Journal of Alzheimer's Disease - Volume 99, issue 2

Authors: Ohno, Masuo

Article Type: Review Article

Abstract: Given continued failure of BACE1 inhibitor programs at symptomatic and prodromal stages of Alzheimer’s disease (AD), clinical trials need to target the earlier preclinical stage. However, trial design is complex in this population with negative diagnosis of classical hippocampal amnesia on standard memory tests. Besides recent advances in brain imaging, electroencephalogram, and fluid-based biomarkers, new cognitive markers should be established for earlier diagnosis that can optimize recruitment to BACE1 inhibitor trials in presymptomatic AD. Notably, accelerated long-term forgetting (ALF) is emerging as a sensitive cognitive measure that can discriminate between asymptomatic individuals with high risks for developing AD and healthy …controls. ALF is a form of declarative memory impairment characterized by increased forgetting rates over longer delays (days to months) despite normal storage within the standard delays of testing (20–60 min). Therefore, ALF may represent a harbinger of preclinical dementia and the impairment of systems memory consolidation, during which memory traces temporarily stored in the hippocampus become gradually integrated into cortical networks. This review provides an overview of the utility of ALF in a rational design of next-generation BACE1 inhibitor trials in preclinical AD. I explore potential mechanisms underlying ALF and relevant early-stage biomarkers useful for BACE1 inhibitor evaluation, including synaptic protein alterations, astrocytic dysregulation and neuron hyperactivity in the hippocampal-cortical network. Furthermore, given the physiological role of the isoform BACE2 as an AD-suppressor gene, I also discuss the possible association between the poor selectivity of BACE1 inhibitors and their side effects (e.g., cognitive worsening) in prior clinical trials. Show more

Keywords: Accelerated long-term forgetting, Alzheimer’s disease, amyloid-β , BACE1 inhibitors, BACE2, biomarkers, clinical trials, mouse models, preclinical stage, side effects

DOI: 10.3233/JAD-231451

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 431-445, 2024

Authors: Huang, Zhen

Article Type: Review Article

Abstract:  Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aβ and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aβ-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer’s disease (AD). Specifically, I discuss evidence that Aβ and ApoE, two crucial players …in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aβ and inhibiting its assembly into toxic oligomers. Conversely, Aβ oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of “eat-me” signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aβ-orchestrated plasticity, in which sleep is not only induced by Aβ but is also required for Aβ-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research. Show more

Keywords: Alzheimer’s disease, amyloid-β, ApoE, dendritic spine, DNA damage repair, homeostatic plasticity, mGluR5, phosphatidylserine, sleep, synaptic competition

DOI: 10.3233/JAD-240042

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 447-470, 2024

Authors: Zupanic, Eva | Emersic, Andreja | Wimo, Anders | Winblad, Bengt | Speh, Andreja | Kramberger, Milica Gregoric

Article Type: Short Communication

Abstract: Slovenia, situated in Central Europe with a population of 2.1 million, has an estimated 44,278 individuals with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s dementia, rendering them potential candidates for disease-modifying treatment (DMT), such as lecanemab. We identified 114 potential candidates whose real-life expenses for diagnostic process surmount to more than €80,000. Treating all potential candidates nationwide would amount to €1.06 billion, surpassing Slovenia’s entire annual medication expenditure for 2022 (€743 million). The introduction of DMTs and the associated logistics, along with potential complications, will significantly change societal, professional, and patient approach to treatment of Alzheimer’s disease.

Keywords: Alzheimer’s disease, disease modifying treatment, health economics, lecanemab

DOI: 10.3233/JAD-240190

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 471-476, 2024

Authors: Miller, Morgan R. | Lariviere, Lavender | Pagnier, Guillaume J. | Aygar, Sema | Wieckiewicz, Natalia | Maesako, Masato | Bacskai, Brian J. | Kastanenka, Ksenia V.

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease with limited therapeutic strategies. NB-02 is a novel botanical drug that has shown promise as a protective and therapeutic treatment for AD in an APP/PS1 preclinical mouse model. In this paper, we investigate the underlying mechanisms by which NB-02 provides these therapeutic advantages using in vitro neuron-astrocyte co-cultures. Pretreatment with NB-02 prevented pathological calcium elevations in neurons and astrocytes after application of toxic soluble amyloid-β (Aβ) oligomers. NB-02 also prevented cell death associated with the addition of soluble Aβ oligomers suggesting NB-02 is effective at protecting both neurons and astrocytes from …Aβ-mediated damage. Show more

Keywords: Alzheimer’s disease, amyloid, astrocyte, calcium, DA-9803, NB-02, neuron, oligomer, therapy

DOI: 10.3233/JAD-231387

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 477-483, 2024

Authors: de Oliveira, Fabricio Ferreira

Article Type: Article Commentary

Abstract: Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer’s disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer’s disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.

Keywords: Alzheimer’s disease, amyloidosis, APOE , biomarkers, dementia, hypertension, renin-angiotensin system, tau proteins

DOI: 10.3233/JAD-240032

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 485-488, 2024

Authors: Gale, Seth A.

Article Type: Article Commentary

Abstract: As the biological, biomarker-driven framework of Alzheimer’s disease (AD) becomes formalized through revised, consensus clinical criteria, clinicians will confront more and more patients in the earliest, asymptomatic stages of disease. The language and diction used by practitioners to characterize these early patients, whether they are diagnosed with AD, and how their condition is documented in medical and legal records have important implications for both their care and their medical-legal status outside of the health system. Investigation is needed urgently to better understand clinicians’ views and practices regarding early AD, as we adapt to new disease definitions in this unprecedented era …of care. Show more

Keywords: Alzheimer’s disease, asymptomatic Alzheimer’s disease, biomarkers, data privacy, language, legal liability, medical law, nosology, preclinical Alzheimer’s disease

DOI: 10.3233/JAD-240195

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 489-492, 2024

Authors: Gaster, Barak | Suchsland, Monica Zigman | Fitzpatrick, Annette L. | Liao, Joshua M. | Belza, Basia | Hsu, Amy P. | McKiddy, Sarah | Park, Christina | Olivari, Benjamin S. | Singh, Angad P. | Raetz, Jaqueline

Article Type: Research Article

Abstract: Background: The prevalence of Alzheimer’s disease and related disorders (ADRD) is rising. Primary care providers (PCPs) will increasingly be required to play a role in its detection but lack the training to do so. Objective: To develop a model for cognitive evaluation which is feasible in primary care and evaluate its implementation in a large health system. Methods: The Cognition in Primary Care Program consists of web-based training together with integrated tools built into the electronic record. We implemented the program among PCPs at 14 clinics in a large health system. We (1) surveyed PCPs to …assess the impact of training on their confidence to evaluate cognition, (2) measured the number of cognitive assessments they performed, and (3) tracked the number of patients diagnosed with mild cognitive impairment (MCI). Results: Thirty-nine PCPs completed the training which covered how to evaluate cognition. Survey response rate from those PCPs was 74%. Six months after the end of the training, they reported confidence in assessing cognition (mean 4.6 on 5-point scale). Cognitive assessments documented in the health record increased from 0.8 per month before the training to 2.5 in the six months after the training. Patients who were newly diagnosed with MCI increased from 4.2 per month before the training to 6.0 per month in the six months after the training. Conclusions: This model for cognitive evaluation in a large health system was shown to increase cognitive testing and increase diagnoses of MCI. Such improvements are essential for the timely detection of ADRD. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, continuing medical education, dementia, early detection of disease, mild cognitive impairment, primary care

DOI: 10.3233/JAD-231200

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 493-501, 2024

Authors: Xu, Feifan | Xu, Jiajie | Wang, Qiong | Gao, Feng | Fu, Jiayu | Yan, Tingmeng | Dong, Qiang | Su, Ya | Cheng, Xin

Article Type: Research Article

Abstract: Background: Neuroinflammation is a major cause of secondary brain injury in intracerebral hemorrhage (ICH). To date, the prognostic value of YKL-40 (chitinase-3-like-1 protein), a biomarker of neuroinflammation, in cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-ICH) remains undiscovered. Objective: To evaluate the relationships between serum YKL-40 and CAA-ICH recurrence. Methods: Clinical and imaging information of 68 first-onset probable CAA-ICH cases and 95 controls were collected at baseline. Serum YKL-40 was measured by Luminex assay. Cox proportional hazards model was used to analyze the associations between YKL-40 level and CAA-ICH recurrence. Results: Serum YKL-40 level was significantly …higher in CAA-ICH cases than healthy controls (median [interquartile range, IQR], 46.1 [19.8, 93.4] versus 24.4 [13.9, 59.0] ng/mL, p  = 0.004). Higher level of YKL-40 predicted increased risk of CAA-ICH recurrence adjusted for age, ICH volume and enlarged perivascular space score (ePVS) (above versus below 115.5 ng/ml, adjusted hazard ratios 4.721, 95% confidence intervals 1.829–12.189, p  = 0.001) within a median follow-up period of 2.4 years. Adding YKL-40 to a model of only MRI imaging markers including ICH volume and ePVS score improved the discriminatory power (concordance index from 0.707 to 0.772, p  = 0.001) and the reclassification power (net reclassification improvement 28.4%; integrated discrimination index 11.0%). Conclusions: Serum YKL-40 level might be a candidate prognostic biomarker for CAA-ICH recurrence. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, intracerebral hemorrhage, recurrence, YKL-40

DOI: 10.3233/JAD-231125

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 503-511, 2024

Authors: Thunell, Johanna A. | Joyce, Geoffrey F. | Ferido, Patricia M. | Chen, Yi | Guadamuz, Jenny S. | Qato, Dima M. | Zissimopoulos, Julie M.

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) and prescribed central nervous system (CNS) active drugs to treat them are prevalent among persons living with Alzheimer’s disease and related dementias (PLWD) and lead to negative outcomes for PLWD and their caregivers. Yet, little is known about racial/ethnic disparities in diagnosis and use of drugs to treat BPSD. Objective: Quantify racial/ethnic disparities in BPSD diagnoses and CNS-active drug use among community-dwelling PLWD. Methods: We used a retrospective cohort of community-dwelling Medicare Fee-for-Service beneficiaries with dementia, continuously enrolled in Parts A, B and D, 2017–2019. Multivariate logistic models …estimated rates of BPSD diagnosis and, conditional on diagnosis, CNS-active drug use. Results: Among PLWD, 67.1% had diagnoses of an affective, psychosis or hyperactivity symptom. White (68.3%) and Hispanic (63.9%) PLWD were most likely, Blacks (56.6%) and Asians (52.7%) least likely, to have diagnoses. Among PLWD with BPSD diagnoses, 78.6% took a CNS-active drug. Use was highest among whites (79.3%) and Hispanics (76.2%) and lowest among Blacks (70.8%) and Asians (69.3%). Racial/ethnic differences in affective disorders were pronounced, 56.8% of white PLWD diagnosed; Asians had the lowest rates (37.8%). Similar differences were found in use of antidepressants. Conclusions: BPSD diagnoses and CNS-active drug use were common in our study. Lower rates of BPSD diagnoses in non-white compared to white populations may indicate underdiagnosis in clinical settings of treatable conditions. Clinicians’ review of prescriptions in this population to reduce poor outcomes is important as is informing care partners on the risks/benefits of using CNS-active drugs. Show more

Keywords: Alzheimer’s disease, antidepressants, antipsychotics, behavioral and psychological symptoms of dementia, dementia

DOI: 10.3233/JAD-231266

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 513-523, 2024

Authors: Liu, Mengqing | Ma, Nenghong | Yang, Xiao | Sun, Miao | Li, Xiaowen | Liu, Yuhui | Chang, Qing | Hei, Changchun

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. Objective: This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-β (Aβ) metabolism in vitro . Methods: …In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aβ. Results: Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro . Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aβ. Conclusions: GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, glucagon-like peptide-1 (GLP-1), tau protein phosphorylation

DOI: 10.3233/JAD-240001

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 525-533, 2024