Journal of Alzheimer's Disease - Volume 94, issue 4

Authors: Xia, Zhao-Di | Ma, Ruo-Xin | Wen, Jin-Feng | Zhai, Yu-Fei | Wang, Yu-Qi | Wang, Feng-Yun | Liu, Dan | Zhao, Xiao-Long | Sun, Bao | Jia, Pu | Zheng, Xiao-Hui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the most common cause of dementia, is a chronic neurodegenerative disease induced by multiple factors. The high incidence and the aging of the global population make it a growing global health concern with huge implications for individuals and society. The clinical manifestations are progressive cognitive dysfunction and lack of behavioral ability, which not only seriously affect the health and quality of life of the elderly, but also bring a heavy burden to the family and society. Unfortunately, almost all the drugs targeting the classical pathogenesis have not achieved satisfactory clinical effects in the past two decades. Therefore, …the present review provides more novel ideas on the complex pathophysiological mechanisms of AD, including classical pathogenesis and a variety of possible pathogenesis that have been proposed in recent years. It will be helpful to find out the key target and the effect pathway of potential drugs and mechanisms for the prevention and treatment of AD. In addition, the common animal models in AD research are outlined and we examine their prospect for the future. Finally, Phase I, II, III, and IV randomized clinical trials or on the market of drugs for AD treatment were searched in online databases (Drug Bank Online 5.0, the U.S. National Library of Medicine, and Alzforum). Therefore, this review may also provide useful information in the research and development of new AD-based drugs. Show more

Keywords: Alzheimer’s disease, animal model, drug discovery, neurodegenerative, pathogenesis

DOI: 10.3233/JAD-230326

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1265-1301, 2023

Authors: Gibson, Madeline | Yiallourou, Stephanie | Pase, Matthew P.

Article Type: Review Article

Abstract: Midlife hypertension increases risk for dementia. Around one third of adults have diagnosed hypertension; however, many adults are undiagnosed, or remain hypertensive despite diagnosis or treatment. Since blood pressure (BP) follows a circadian rhythm, ambulatory BP monitoring allows for the assessment of BP over a 24-hour period and provides an important tool for improving the diagnosis and management of hypertension. The measurement of 24-hour BP profiles, especially nocturnal BP, demonstrate better predictive ability for cardiovascular disease and mortality than office measurement. However, few studies have examined 24-hour BP profiles with respect to dementia risk. This is an important topic since …improvements in BP management could facilitate the primary prevention of vascular cognitive impairment and dementia. Therefore, this review discusses the evidence linking BP to dementia, with a focus on whether the implementation of 24-hour BP measurements can improve risk prediction and prevention strategies. Pathways linking nocturnal BP to dementia are also discussed as are risk reduction strategies. Overall, limited research suggests an association between 24-hour BP elevation and poorer cognition, cerebral small vessel disease, and dementia. However, most studies were cross-sectional. Further evidence is needed to substantiate 24-hour BP profiles, over and above office BP, as predictors of vascular cognitive impairment and incident dementia. Show more

Keywords: Alzheimer’s disease, ambulatory monitoring, blood pressure, dementia, hypertension

DOI: 10.3233/JAD-230400

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1303-1322, 2023

Authors: Kudo, Shun | Funayama, Michitaka | Kurose, Shin | Shimizu, Yusuke | Takata, Taketo | Mimura, Masaru

Article Type: Short Communication

Abstract: Although shadowing behavior— when one individual closely follows another— is routinely documented among patients with dementia, its mechanisms have yet to be elucidated. In particular, there have been no detailed descriptions of patients with shadowing behavior. To propose its potential backgrounds, we describe a patient with posterior cortical atrophy who exhibited prominent shadowing behavior. He also experienced severe difficulties recognizing external stimuli, including visuospatial dysfunction, several types of agnosia, difficulties in verbal comprehension, disorientation, and its associated depression. This shadowing behavior may be adaptive relative to his extreme difficulty with recognizing the world around him.

Keywords: Alzheimer’s disease, aphasia, agnosia, posterior cortical atrophy, shadowing, visuospatial dysfunction

DOI: 10.3233/JAD-230257

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1323-1330, 2023

Authors: Baumard, Josselin

Article Type: Article Commentary

Abstract: Shadowing is a person-following behavior, commonly observed in dementia (e.g., Alzheimer’s disease). It may be caused by neuropsychological impairments associated with posterior brain lesions, as Kudo et al. described it in a patient with posterior cortical atrophy and no frontal signs. These authors have suggested that shadowing may arise from the combination of visuospatial impairments, aphasia, apraxia, and prosopagnosia. However, how these symptoms may contribute to shadowing remains unclear. It is suggested that the combination of visuospatial impairments, body representation disorders, and apraxia, may result in complete loss of spatial representations and hence, shadowing behavior.

Keywords: Alzheimer’s disease, apraxia, body image, body representations, body schema, dementia, technical reasoning, tool use, visuospatial dysfunction

DOI: 10.3233/JAD-230731

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1331-1333, 2023

Authors: Beba, Alican | Peterson, Stephanie M. | Brennan, Peter C. | O’Byrne, Jamie | Machulda, Mary M. | Jannetto, Paul J. | Vemuri, Prashanthi | Lewallen, David G. | Maradit Kremers, Hilal | Vassilaki, Maria

Article Type: Short Communication

Abstract: Total joint arthroplasty (TJA) implants are composed of metals, ceramics, and/or polyethylene. Studies suggest that the debris released from metal implants may possess neurotoxic properties with reports of neuropsychiatric symptoms and memory deficits, which could be relevant to Alzheimer’s disease and related dementias. This exploratory study examined the cross-sectional correlation of blood metal concentrations with cognitive performance and neuroimaging findings in a convenience sample of 113 TJA patients with history of elevated blood metal concentrations of either titanium, cobalt and/or chromium. Associations with neuroimaging measures were observed but not with cognitive scores. Larger studies with longitudinal follow-up are warranted.

Keywords: Alzheimer’s disease, blood metal concentrations, chromium, cobalt, cognitive function, cognitive scores, magnetic resonance imaging, titanium, total joint arthroplasty

DOI: 10.3233/JAD-221182

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1335-1342, 2023

Authors: Miguel, Laetitia | Gervais, Juliette | Nicolas, Gaël | Lecourtois, Magalie

Article Type: Short Communication

Abstract: SORL1 loss of function is associated with Alzheimer’s disease (AD) risk through increased Aβ peptide secretion. We expressed 10 maturation-defective rare missense SORL1 variants in HEK cells and showed that decreasing growing temperature led to a significant increase in the maturation of the encoded protein SorLA for 6/10. In edited hiPSC carrying two of these variants, maturation of the protein was restored partially by decreasing the culture temperature and was associated with concomitant decrease in Aβ secretion. Correcting SorLA maturation in the context of maturation-defective missense variants could thus be a relevant strategy to improve SorLA protective function …against AD. Show more

Keywords: Alzheimer’s disease, amyloid, CRISPR-Cas Systems, induced pluripotent stem cells, missense mutations, SORL1, temperature

DOI: 10.3233/JAD-230211

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1343-1349, 2023

Authors: Vítor, Joana | Saracino, Dario | Ströer, Sebastian | Camuzat, Agnès | Dorgham, Karim | Clot, Fabienne | Martin-Hardy, Philippe | Pasquier, Florence | Le Ber, Isabelle

Article Type: Short Communication

Abstract: GRN mutations, causing frontotemporal dementia, can be associated with atypical white matter hyperintensities (WMH). We hypothesized that the presence of WMH may impact neurofilament light chain (NfL) levels, markers of neuroaxonal damage. We analyzed plasma NfL in 20 GRN patients and studied their association to visually-scored WMH burden. The 12 patients displaying atypical WMH had significantly higher NfL levels (98.4±34.9 pg/mL) than those without WMH (47.2±29.4 pg/mL, p  = 0.003), independently from age, disease duration and Fazekas-Schmidt grade. NfL correlated with WMH burden (rho = 0.55, p  = 0.01). This study prompts considering WMH burden as a variability factor when evaluating NfL …levels in GRN patients. Show more

Keywords: Amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobar degeneration, GRN , leukopathy, neurofilament light chain, progranulin, white matter hyperintensities

DOI: 10.3233/JAD-230315

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1351-1360, 2023

Authors: Lansdell, Theresa A. | Xu, Hui | Galligan, James J. | Dorrance, Anne M.

Article Type: Research Article

Abstract: Background: Nearly two-thirds of patients diagnosed with Alzheimer’s disease (AD) are female. In addition, female patients with AD have more significant cognitive impairment than males at the same disease stage. This disparity suggests there are sex differences in AD progression. While females appear to be more affected by AD, most published behavioral studies utilize male mice. In humans, there is an association between antecedent attention-deficit/hyperactivity disorder and increased risk of dementia. Functional connectivity studies indicate that dysfunctional cortico-striatal networks contribute to hyperactivity in attention deficit hyperactivity disorder. Higher plaque density in the striatum accurately predicts the presence of clinical AD …pathology. In addition, there is a link between AD-related memory dysfunction and dysfunctional dopamine signaling. Objective: With the need to consider sex as a biological variable, we investigated the influence of sex on striatal plaque burden, dopaminergic signaling, and behavior in prodromal 5XFAD mice. Methods: Six-month-old male and female 5XFAD and C57BL/6J mice were evaluated for striatal amyloid plaque burden, locomotive behavior, and changes in dopaminergic machinery in the striatum. Results: 5XFAD female mice had a higher striatal amyloid plaque burden than male 5XFAD mice. 5XFAD females, but not males, were hyperactive. Hyperactivity in female 5XFAD mice was associated with increased striatal plaque burden and changes in dopamine signaling in the dorsal striatum. Conclusion: Our results indicate that the progression of amyloidosis involves the striatum in females to a greater extent than in males. These studies have significant implications for using male-only cohorts in the study of AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-beta, dopamine neurotransmission, hyperlocomotion, 5XFAD

DOI: 10.3233/JAD-220905

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1361-1375, 2023

Authors: La Barbera, Livia | D’Amelio, Marcello

Article Type: Article Commentary

Abstract: In the last years, many clinical studies highlighted sex-specific differences in the pathophysiology of Alzheimer’s disease (AD). The recent paper published in the Journal of Alzheimer’s Disease shows the influence of sex on amyloid-β plaque deposition, behavior, and dopaminergic signaling in the 5xFAD mouse model of AD, with worse alterations in female mice. This commentary focuses on the importance of recognizing sex as a key variable to consider for a more precise clinical practice, with the challenge to develop sex-specific therapeutic interventions in neurodegenerative diseases such as AD.

Keywords: Alzheimer’s disease, amyloid-β , dopamine, 5xFAD

DOI: 10.3233/JAD-230681

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1377-1380, 2023

Authors: Merten, Natascha | Pinto, A. Alex | Paulsen, Adam J. | Chen, Yanjun | Engelman, Corinne D. | Hancock, Laura M. | Johnson, Sterling C. | Schubert, Carla R.

Article Type: Research Article

Abstract: Background: Pathological biomarkers of Alzheimer’s disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life. Objective: We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aβ)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)). Methods: In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age …49 years, standard deviation (SD) = 9; 54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes. Results: We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aβ42 /Aβ40 . TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels. Conclusion: Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, dementia, education, healthy lifestyle, inflammation, neurofilament light protein, tau protein, vascular diseases

DOI: 10.3233/JAD-221287

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1381-1395, 2023