Journal of Alzheimer's Disease - Volume 100, issue 1

Authors: Liang, Xiao | Wang, Yangyang | Li, Siyu | Fan, Jianing | Zhou, Fanlin | Li, Xiaoju | Li, Shijie | Li, Yu

Article Type: Research Article

Abstract: Background: Mitochondrial dysfunction exists in Alzheimer’s disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked …by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-β secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy. Show more

Keywords: Alzheimer’s disease, mitophagy, Rab7, TBC1D5

DOI: 10.3233/JAD-231300

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 279-296, 2024

Authors: Shrestha, Srishti | Zhu, Xiaoqian | Sullivan, Kevin J. | Simino, Jeannette | Lutsey, Pamela L. | Gottesman, Rebecca F. | London, Stephanie J. | Griswold, Michael E. | Mosley, Jr., Thomas H.

Article Type: Research Article

Abstract: Background: Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke. Objective: We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations. Methods: Lung function was measured at participants’ midlife in 1990–1992 (mean age = 56±5 years) and later-life in 2011–2013 (mean age = 76±5 years), and brain MRI was performed in 2011–2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic …regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders. Results: In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, n  = 1,223), higher forced-expiratory volume in one second (FEV1 ) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54–14.71) cm3 greater total brain volume per one-liter higher FEV1 ]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, n  = 1,787), higher FVC levels were significantly associated with lower later-life brain volumes. Conclusions: Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers. Show more

Keywords: Alzheimer’s disease, brain volumes, cerebral infarct, lung function, white matter hyperintensity volume

DOI: 10.3233/JAD-240162

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 297-308, 2024

Authors: Lee, Cecilia S. | Ferguson, Alina N. | Gibbons, Laura E. | Walker, Rod | Su, Yu-Ru | Krakauer, Chloe | Brush, Michael | Kam, Jason | Larson, Eric B. | Arterburn, David E. | Crane, Paul K. | Takahashi, Missy | Zhang, Yi | Jiang, Yu | Wu, Yue | Cooper, Julie | Pope, Beth | Blazes, Marian | Lee, Aaron Y. | Lee, Michael L. | Wang, Ruikang | Cronkite, David | Hess, Chantelle | Bowers, Will | Schaaf, Beverly | Gray, Regan | Guerrero, Linda | Sankaran, Sundary | Gatto, Nicole

Article Type: Research Article

Abstract: Background: Conflicting research on retinal biomarkers of Alzheimer’s disease and related dementias (AD/ADRD) is likely related to limited sample sizes, study design, and protocol differences. Objective: The prospective Eye Adult Changes in Thought (Eye ACT) seeks to address these gaps. Methods: Eye ACT participants are recruited from ACT, an ongoing cohort of dementia-free, older adults followed biennially until AD/ADRD, and undergo visual function and retinal imaging assessment either in clinic or at home. Results: 330 participants were recruited as of 03/2023. Compared to ACT participants not in Eye ACT (N  = 1868), Eye ACT participants (N … = 330) are younger (mean age: 70.3 versus 71.2, p  = 0.014), newer to ACT (median ACT visits since baseline: 3 versus 4, p  < 0.001), have more years of education (17.7 versus 16.2, p  < 0.001) and had lower rates of visual impairment (12% versus 22%, p  < 0.001). Compared to those seen in clinic (N  = 300), Eye ACT participants seen at home (N  = 30) are older (77.2 versus 74.9, p  = 0.015), more frequently female (60% versus 49%, p  = 0.026), and have significantly worse visual acuity (71.1 versus 78.9 Early Treatment Diabetic Retinopathy Study letters, p  < 0.001) and contrast sensitivity (–1.9 versus –2.1 mean log units at 3 cycles per degree, p  = 0.002). Cognitive scores and retinal imaging measurements are similar between the two groups. Conclusions: Participants assessed at home had significantly worse visual function than those seen in clinic. By including these participants, Eye ACT provides a unique longitudinal cohort for evaluating potential retinal biomarkers of dementia. Show more

Keywords: Adult Changes in Thought (ACT), age-related macular degeneration, Alzheimer’s disease, Cognitive Abilities Screening Instrument (CASI) score, contrast sensitivity, Eye Adult Changes in Thought (Eye ACT), ophthalmology, optical coherence measurement, prospective study, visual acuity

DOI: 10.3233/JAD-240203

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 309-320, 2024

Authors: Chen, Yu-Han | Wang, Zhi-Bo | Liu, Xi-Peng | Mao, Zhi-Qi

Article Type: Research Article

Abstract: Background: Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer’s disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. Objective: To test the association between plasma insulin and cerebrospinal fluid (CSF) AD pathology. Methods: A total of 304 participants were included in the Alzheimer’s Disease Neuroimaging Initiative, assessing plasma insulin and CSF AD pathology. We explored the cross-sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. Results: In the non-demented group, amyloid-β (Aβ)+ participants (e.g., as …reflected by CSF Aβ42 ) exhibited significantly lower plasma insulin levels compared to non-demented Aβ–participants (p  < 0.001). This reduction in plasma insulin was more evident in the A+T+ group (as shown by CSF Aβ42 and pTau181 levels) when compared to the A–T– group within the non-dementia group (p  = 0.002). Additionally, higher plasma insulin levels were consistently associated with more normal CSF Aβ42 levels (p  < 0.001) across all participants. This association was particularly significant in the Aβ–group (p  = 0.002) and among non-demented individuals (p  < 0.001). Notably, baseline plasma insulin was significantly correlated with longitudinal changes in CSF Aβ42 (p  = 0.006), whereas baseline CSF Aβ42 did not show a similar correlation with changes in plasma insulin over time. Conclusions: These findings suggest an association between plasma insulin and early Aβ pathology in the early stages of AD, indicating that plasma insulin may be a potential predictor of changes in early Aβ pathology. Show more

Keywords: Alzheimer’s disease, amyloid, diabetes, plasma insulin, pTau

DOI: 10.3233/JAD-240289

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 321-332, 2024

Authors: Lalive, Hadrien M. | Griffa, Alessandra | Carlier, Sabrina | Nasuti, Mirco | Di Noto, Tommaso | Maréchal, Bénédicte | Rouaud, Olivier | Allali, Gilles

Article Type: Research Article

Abstract: Background: Amnestic syndrome of the hippocampal type (ASHT) in Memory Clinics is a presentation common to Alzheimer’s disease (AD). However, ASHT can be found in other neurodegenerative disorders. Objective: To compare brain morphometry including hippocampal volumes between amnestic older adults with and without AD pathology and investigate their relationship with memory performance and cerebrospinal fluid (CSF) biomarkers. Methods: Brain morphometry of 92 consecutive patients (72.5±6.8 years old; 39% female) with Free and Cued Selective Recall Reminding Test (FCSRT) total recall < 40/48 was assessed with an automated algorithm and compared between AD and non-AD patients, as defined by …CSF biomarkers. Results: AD and non-AD patients presented comparable brain morphology. Total recall was associated to hippocampal volume irrespectively from AD pathology. Conclusions: Brain morphometry, including hippocampal volumes, is similar between AD and non-AD older adults with ASHT evaluated in a Memory Clinic, underlying the importance of using molecular biomarkers for the diagnosis of AD. Show more

Keywords: Alzheimer’s disease, amnestic, hippocampus, magnetic resonance imaging

DOI: 10.3233/JAD-240026

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 333-343, 2024

Authors: Michalowsky, Bernhard | Rädke, Anika | Scharf, Annelie | Mühlichen, Franka | Buchholz, Maresa | Platen, Moritz | Kleinke, Fabian | Penndorf, Peter | Pfitzner, Stefanie | van den Berg, Neeltje | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Determining unmet need patterns and associated factors in primary care can potentially specify assessment batteries and tailor interventions in dementia more efficiently. Objective: To identify latent unmet healthcare need patterns and associated sociodemographic and clinical factors. Methods: This Latent Class Analysis (LCA) includes n  = 417 community-dwelling people living with dementia. Subjects completed a comprehensive, computer-assisted face-to-face interview to identify unmet needs. One-hundred-fifteen predefined unmet medical, medication, nursing, psychosocial, and social care needs were available. LCA and multivariate logistic regressions were performed to identify unmet needs patterns and patient characteristics belonging to a specific pattern, respectively. …Results: Four profiles were identified: [1 ] “few needs without any psychosocial need” (n  = 44 (11%); mean: 7.4 needs), [2 ] “some medical and nursing care needs only” (n  = 135 (32%); 9.7 needs), [3 ] “some needs in all areas” (n  = 139 (33%); 14.3 needs), and [4 ] “many medical and nursing needs” (n  = 99 (24%); 19.1 needs). Whereas the first class with the lowest number of needs comprised younger, less cognitively impaired patients without depressive symptoms, the fourth class had the highest number of unmet needs, containing patients with lower health status, less social support and higher comorbidity and depressive symptoms. Better access to social care services and higher social support reduced unmet needs, distinguishing the second from the third class (9.7 versus 14.3 needs). Conclusions: Access to the social care system, social support and depressive symptoms should be assessed, and the patient’s health status and comorbidities monitored to more comprehensively identify unmet needs patterns and more efficiently guide tailored interventions. Show more

Keywords: Alzheimer’s disease, dementia, latent class analysis, primary care, profiles, unmet needs

DOI: 10.3233/JAD-240025

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 345-356, 2024

Authors: Lee, Ann J. | Stark, Jessica H. | Hayes, Scott M.

Article Type: Research Article

Abstract: Background: Executive dysfunction in mild cognitive impairment (MCI) has been associated with gray matter atrophy. Prior studies have yielded limited insight into associations between gray matter volume and executive function in early and late amnestic MCI (aMCI). Objective: To examine the relative importance of predictors of executive function at 24 months and relationships between baseline regional gray matter volume and executive function performance at 24-month follow-up in non-demented older adults. Methods: 147 participants from the Alzheimer’s Disease Neuroimaging Initiative (mean age = 70.6 years) completed brain magnetic resonance imaging and neuropsychological testing and were classified as cognitively normal …(n  = 49), early aMCI (n  = 60), or late aMCI (n  = 38). Analyses explored the importance of demographic, APOE ɛ 4, biomarker (p-tau/Aβ42 , t-tau/Aβ42 ), and gray matter regions-of-interest (ROI) variables to 24-month executive function, whether ROIs predicted executive function, and whether relationships varied by baseline diagnostic status. Results: Across all participants, baseline anterior cingulate cortex and superior parietal lobule volumes were the strongest predictors of 24-month executive function performance. In early aMCI, anterior cingulate cortex volume was the strongest predictor and demonstrated a significant interaction such that lower volume related to worse 24-month executive function in early aMCI. Educational attainment and inferior frontal gyrus volume were the strongest predictors of 24-month executive function performance for cognitively normal and late aMCI groups, respectively. Conclusions: Baseline frontoparietal gray matter regions were significant predictors of executive function performance in the context of aMCI and may identify those at risk of Alzheimer’s disease. Anterior cingulate cortex volume may predict executive function performance in early aMCI. Show more

Keywords: Aging, Alzheimer’s disease, anterior cingulate cortex, executive function, gray matter, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-231468

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 357-374, 2024

Article Type: Correction

DOI: 10.3233/JAD-249010

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 375-375, 2024