, 2024

Authors: Aljassabi, Ali | Zieneldien, Tarek | Kim, Janice | Regmi, Deepika | Cao, Chuanhai

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is an extremely complex and heterogeneous pathology influenced by many factors contributing to its onset and progression, including aging, amyloid-beta (Aβ) plaques, tau fibril accumulation, inflammation, etc. Despite promising advances in drug development, there is no cure for AD. Although there have been substantial advancements in understanding the pathogenesis of AD, there have been over 200 unsuccessful clinical trials in the past decade. In recent years, immunotherapies have been at the forefront of these efforts. Immunotherapy alludes to the immunological field that strives to identify disease treatments via the enhancement, suppression, or induction of immune responses. Interestingly, …immunotherapy in AD is a relatively new approach for non-infectious disease. At present, antibody therapy (passive immunotherapy) that targets anti-Aβ aimed to prevent the fibrillization of Aβ peptides and disrupt pre-existing fibrils is a predominant AD immunotherapy due to the continuous failure of active immunotherapy for AD. The most rational and safe strategies will be those targeting the toxic molecule without triggering an abnormal immune response, offering therapeutic advantages, thus making clinical trial design more efficient. This review offers a concise overview of immunotherapeutic strategies, including active and passive immunotherapy for AD. Our review encompasses approved methods and those presently under investigation in clinical trials, while elucidating the recent challenges, complications, successes, and potential treatments. Thus, immunotherapies targeting Aβ throughout the disease progression using a mutant oligomer-Aβ stimulated dendritic cell vaccine may offer a promising therapy in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , dendritic cell, immunotherapies, vaccine

DOI: 10.3233/JAD-231163

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 755-772, 2024

Authors: Carr, Rachel H. | Eom, Gina D. | Brown, Eric E.

Article Type: Systematic Review

Abstract: Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition now recognized to persist into older adulthood, has been postulated to be a risk factor for neurocognitive disorders given the overlap in clinical features and neurobiology, as well as the complex interplay between ADHD and known risk factors for dementia. Studies have emerged assessing this relationship, but there has not yet been a comprehensive systematic review addressing this topic. Objective: To assess whether ADHD is a risk factor for neurocognitive disorders and to explore possible mechanisms for such an association. Methods: A systematic review of …the literature was conducted using Medline, Embase, and PsycINFO from inception until June 4, 2023. Studies were included if they assessed whether or how ADHD may be a risk factor for neurocognitive disorders. Studies were excluded if they were not primary literature, not published in a peer-reviewed journal, not in English, and/or used non-human subjects. Study quality was assessed using the QualSyst tool. Results: Sixteen studies met inclusion criteria. Seven studies found a positive association between ADHD and neurocognitive disorders (all-cause dementia in four studies, Alzheimer’s disease in three studies, Lewy body dementia in two studies, and mild cognitive impairment in one study). Four studies did not find an association. Five studies pertained to possible mechanisms for an association, including genetics, with minimal significant findings. Conclusions: ADHD may be a risk factor for certain neurocognitive disorders, although the evidence base is limited, and the absolute risk is small. Possible explanations include genetic and lifestyle factors. Show more

Keywords: Aged, Alzheimer’s disease, attention deficit disorder with hyperactivity, cognitive dysfunction, dementia, Lewy body disease, systematic review

DOI: 10.3233/JAD-230904

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 773-792, 2024

Authors: Cabrera-León, Ylermi | Báez, Patricio García | Fernández-López, Pablo | Suárez-Araujo, Carmen Paz

Article Type: Systematic Review

Abstract: Background: The growing number of older adults in recent decades has led to more prevalent geriatric diseases, such as strokes and dementia. Therefore, Alzheimer’s disease (AD), as the most common type of dementia, has become more frequent too. Background: Objective: The goals of this work are to present state-of-the-art studies focused on the automatic diagnosis and prognosis of AD and its early stages, mainly mild cognitive impairment, and predicting how the research on this topic may change in the future. Methods: Articles found in the existing literature needed to fulfill several …selection criteria. Among others, their classification methods were based on artificial neural networks (ANNs), including deep learning, and data not from brain signals or neuroimaging techniques were used. Considering our selection criteria, 42 articles published in the last decade were finally selected. Results: The most medically significant results are shown. Similar quantities of articles based on shallow and deep ANNs were found. Recurrent neural networks and transformers were common with speech or in longitudinal studies. Convolutional neural networks (CNNs) were popular with gait or combined with others in modular approaches. Above one third of the cross-sectional studies utilized multimodal data. Non-public datasets were frequently used in cross-sectional studies, whereas the opposite in longitudinal ones. The most popular databases were indicated, which will be helpful for future researchers in this field. Conclusions: The introduction of CNNs in the last decade and their superb results with neuroimaging data did not negatively affect the usage of other modalities. In fact, new ones emerged. Show more

Keywords: Alzheimer’s disease, blood, computer-assisted diagnosis, deep learning, gait, genes, mild cognitive impairment, neural networks (computer), neuropsychological tests, speech

DOI: 10.3233/JAD-231271

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 793-823, 2024

Authors: Terao, Itsuki | Kodama, Wakako

Article Type: Systematic Review

Abstract: Background: The Food and Drug Administration (FDA) has approved lecanemab and aducanumab and is reviewing donanemab, but they have questionable efficacy, serious side effects and are costly, whereas melatonin administration and aerobic exercise for a short time may overcome these problems. Objective: We aim to compare the efficacy on cognitive function, tolerability and acceptability of melatonin administration and aerobic exercise for a short time with donanemab, lecanemab, and aducanumab in people with mild AD and MCI. Methods: We systematically reviewed relevant randomized placebo-controlled trials (RCTs) in PubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov …and performed network meta-analyses. Results: The analysis included 10 randomized placebo-controlled trials with 4,599 patients. Although melatonin and aerobic exercise for a short time were significantly more effective than donanemab, lecanemab, aducanumab and placebo in the primary analysis, there was significant heterogeneity. In the sensitivity analysis excluding exercise, melatonin was significantly more effective than donanemab, lecanemab, aducanumab and placebo, with no significant heterogeneity. Aerobic exercise for a short time was significantly less acceptable than donanemab, aducanumab and placebo. Donanemab, lecanemab, and aducanumab were significantly less tolerable than placebo and donanemab and lecanemab were significantly less acceptable than placebo. CONCLUSIONS: Melatonin may be a better potential disease-modifying treatment for cognitive decline in mild AD and MCI. Aerobic exercise for a short time might also be better than donanemab, lecanemab and aducanumab if continued, as it is well tolerated and more effective, although less valid due to heterogeneity. Another limitation is the small number of participants. Show more

Keywords: Aducanumab, Alzheimer’s disease, donanemab, exercise, melatonin, meta-analysis

DOI: 10.3233/JAD-230911

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 825-835, 2024

Authors: Brooks, Wesley Harrell

Article Type: Research Article

Abstract: A hypothesis of Alzheimer’s disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer’s disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome …21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka “nucleolar satellite”) with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer’s, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases. Show more

Keywords: Alu, Alzheimer’s disease, amyloid-β, autoimmune disease tautology, epigenetics, inactive X chromosome, nucleolus, polyamines, tau

DOI: 10.3233/JAD-231184

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 837-857, 2024

Authors: Cummings, Jeffrey

Article Type: Article Commentary

Abstract: Better means of conducting more efficient clinical trials for the development of Alzheimer’s disease (AD) therapeutics are required. Adaptive clinical trial designs have many advantages based on the ability to make prespecified changes in the trial conduct depending on the ongoing experience in the trial. In their report in the Journal of Alzheimer’s Disease , Lee and colleagues show that in the past 25 years only 2.5% of AD clinical trials have used adaptive designs. The report calls attention to the opportunity to use adaptive designs more often in Phase 2 clinical trials to improve trial efficiency and accelerate treatment …development. Show more

Keywords: Adaptive design, ADCOMS, Alzheimer’s disease, clinical trial, lecanemab, parallel group

DOI: 10.3233/JAD-240145

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 859-861, 2024

Authors: Bergamino, Maurizio | Keeling, Elizabeth | McElvogue, Molly | Schaefer, Sydney Y. | Burke, Anna | Prigatano, George | Stokes, Ashley M.

Article Type: Research Article

Abstract: Background: Dementia is characterized by a cognitive decline in memory and other domains that lead to functional impairments. As people age, subjective memory complaints (SMC) become common, where individuals perceive cognitive decline without objective deficits on assessments. SMC can be an early sign and may precede amnestic mild cognitive impairment (MCI), which frequently advances to Alzheimer’s disease (AD). Objective: This study aims to investigate white matter microstructure in individuals with SMC, in cognitively impaired (CI) cohorts, and in cognitively normal individuals using diffusion kurtosis imaging (DKI) and free water imaging (FWI). The study also explores voxel-based …correlations between DKI/FWI metrics and cognitive scores to understand the relationship between brain microstructure and cognitive function. Methods: Twelve healthy controls (HCs), ten individuals with SMC, and eleven CI individuals (MCI or AD) were enrolled in this study. All participants underwent MRI 3T scan and the BNI Screen (BNIS) for Higher Cerebral Functions. Results: The mean kurtosis tensor and anisotropy of the kurtosis tensor showed significant differences across the three groups, indicating altered white matter microstructure in CI and SMC individuals. The free water volume fraction (f ) also revealed group differences, suggesting changes in extracellular water content. Notably, these metrics effectively discriminated between the CI and HC/SMC groups. Additionally, correlations between imaging metrics and BNIS scores were found for CI and SMC groups. Conclusions: These imaging metrics hold promise in discriminating between individuals with CI and SMC. The observed differences indicate their potential as sensitive and specific biomarkers for early detection and differentiation of cognitive decline. Show more

Keywords: Alzheimer’s disease, BNI Screen for Higher Cerebral Functions, dementia, diffusion kurtosis imaging, free-water imaging, subjective memory complaints

DOI: 10.3233/JAD-230952

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 863-884, 2024

Authors: Zhai, Modi | Zhang, Yu | Yan, Dongxue | Wang, Yuzhen | Li, Wenzhong | Sun, Jie

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is an increasing public health concern with the aging of the global population. Understanding the genetic correlation and potential causal relationships between blood metabolites and AD may provide important insights into the metabolic dysregulation underlying this neurodegenerative disorder. Objective: The aim of this study was to investigate the causal relationship between blood metabolites and AD using Mendelian randomization (MR) analysis. Methods: Association data were obtained from three large-scale genome-wide association studies of 486 blood metabolites (N  = 7,824), AD (71,880 cases and 383,378 controls), early-onset AD (N  = 303,760), and late-onset …AD (N  = 307,112). Causal associations between blood metabolites and AD were assessed using inverse variance weighting (IVW), MR-Egger, and weighted median methods. Bidirectional two-sample MR analysis was used to identify causal blood metabolites. MR-PRESSO, MR-Egger, and Cochran-Q were used to quantify instrumental variable heterogeneity and horizontal pleiotropy. Results: Using MR and sensitivity analysis, we identified 40 blood metabolites with potential causal associations with AD. After applying false discovery rate (FDR) correction, two metabolites, gamma-glutamylphenylalanine (OR = 1.15, 95% CI: 1.06–1.24, p  = 3.88×10–4 , q  = 0.09) and X-11317 (OR = 1.16, 95% CI: 1.08–1.26, p  = 1.14×10–4 , q  = 0.05), retained significant associations with AD. Reverse MR analysis indicated no significant causal effect of AD on blood metabolites. No significant instrumental variable heterogeneity or horizontal pleiotropy was found. Conclusions: This two-sample MR study provides compelling evidence for a potential causal relationship between blood metabolic dysregulation and susceptibility to AD. Further investigation of the biological relevance of the identified metabolites to AD and additional supporting evidence is warranted. Show more

Keywords: Alzheimer’s disease, blood metabolites, causal inference, Mendelian randomization

DOI: 10.3233/JAD-230985

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 885-896, 2024

Authors: Luo, Xiao | Hong, Hui | Li, Kaicheng | Zeng, Qingze | Liu, Xiaocao | Hong, Luwei | Li, Jixuan | Zhang, Xinyi | Zhong, Siyan | Xu, Xiaopei | Chen, Yanxing | Zhang, Minming | Huang, Peiyu

Article Type: Research Article

Abstract: Background: Financial capacity is vital for the elderly, who possess a substantial share of global wealth but are vulnerable to financial fraud. Objective: We explored the link between small vessel disease (SVD) and financial capacity in cognitively unimpaired (CU) older adults via both cross-sectional and longitudinal analyses. Methods: 414 CU participants underwent MRI and completed the Financial Capacity Instrument-Short Form (FCI-SF). Subsequent longitudinal FCI-SF data were obtained from 104, 240, and 141 participants at one, two, and four years, respectively. SVD imaging markers, encompassing white matter hyperintensities (WMH), cerebral microbleeds (CMB), and lacune …were evaluated. We used linear regression analyses to cross-sectionally explore the association between FCI-SF and SVD severity, and linear mixed models to assess how baseline SVD severity impacted longitudinal FCI-SF change. The false discovery rate method was used to adjust multiple comparisons. Results: Cross-sectional analysis revealed a significant association between baseline WMH and Bank Statement (BANK, β=-0.194), as well as between lacune number and Financial Conceptual Knowledge (FC, β= –0.171). These associations were stronger in APOE ɛ4 carriers, with β= –0.282 for WMH and BANK, and β= –0.366 for lacune number and FC. Longitudinally, higher baseline SVD total score was associated with severe FCI-SF total score decrease (β= –0.335). Additionally, baseline WMH burden predicted future decreases in Single Checkbook/Register Task (SNG, β= –0.137) and FC (β= –0.052). Notably, the association between baseline WMH and SNG changes was amplified in APOE ɛ4 carriers (β= –0.187). Conclusions: Severe SVD was associated with worse FCI-SF and could predict the decline of financial capacity in CU older adults. Show more

Keywords: Alzheimer’s disease, cerebral microbleed, cognitive decline, financial capacity, longitudinal study, positron emission tomography, small vessel disease, white matter hyperintensities

DOI: 10.3233/JAD-231089

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 897-906, 2024