Journal of Alzheimer's Disease - Volume 88, issue 2

Article Type: Announcement

DOI: 10.3233/JAD-229009

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 387-388, 2022

Authors: Hao, Jing | Guo, Yanping | Guo, Keke | Yang, Qingcheng

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease of unknown pathological origin. The clinical diagnosis of AD is time-consuming and needs to a combination of clinical evaluation, psychological testing, and imaging assessments. Biomarkers may be good indicators for the clinical diagnosis of AD; hence, it is important to identify suitable biomarkers for the diagnosis and treatment of AD. Peripheral inflammatory biomarkers have been the focus of research in recent years. This review summarizes the role of inflammatory biomarkers in the disease course of AD.

Keywords: Alzheimer’s disease, biomarkers, inflammatory, neurodegeneration

DOI: 10.3233/JAD-215422

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 389-398, 2022

Authors: Baazaoui, Narjes | Iqbal, Khalid

Article Type: Review Article

Abstract: COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as …Alzheimer’s disease, Parkinson’s disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection. Show more

Keywords: ACE receptors, Alzheimer’s disease, dementia, Parkinson’s disease, prion-like proteins, SARS-CoV-2

DOI: 10.3233/JAD-220105

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 399-416, 2022

Authors: Stephan, Blossom C.M. | Tang, Eugene Y.H. | Pakpahan, Eduwin | Biswas, Bijetri | Gupta, Alisha | Fairley, Andrea | Bosco, Alessandro | Richardson, Connor D. | Robinson, Louise | Siervo, Mario

Article Type: Systematic Review

Abstract: Background: Although numerous studies have reported a decrease in dementia risk in the last two decades, it is unclear whether dementia-free cognitive function is also changing across generations. Objective: The objective was to systematically evaluate the published data on generational differences in cognitive function in the older population. Methods: Searches were performed on PubMed, Embase, and PsychInfo for articles published in English before 28 June 2021. Included studies were from population-based samples that reported generational differences in cognition in individuals without dementia, aged ≥60 years. Results: 28,101 studies were identified and 15 selected covering …the period from 1971 to 2015: including studies from China, Europe, and the USA. The results show generally consistent findings of improvements or stability in dementia free cognitive function in later versus earlier born generations, but not for all cognitive domains. Prevalence of mild cognitive impairment and cognitive impairment no dementia has remained stable in the USA, UK, and China over the last two decades. Results: Prevalence of vascular related mild cognitive impairment has increased in China. Improvements in cognition may only partially be explained by increased educational attainment across generations. Conclusion: This review provides evidence for generational effects in dementia-free cognitive function, predominately stability or improvements in performance, in later compared to earlier born individuals across different world regions. There is an urgent need to determine the factors driving such changes and whether they are being experienced in all world regions, particularly low- and middle-income countries where the burden of cognitive impairment is greatest and rising. Show more

Keywords: Cognitive function, epidemiology, generational effects, secular trends

DOI: 10.3233/JAD-220162

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 417-428, 2022

Authors: Serwer, Philip | Wright, Elena T. | Hunter, Barbara

Article Type: Research Article

Abstract: Protein amyloid-β (Aβ) oligomers with β-sheet-like backbone (β-structured) form extracellular amyloid plaques associated with Alzheimer’s disease (AD). However, the relationship to AD is not known. Some investigations suggest that the toxic Aβ component has α -sheet-like backbone (α -structured) subsequently detoxified by intracellular α -to-β conversion before plaque formation. Our objective is to compare this latter hypothesis with observations made by electron microscopy of thin sections of AD-cerebral cortex. We observe irregular, 200–2,000 nm, intracellular, lipofuscin-like inclusions. Some are light-staining and smooth. Others are dark-staining and made granular by fibers that are usually overlapping and are sometimes individually seen. Aspects unusual …for lipofuscin include 1) dark and light inclusions interlocking as though previously one inclusion, 2) dark inclusion-contained 2.6 nm thick sub-fibers that are bent as though α -structured, and 3) presence of inclusions in lysosomes and apparent transfer of dark inclusion material to damaged, nearby lysosomal membranes. These data suggest the following additions to α -structure-based hypotheses: 1) Lipofuscin-associated, α -structured protein toxicity to lysosomal membranes is in the chain of AD causation; 2) α -to-β detoxification of α -structured protein occurs in lipofuscin and causes dark-to-light transition that, when incomplete, is the origin of cell-to-cell transmission essential for development of AD. Show more

Keywords: Alpha-sheet, amyloid, electron microscopy, lipofuscin, molecular model, thin sectioning

DOI: 10.3233/JAD-220311

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 429-438, 2022

Authors: Tsai, Yi-Liang | Yen, Chieh-Tsung | Wang, Yuh-Feng

Article Type: Research Article

Abstract: The typical symptoms of patients with Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and tau hyperphosphorylation. However, recent studies show that these symptoms are not the cause of the disease but are generated after the pathogenesis. Compared with other types of dementia, AD has the obvious features of pineal gland calcification and decreased melatonin production. The pineal gland is mainly composed of pinealocytes that release melatonin and astrocytes. Astrocytes function to maintain a balanced concentration of calcium ions, provide nerve cell nutrients, and migrate nutrients in vivo . Calcium ions are among the most important neurotransmitters. Once triggered, a calcium …wave can be formed between astrocytes to activate other astrocytes to transmit information. Most calcium is stored in the skeleton. Bone tissue is composed mainly of osteocytes, osteoblasts, and osteoclasts. Of these, osteocyte is a kind of astrocyte which regulates the activity of osteoclasts and osteoblasts. The pineal gland is composed mainly of astrocytes; osteocytes are also a kind of astrocyte. Therefore, we conclude that when astrocytes are gradually disabled, calcium may be lost from the bones, prompting osteoporosis. The calcium ions then released into the blood may accumulate and cause ectopic calcification in the pineal gland, which promotes the occurrence of AD. Finally, this study used aspects of drugs and hormones (bone and calcium metabolism hormones and melatonin) to infer the hypothesis, which proposes that astrocyte dysregulation promotes the long-term imbalance of calcium ions in vivo and leads to osteoporosis and AD. Show more

Keywords: Alzheimer’s disease, astrocyte, bone, calcium ion, osteoporosis

DOI: 10.3233/JAD-220218

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 439-445, 2022

Authors: Riphagen, Joost M. | van Hooren, Roy W.E. | Kenis, Gunter | Verhey, Frans R.J. | Jacobs, Heidi I.L.

Article Type: Short Communication

Abstract: The brain-derived neurotropic growth factor (BDNF ) gene has been linked to dementia, inflammation, and Apolipoprotein E (APOE ) ɛ4 status. We used cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and phosphorylated tau (p-tau) to investigate associations with BDNF polymorphisms and modifications by APOE ɛ4 or inflammation in a memory clinic population (n  = 114; subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease). We found distinct pathways to Alzheimer’s disease pathology: Val-Met displayed lower CSF-Aβ42 in APOE ɛ4+ carriers, independent of p-tau, while Val-Val displayed greater p-tau at higher IL-6 and sub-threshold Aβ42 . This may contribute to …resolving some inconsistencies in the BDNF literature and provide possible inroads to specific Aβ and tau interventions depending on BDNF polymorphism. Show more

Keywords: Alzheimer’s disease, amyloid-β, brain-derived neurotropic growth factor, inflammation, interleukin 6, phosphorylated tau

DOI: 10.3233/JAD-215353

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 447-453, 2022

Authors: Høilund-Carlsen, Poul F. | Revheim, Mona-Elisabeth | Alavi, Abass

Article Type: Article Commentary

Abstract: Three decades with the amyloid hypothesis, nearly two with amyloid-PET imaging, and one with testing of anti-amyloid therapy have not yielded benefits to patients with Alzheimer’s disease (AD). It is time to focus on more promising options, e.g., infection, low dose radiation, and atherosclerosis. The relevance of the latter in managing AD has fluctuated from being significant to insignificant. Current methodologies for detecting cerebral atherosclerosis reflect advanced changes in only major arteries. In contrast, 18 F-sodium fluoride PET imaging assessing early-stage cerebral atherosclerosis regionally or in the entire vascular bed may provide new insight in this age-related process in dementia.

Keywords: Alzheimer’s disease, amyloid-β, dementia, 18F-sodium fluoride PET, NaF

DOI: 10.3233/JAD-220190

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 455-458, 2022

Authors: Wanigatunga, Amal A. | Liu, Fangyu | Wang, Hang | Urbanek, Jacek K. | An, Yang | Spira, Adam P. | Dougherty, Ryan J. | Tian, Qu | Moghekar, Abhay | Ferrucci, Luigi | Simonsick, Eleanor M. | Resnick, Susan M. | Schrack, Jennifer A.

Article Type: Research Article

Abstract: Background: Gradual disengagement from daily physical activity (PA) could signal present or emerging mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Objective: This study examined whether accelerometry-derived patterns of everyday movement differ by cognitive diagnosis in participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods: Activity patterns, overall and by time-of-day, were cross-sectionally compared between participants with adjudicated normal cognition (n  = 549) and MCI/AD diagnoses (n  = 36; 5 participants [14%] living with AD) using covariate-adjusted regression models. Results: Compared to those with normal cognition, those with MCI/AD had 2.1% higher activity fragmentation (SE = 1.0%, …p  = 0.036) but similar mean total activity counts/day (p  = 0.075) and minutes/day spent active (p  = 0.174). Time-of-day analyses show MCI/AD participants had lower activity counts and minutes spent active during waking hours (6:00 am–5:59 pm; p  < 0.01 for all). Also, they had lower activity fragmentation from 12:00–5:59 am (p  < 0.001), but higher fragmentation from 12:00–5:59 pm (p  = 0.026). Conclusion: Differences in the timing and patterns of physical activity throughout the day linked to MCI/AD diagnoses warrant further investigation into potential clinical utility. Show more

Keywords: Accelerometry, Alzheimer’s disease, diurnal patterns, mild cognitive impairment

DOI: 10.3233/JAD-215544

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 459-469, 2022

Authors: Frame, Gabrielle | Schuller, Adam | Smith, Matthew A. | Crish, Samuel D. | Dengler-Crish, Christine M.

Article Type: Research Article

Abstract: Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cells (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice …across disease stages. Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function. Show more

Keywords: Amyloidosis, dementia, pattern electroretinogram, preclinical, presymptomatic, retina, vision

DOI: 10.3233/JAD-220016

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 471-492, 2022