Journal of Alzheimer's Disease - Volume 67, issue 1

Authors: Delgado, Carolina | Vergara, Rodrigo C. | Martínez, Melissa | Musa, Gada | Henríquez, Fernando | Slachevsky, Andrea

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms and cognitive impairment are independent contributors of functional impairment in activities of daily living (ADL) in Alzheimer’s disease (AD) patients. ADL could be divided according to its complexity in three subdomains: basic (BADL), instrumental (IADL), and advanced (a-ADL). Objective: Studying the cognitive and neuropsychiatric determinants of BADL, IADL, and a-ADL in normal cognitive elders and AD patients. Methods: 144 subjects were graduated using the clinical dementia rating (CDR) in CDR = 0, n  = 52 (control group) and 92 AD patients CDR = 0.5, n  = 34 and CDR = 1&2, n  = 58. They were assessed with measures of cognitive performance …and neuropsychiatric symptoms that were included in regression models to measure the best predictors for each ADL subdomain at every CDR status. Results: AD patients were significantly older, and had significantly more severe functional impairment, neuropsychiatric symptoms, and cognitive decline than controls. The best predictors of functional impairment in controls and CDR = 0.5 AD patients were neuropsychiatric symptoms; in the CDR 0.5 patients, apathy severity was the most important determinant of IADL and a-ADL impairment. While in the CDR 1&2 AD patients, cognitive impairment was the principal determinant of functional impairment, being memory the best determinant of IADL and a-ADL impairment, while global cognition was of BADL impairment. Conclusions: The contribution of cognitive impairment and neuropsychiatric symptoms varied according to the subdomain of ADL, and the CDR. In very mild AD and controls the neuropsychiatric symptoms are the best predictors of more complex ADL impairment, while cognitive impairment is more important at mild to moderate states of AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, apathy, cognitive decline, depression, disability, elderly, memory, neuropsychiatric symptoms

DOI: 10.3233/JAD-180771

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 381-392, 2019

Authors: Hui, Liang | Soliman, Mahmoud L. | Geiger, Nicholas H. | Miller, Nicole M. | Afghah, Zahra | Lakpa, Koffi L. | Chen, Xuesong | Geiger, Jonathan D.

Article Type: Review Article

Abstract: Cholesterol dyshomeostasis has been linked to the pathogenesis of sporadic Alzheimer’s disease (AD). In furthering the understanding of mechanisms by which increased levels of circulating cholesterol augments the risk of developing sporadic AD, others and we have reported that low-density lipoprotein (LDL) enters brain parenchyma by disrupting the blood-brain barrier and that endolysosome de-acidification plays a role in LDL-induced amyloidogenesis in neurons. Here, we tested the hypothesis that endolysosome de-acidification was central to amyloid-β (Aβ) generation and that acidifying endolysosomes protects against LDL-induced increases in Aβ levels in neurons. We demonstrated that LDL, but not HDL, de-acidified endolysosomes and increased …intraneuronal and secreted levels of Aβ. ML-SA1, an agonist of endolysosome-resident TRPML1 channels, acidified endolysosomes, and TRPML1 knockdown attenuated ML-SA1-induced endolysosome acidification. ML-SA1 blocked LDL-induced increases in intraneuronal and secreted levels of Aβ as well as Aβ accumulation in endolysosomes, prevented BACE1 accumulation in endolysosomes, and decreased BACE1 activity levels. LDL downregulated TRPML1 protein levels, and TRPML1 knockdown worsens LDL-induced increases in Aβ. Our findings suggest that endolysosome acidification by activating TRPML1 may represent a protective strategy against sporadic AD. Show more

Keywords: Amyloid-β, BACE1, cholesterol, endolysosome pH, low-density lipoprotein, ML-SA1, neurons, TRPML1

DOI: 10.3233/JAD-180941

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 393-410, 2019

Authors: Malek-Ahmadi, Michael | Chen, Kewei | Perez, Sylvia E. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) is a vascular neuropathology commonly reported in non-cognitively impaired (NCI), mild cognitive impairment, and Alzheimer’s disease (AD) brains. However, it is unknown whether similar findings are present in non-demented elderly subjects. Objective: This study determined the association between CAA and cognition among elderly NCI subjects with varying levels of AD pathology. Methods: Data from 182 cases that received a diagnosis of NCI at their first clinical assessment were obtained from the Rush Religious Orders study (RROS). A cognitive composite score was used to measure cognitive decline. CAA was dichotomized as present …or absent. Cases were also dichotomized according to CERAD neuropathological diagnosis and Braak staging. A mixed model-repeated measures analysis assessed decline on the cognitive composite score. Results: CAA, alone, was not associated with cognitive decline [–0.87 (95% CI: –3.33, 1.58), p  = 0.49]. However, among those with CAA, the High CERAD group had significantly greater decline relative to the Low CERAD group [–4.08 (95% CI: –7.10, –1.06), p  = 0.008]. The High and Low CERAD groups were not significantly different [–1.77 (95% CI: –6.14, 2.60), p  = 0.43] in those without CAA. Composite score decline in the High and Low Braak groups with [–1.32 (95% CI: –4.40, 1.75), p  = 0.40] or without [0.27 (95% CI: –4.01, 4.56), p  = 0.90] CAA was not significantly different. Conclusion: The current data shows that an interaction between CAA and plaque load is associated with greater decline on a cognitive composite score used to test non-cognitively impaired elderly participants in AD prevention trials. Show more

Keywords: Amyloid, dementia, episodic memory, executive function, neuropathology, preclinical, prevention, vascular

DOI: 10.3233/JAD-180765

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 411-422, 2019

Authors: Turchetta, Chiara Stella | Perri, Roberta | Fadda, Lucia | Caruso, Giulia | De Simone, Maria Stefania | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Correction

DOI: 10.3233/JAD-189013

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 423-423, 2019