Journal of Alzheimer's Disease - Volume 85, issue 4

Authors: Dunk, Michelle M. | Driscoll, Ira | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: APOE ɛ 4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE , and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE -related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N  = 1,534) were classified as controls (cognitively normal; N  = 404), early mild cognitive impairment (MCI; N  = 294), late MCI (N … = 539), or AD (N  = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4 + compared to APOE3 and APOE2+ (p s < 0.04) carriers. Those with AD and late MCI (p s < 0.001) had higher total cholesterol than the control group. Comparing APOE4 + to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04–7.32), 1.05 for early MCI (1.01–3.22), 1.13 for late MCI (1.05–11.70), 1.21 for AD (1.09–54.05), and 1.13 for composite dementia (MCI or AD; 1.06–11.59) (p s < 0.05, F-statistics > 10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, cholesterol, dementia, lipid metabolism

DOI: 10.3233/JAD-215091

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1519-1528, 2022

Authors: Kurano, Makoto | Tsukamoto, Kazuhisa | Sakai, Eri | Hara, Masumi | Yatomi, Yutaka

Article Type: Research Article

Abstract: Background: Sphingosine 1-phosphate (S1P) and ceramides have been implicated in the development of Alzheimer’s disease. Apolipoprotein E (ApoE) isoforms are also involved in the development of Alzheimer’s disease. Objective: We aimed at elucidating the potential association of the ApoE isoforms with sphingolipid metabolism in the central nervous system. Methods: We investigated the modulations of apolipoprotein M (apoM), a carrier of S1P, S1P, and ceramides in Apoeshl mice, which spontaneously lack apoE, and U251 cells and SH-SY5Y cells infected with adenovirus vectors encoding for apoE2, apoE3, and apoE4. Results: In the brains of Apoeshl …mice, the levels of apoM were lower, while those of ceramides were higher. In U251 cells, cellular apoM and S1P levels were the highest in the cells overexpressing apoE2 among the apoE isoforms. The cellular and medium contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 and increased in the cells overexpressing apoE4. In SH-SY5Y cells, apoM mRNA and medium S1P levels were also the highest in the cells overexpressing apoE2. The cellular contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 = apoE4 and those in medium decreased in the order of the cells overexpressing apoE3 > apoE2, while increased in the cells overexpressing apoE4. Conclusion: The modulation of apoM and S1P might partly explain the protective effects of apoE2 against Alzheimer’s disease, and the modulation of ceramides might be one of the mechanisms explaining the association of apoE4 with the development of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, ApoE isoforms, apolipoprotein M, ceramide, sphingosine 1-phosphate

DOI: 10.3233/JAD-215205

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1529-1544, 2022

Authors: Luo, Xiao | Hong, Hui | Wang, Shuyue | Li, Kaicheng | Zeng, Qingze | Hong, Luwei | Liu, Xiaocao | Li, Zheyu | Fu, Yanv | Jiaerken, Yeerfan | Xu, XiaoPei | Yu, Xinfeng | Huang, Peiyu | Zhang, Minming

Article Type: Research Article

Abstract: Background: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. Objective: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. Methods: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers …as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). Results: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p  < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = –0.25) and EC (r = –0.25) of middle temporal gyrus was related with SPPB in all participants (p  < 0.05, corrected). Conclusion: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions. Show more

Keywords: Cerebral microinfarcts, cerebral small vascular disease, degree centrality, eigenvector centrality, motor function, resting-state functional MRI

DOI: 10.3233/JAD-215227

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1545-1554, 2022

Authors: Abdelhamid, Mona | Zhou, Chunyu | Ohno, Kazuya | Kuhara, Tetsuya | Taslima, Ferdous | Abdullah, Mohammad | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Research Article

Abstract: Background: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer’s disease (AD); their molecular mechanisms, however, have not yet been fully illustrated. Objective: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in AppNL -G -F mice. Methods: Three-month-old AppNL -G -F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-β (Aβ) levels, Aβ fibril, amyloid-β protein precursor and its processing enzymes, its …metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aβ ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis. Results: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in AppNL -G -F mice and decreased hippocampal Aβ levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus. Conclusion: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression. Show more

Keywords: ADAM10, Alzheimer’s disease, amyloid-β production, Bifidobacterium breve MCC1274, ERK, glial activation, HIF-1α , novel object recognition, synapses

DOI: 10.3233/JAD-215025

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1555-1571, 2022

Authors: Wang, Xiaoqi | Bi, Qiuhui | Lu, Jie | Chan, Piu | Hu, Xiaochen | Su, Li | Jessen, Frank | Lin, Hua | Han, Chunlei | Shu, Ni | Liu, Hesheng | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer’s disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. Objective: We aim to explore the difference in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. Methods: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18 F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was …quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n  = 34) and sd-SCD (n  = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. Results: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F  = 5.033, p  = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F  = 12.309, p  = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. Conclusion: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals. Show more

Keywords: Alzheimer’s disease, amyloid, multidomain, single memory domain, subjective cognitive decline

DOI: 10.3233/JAD-215373

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1573-1582, 2022

Authors: Ren, Yifei | Dong, Yi | Hou, Tingting | Han, Xiaolei | Liu, Rui | Wang, Yongxiang | Xu, Shan | Wang, Xiang | Monastero, Roberto | Cong, Lin | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Few studies have examined occurrence and progression of cognitive impairment, no dementia (CIND) in rural China. Objective: To determine the prevalence and incidence of CIND in rural-dwelling Chinese older adults, and to examine risk and protective factors associated with progression to CIND and dementia. Methods: This population-based study included 2,781 dementia-free participants (age≥65 years) who were examined at baseline (2014) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected following a structured questionnaire. We defined CIND according to subjective cognitive complaints and the age- and education-specific Mini-Mental State Examination (MMSE) score. Data …were analyzed with the multinomial logistic regression models. Results: The overall prevalence of CIND was 10.54% and the incidence was 28.26 per 1,000 person-years. CIND at baseline was associated with the multi-adjusted odds ratio (OR) of 2.06 (95% confidence interval = 1.23–3.47) for incident dementia. Multinomial logistic regression analysis suggested that compared with no CIND, the multi-adjusted OR of incident CIND was 2.21 (1.51–3.23) for women and 0.62 (0.38–0.99) for high social support, whereas the multi-adjusted OR of incident dementia was 1.14 (1.09–1.18) for older age, 0.29 (0.16–0.53) for high education, and 2.91 (1.47–5.74) for having a stroke history. Conclusion: CIND affects over one-tenth of older adults living in rural communities of western Shandong province. People with CIND are twice as likely to progress to dementia as people without CIND. Female sex, low education, stroke history, and low social support are associated with an increased risk of progression from normal cognition to CIND or dementia. Show more

Keywords: Cognitive impairments, incidence, population-based study, prevalence, risk factors, rural

DOI: 10.3233/JAD-215236

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1583-1592, 2022

Authors: Cheng, Jauhtai | Fairchild, J. Kaci | McNerney, M. Windy | Noda, Art | Ashford, J. Wesson | Suppes, Trisha | Chao, Steven Z. | Taylor, Joy | Rosen, Allyson C. | Durazzo, Timothy C. | Lazzeroni, Laura C. | Yesavage, Jerome

Article Type: Research Article

Abstract: Background: Despite decades of research efforts, current treatments for Alzheimer’s disease (AD) are of limited effectiveness and do not halt the progression of the disease and associated cognitive decline. Studies have shown that repetitive transcranial magnetic stimulation (rTMS) may improve cognition. Objective: We conducted a pilot study to investigate the effect of rTMS on cognitive function in Veterans with numerous medical comorbidities. Methods: Participants underwent 20 sessions, over the course of approximately 4 weeks, of 10 Hz rTMS at the left dorsolateral prefrontal cortex with intensity of 120% resting motor threshold. Outcome measures including memory, language, …verbal fluency, and executive functions were acquired at baseline, end of treatment, and 4 months after the last rTMS session. Twenty-six Veterans completed the study (13 in the active rTMS group, 13 in the sham rTMS group). Results: The study protocol was well-tolerated. Active, compared to sham, rTMS showed improved auditory-verbal memory at the end of treatment and at 4-month follow-up. However, the active rTMS group demonstrated a trend in decreased semantic verbal fluency at the end of treatment and at 4-month follow up. Conclusion: These preliminary results show rTMS is safe in general in this elderly Veteran population with multiple co-morbidities. Patients in the sham group showed an expected, slight decline in the California Verbal Learning Test scores over the course of the study, whereas the active treatment group showed a slight improvement at the 4-month post-treatment follow up. These effects need to be confirmed by studies of larger sample sizes. Show more

Keywords: Brain stimulation, california verbal learning test, repetitive transcranial magnetic stimulation, veterans

DOI: 10.3233/JAD-210349

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1593-1600, 2022

Authors: Khorani, Mona | Bobe, Gerd | Matthews, Donald G. | Magana, Armando Alcazar | Caruso, Maya | Gray, Nora E. | Quinn, Joseph F. | Stevens, Jan F. | Soumyanath, Amala | Maier, Claudia S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: To gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and …were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse. Show more

Keywords: Alzheimer’s disease, excitatory and inhibitory imbalance, fatty acids, hAPP695SW , hippocampus, metabolomics, Tg2576

DOI: 10.3233/JAD-215084

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1601-1619, 2022

Authors: Wu, Benson | Toseef, Mohammad Usama | Stickel, Ariana M. | González, Hector M. | Tarraf, Wassim

Article Type: Research Article

Abstract: Background: Life-course approaches to identify and help improve modifiable risk factors, particularly in midlife, may mitigate cognitive aging. Objective: We examined how midlife self-rated physical functioning and health may predict cognitive health in older age. Methods: We used data from the Health and Retirement Study (1998–2016; unweighted-N  = 4,685). We used survey multinomial logistic regression and latent growth curve models to examine how midlife (age 50–64 years) activities of daily living (ADL), physical function, and self-reported health affect cognitive trajectories and cognitive impairment not dementia (CIND) and dementia status 18 years later. Then, we tested for sex …and racial/ethnic modifications. Results: After covariates-adjustment, worse instrumental ADL (IADL) functioning, mobility, and self-reported health were associated with both CIND and dementia. Hispanics were more likely to meet criteria for dementia than non-Hispanic Whites given increasing IADL impairment. Conclusion: Midlife health, activities limitations, and difficulties with mobility are predictive of dementia in later life. Hispanics may be more susceptible to dementia in the presence of midlife IADLs. Assessing midlife physical function and general health with brief questionnaires may be useful for predicting cognitive impairment and dementia in later life. Show more

Keywords: Cognitive function, cognitive impairment, dementia, midlife health risks

DOI: 10.3233/JAD-215192

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1621-1637, 2022

Authors: Massetti, Noemi | Russo, Mirella | Franciotti, Raffaella | Nardini, Davide | Mandolini, Giorgio Maria | Granzotto, Alberto | Bomba, Manuela | Delli Pizzi, Stefano | Mosca, Alessandra | Scherer, Reinhold | Onofrj, Marco | Sensi, Stefano L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition driven by multifactorial etiology. Mild cognitive impairment (MCI) is a transitional condition between healthy aging and dementia. No reliable biomarkers are available to predict the conversion from MCI to AD. Objective: To evaluate the use of machine learning (ML) on a wealth of data offered by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Alzheimer’s Disease Metabolomics Consortium (ADMC) database in the prediction of the MCI to AD conversion. Methods: We implemented an ML-based Random Forest (RF) algorithm to predict conversion from MCI to AD. Data related to the …study population (587 MCI subjects) were analyzed by RF as separate or combined features and assessed for classification power. Four classes of variables were considered: neuropsychological test scores, AD-related cerebrospinal fluid (CSF) biomarkers, peripheral biomarkers, and structural magnetic resonance imaging (MRI) variables. Results: The ML-based algorithm exhibited 86% accuracy in predicting the AD conversion of MCI subjects. When assessing the features that helped the most, neuropsychological test scores, MRI data, and CSF biomarkers were the most relevant in the MCI to AD prediction. Peripheral parameters were effective when employed in association with neuropsychological test scores. Age and sex differences modulated the prediction accuracy. AD conversion was more effectively predicted in females and younger subjects. Conclusion: Our findings support the notion that AD-related neurodegenerative processes result from the concerted activity of multiple pathological mechanisms and factors that act inside and outside the brain and are dynamically affected by age and sex. Show more

Keywords: Alzheimer’s disease, conversion, dementia, machine learning, mild cognitive impairment, random forest

DOI: 10.3233/JAD-210573

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1639-1655, 2022