Journal of Alzheimer's Disease - Volume 101, issue 3

Authors: Butler, Tracy | Tey, Sin-Ruow | Galvin, James E. | Perry, George | Bowen, Richard L. | Atwood, Craig S.

Article Type: Review Article

Abstract: The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer’s disease (AD), the major form of dementia in our society. In particular, the …elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , andropause, cell cycle, cognition, endocrine dyscrasia, 17β-estradiol, GnRH analogues, gonadotropins, hypothalamic-pituitary-gonadal axis, menopause, neurodegeneration, neuropathology, progesterone, tau

DOI: 10.3233/JAD-240334

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 705-713, 2024

Authors: Connolly, Evie Margaret | Mc Ardle, Ríona | Bimpong, Kweku Andrew Ampadu | Slight, Sarah

Article Type: Systematic Review

Abstract: Background: Dementia is a major cause of disability and dependency globally. Mild cognitive impairment (MCI) is considered an early indicator of developing dementia. There are growing efforts to detect and diagnose MCI earlier; consequently, we need to understand the perspectives of individuals and carers regarding the implications of an MCI diagnosis. Objective: To systematically review qualitative literature to understand the impact of a MCI diagnosis on both the individual and their carers, focusing on wellbeing, everyday behaviors, and healthcare utilization. Methods: Key search terms were input into five databases. Studies were included if they were peer-reviewed …qualitative research published in English that obtained perspectives of community-dwellers with MCI or carers and focused on either their wellbeing, everyday behaviors and/or healthcare utilization. The protocol was pre-registered on PROSPERO (CRD42021291995). Data was synthesized narratively. Results: Key findings from 15 eligible articles highlighted the negative impact of an MCI diagnosis on the wellbeing of both individuals and carers, due to stigma and limited understanding regarding diagnosis/prognosis. Changes in everyday behavior varied, particularly regarding motivation to engage with physical activity, hobbies and social opportunities. Both individuals and carers were sometimes dissatisfied with healthcare services; ineffective communication during clinical consolations highlighted as a reason for lack of trust in clinicians. Conclusions: Results indicate that an MCI diagnosis impacts both people with MCI and their carers across key facets of life. There is a critical need to effectively communicate the diagnosis and prognosis of MCI to support wellbeing and everyday activities and ensure trust in healthcare services. Show more

Keywords: Alzheimer’s disease, caregivers, cognitive dysfunction, early diagnosis, mild cognitive impairment, quality of life, systematic review

DOI: 10.3233/JAD-231466

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 715-729, 2024

Authors: Cardoso, Remy | Teunissen, Charlotte E. | Oliveira, Catarina Resende

Article Type: Article Commentary

Abstract: Biomarkers that accurately identify mild cognitive impairment (MCI) are of greater importance for Alzheimer’s disease (AD) management and treatment. On the other hand, blood-based biomarkers are not only more practical but also less invasive than the common cerebrospinal fluid biomarkers. In their report in the Journal of Alzheimer ’s Disease , Wang and collaborators identified 67 upregulated and 220 downregulated long noncoding RNAs (lncRNAs). They further demonstrated that 4 of these lncRNAs could discriminate MCI from cognitively healthy individuals. Apart from their significance as potential biomarkers for MCI diagnosis, these lncRNAs can offer additional information on the cellular mechanisms of …AD pathology. Show more

Keywords: Alzheimer’s disease, biomarkers, lncRNA, mild cognitive impairment, plasma

DOI: 10.3233/JAD-240724

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 731-734, 2024

Authors: Maccioni, Ricardo Benjamín | Prieto, Raul

Article Type: Editorial

DOI: 10.3233/JAD-240864

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 735-736, 2024

Authors: Huynh, Andrew Liem Hieu | Wang, Yihan | Ma, Liwei | Low, Yi Ling Clare | Chen, Weisi | Fowler, Christopher | Tan, Edwin C.K. | Masters, Colin L. | Jin, Liang | Pan, Yijun

Article Type: Research Article

Abstract: Background: Observational Alzheimer’s disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied. Objective: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia. Methods: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of …AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities. Results: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation – AIBL 79±7 years, PBS/census 81±7, p  < 0.001, dementia/census 83±8, p  < 0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, p  = 0.020, dementia/census 29%, p  < 0.001; CALD – AIBL 3%, PBS/census 20%, p  < 0.001, dementia/census 22%, p  < 0.001). Conclusions: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD. Show more

Keywords: Alzheimer’s disease, Australian Biomarkers Imaging and Lifestyle study, Australian census, culturally and linguistically diverse, dementia, generalizability

DOI: 10.3233/JAD-240241

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 737-749, 2024

Authors: Kitagawa, Kazuo | Toi, Sono | Hosoya, Megumi | Seki, Misa | Yamagishi, Sae | Hoshino, Takao | Yoshizawa, Hiroshi

Article Type: Research Article

Abstract: Background: Total small vessel disease (SVD) score is used to measure the burden of SVD. Objective: This study aimed to clarify the predictive value of total SVD score for incident dementia and functional outcomes in independent outpatients with vascular risk factors. Methods: We derived data from a Japanese cohort in which patients underwent magnetic resonance imaging and cognitive examinations. They were followed up until March 2023. The primary outcomes was dementia. Secondary outcome was functional outcomes. We measured a modified Rankin scale (mRS) score at the last visit and defined poor functional outcomes as mRS score …≥3. Results: After excluding those with a mRS score ≥2, Mini-Mental State Examination score in Japanese version < 24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, dementia occurred in 31 patients. In multivariate analysis, the score 4 group showed a significantly higher risk of incident dementia than the score 0–3 groups (adjusted hazard ratio, 6.25; 95% CI, 1.83–21.40, p  = 0.003). The total SVD score was also independently related to poor functional outcome. Conclusions: The total SVD score of 4, and ≥1 could predict dementia and poor functional outcomes, respectively. Our results suggest intensive management of patients with SVD to prevent dementia and to maintain independent activities of daily living. Show more

Keywords: Alzheimer’s disease, dementia, functional outcome, small vessel disease score

DOI: 10.3233/JAD-240166

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 751-760, 2024

Authors: Wang, Jing | Zhang, Gong | Lai, Hao | Li, Zengbin | Shen, Mingwang | Li, Chao | Kwan, Patrick | O’Brien, Terence J. | Wu, Ting | Yang, Siyu | Zhang, Xueli | Zhang, Lei

Article Type: Research Article

Abstract: Background: Cognitive impairment is a clinical manifestation that occurs in the course of dementia like Alzheimer’s disease. The association between cognitive impairment and gut microbiota is unclear. Objective: We aimed to identify gut microbiota characteristics and key gut microbiota biomarkers associated with cognitive impairment in a relatively large cohort of older adults in China. Methods: A total of 229 adults aged ≥60 years from Shenzhen, China were recruited into this cross-sectional study. Participants were divided into cognitive impairment (CI) and no cognitive impairment (NCI) groups according to the results of the Mini-Mental State Examination. Diversity analysis …and network analysis were used to characterize the gut microbiota between the two groups. The linear discriminant analysis effect size method and machine learning approaches were sequentially performed to identify gut microbiota biomarkers. The relationship between biomarkers and lifestyle factors was explored using Transformation-based redundancy analysis (tb-RDA). Results: A total of 74 CI participants and 131 NCI participants were included in the analysis. The CI group demonstrated lower α -diversity compared to the NCI group (Shannon: 2.798 versus 3.152, p  < 0.001). The density of the gut microbiota interaction network was lower in the CI group (0.074) compared to the NCI group (0.081). Megamonas, Blautia, Pseudomonas, Stenotrophomonas, and Veillonella were key biomarkers for CI. The tb-RDA revealed that increased fruit intake and exercise contribute to a higher abundance of Megamonas, Blautia, and Veillonella. Conclusions: We identified a significantly reduced abundance of certain beneficial gut microbiota in older Chinese adults with cognitive impairment. Show more

Keywords: Alzheimer’s disease, biomarker, cognitive impairment, gut microbiota, lifestyle factors, older adults, Random forest

DOI: 10.3233/JAD-240597

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 761-771, 2024

Authors: Ururahy, Raul dos Reis | do Val, Marina Scott | Ciciliati, Aline Maria Macagnan | Leite, Renata Elaine Paraizo | Paes, Vitor Ribeiro | Rodrigues, Roberta Diehl | Grinberg, Lea Tenenholz | Pasqualucci, Carlos Augusto | Jacob Filho, Wilson | Suemoto, Claudia Kimie

Article Type: Research Article

Abstract: Background: The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy studies are key to detecting preclinical neurodegenerative and cerebrovascular diseases that could be underlying weight changes. Objective: We investigated the association between dementia-related brain lesions and BMI and evaluated whether the cognitive function was a mediator of this association. Methods: In 1,170 participants, sociodemographic data, clinical history, and …cognitive post-mortem evaluation were assessed with an informant. Neuropathological evaluation was performed in all cases. Linear regression models were used to investigate the association between neuropathological lesions (exposure variable) and BMI (outcome) adjusted for demographic, clinical, and cognitive variables in the whole sample, and in only those with normal cognition. Corrections for multiple comparisons were performed. In addition, a mediation analysis was performed to investigate the direct and indirect effects of cognitive abilities on the association between neuropathology and BMI. Results: Individuals with lower BMI had a higher burden of neuropathological lesions and poorer cognitive abilities. Only neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI, while other neurodegenerative and cerebrovascular lesions were not. NFT were indirectly associated with BMI through cognitive abilities, and also directly, even in participants with normal cognition. Conclusions: Neurofibrillary tangles were directly associated with low BMI even in individuals with preclinical Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, autopsy, body mass index, dementia, mediation, neuropathology

DOI: 10.3233/JAD-231366

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 773-785, 2024

Authors: Oasa, Sho | Chen, Gefei | Schultzberg, Marianne | Terenius, Lars

Article Type: Research Article

Abstract: Background: Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer’s disease (AD). Aggregates are also recognized by microglia, which in early phases may be protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic. Objective: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide. Methods: The effects of the decoys (NSC 69318, …NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed. Results: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40 - and Aβ42 -induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42 , and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys. Conclusions: Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously. Show more

Keywords: Alzheimer’s disease, amyloid-β, cytokine, inflammation, interleukin, tumor necrosis factor

DOI: 10.3233/JAD-231399

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 787-796, 2024

Authors: Kostenko, Anna | Prezzavento, Orazio | de Leo, Gioacchino | D’Arco, David | Gulino, Rosario | Caccamo, Antonella | Leanza, Giampiero

Article Type: Research Article

Abstract: Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist …just prior to the beginning of each behavioral testing session. Results: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer’s disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, neurotransmitters, noradrenaline, sigma-1 agonist

DOI: 10.3233/JAD-240618

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 797-811, 2024