Journal of Alzheimer's Disease - Volume 82, issue 4

Authors: Mouchet, Julie | Betts, Keith A. | Georgieva, Mihaela V. | Ionescu-Ittu, Raluca | Butler, Lesley M. | Teitsma, Xavier | Delmar, Paul | Kulalert, Thomas | Zhu, JingJing | Lema, Neema | Desai, Urvi

Article Type: Research Article

Abstract: Background: Progression trajectories of patients with mild cognitive impairment (MCI) are currently not well understood. Objective: To classify patients with incident MCI into different latent classes of progression and identify predictors of progression class. Methods: Participants with incident MCI were identified from the US National Alzheimer’s Coordinating Center Uniform Data Set (09/2005-02/2019). Clinical Dementia Rating (CDR® ) Dementia Staging Instrument-Sum of Boxes (CDR-SB), Functional Activities Questionnaire (FAQ), and Mini-Mental State Examination (MMSE) score longitudinal trajectories from MCI diagnosis were fitted using growth mixture models. Predictors of progression class were identified using multivariate multinomial logistic regression models; …odds ratios (ORs) and 95% confidence intervals (CIs) were reported. Results: In total, 21%, 22%, and 57% of participants (N  = 830) experienced fast, slow, and no progression on CDR-SB, respectively; for FAQ, these figures were 14%, 23%, and 64%, respectively. CDR-SB and FAQ class membership was concordant for most participants (77%). Older age (≥86 versus≤70 years, OR [95% CI] = 5.26 [1.78–15.54]), one copy of APOE ɛ4 (1.94 [1.08–3.47]), higher baseline CDR-SB (2.46 [1.56–3.88]), lower baseline MMSE (0.85 [0.75–0.97]), and higher baseline FAQ (1.13 [1.02–1.26]) scores were significant predictors of fast progression versus no progression based on CDR-SB (all p  < 0.05). Predictors of FAQ class membership were largely similar. Conclusion: Approximately a third of participants experienced progression based on CDR-SB or FAQ during the  4-year follow-up period. CDR-SB and FAQ class assignment were concordant for the vast majority of participants. Identified predictors may help the selection of patients at higher risk of progression in future trials. Show more

Keywords: Alzheimer’s disease, latent class analysis, mild cognitive impairment, progression

DOI: 10.3233/JAD-210305

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1667-1682, 2021

Authors: Barrett, Tomás | Stangis, Katherine A. | Saito, Takashi | Saido, Takaomi | Park, Kevin H.J.

Article Type: Research Article

Abstract: Background: Aberrant cell cycle re-entry is a well-documented process occurring early in Alzheimer’s disease (AD). This is an early feature of the disease and may contribute to disease pathogenesis. Objective: To assess the effect of forced neuronal cell cycle re-entry in mice expressing humanized Aβ, we crossed our neuronal cell cycle re-entry mouse model with App NLF knock-in (KI) mice. Methods: Our neuronal cell cycle re-entry (NCCR) mouse model is bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. The NCCR mice were crossed with App NLF KI mice to generate NCCR-App NLF …animals. Using this tet-off system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. The animals were examined at the following time points: 9, 12, and 18 months of age. Various neuropathological features in our mice were evaluated by image analysis and stereology on brain sections stained using either immunofluorescence or immunohistochemistry. Results: We show that neuronal cell cycle re-entry in humanized Aβ plaque producing App NLF KI mice results in the development of additional AD-related pathologies, namely, pathological tau, neuroinflammation, brain leukocyte infiltration, DNA damage response, and neurodegeneration. Conclusion: Our findings show that neuronal cell cycle re-entry enhances AD-related neuropathological features in App NLF mice and highlight our unique AD mouse model for studying the pathogenic role of aberrant cell cycle re-entry in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , brain leukocyte infiltration, cell cycle, DNA damage response, neuroinflammation, tau

DOI: 10.3233/JAD-210091

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1683-1702, 2021

Authors: Kucera, Matej | Wolfova, Katrin | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: Several early-life factors have been associated with higher risk of developing dementia. It is unclear whether season of birth (SOB) can affect cognitive aging in older adults or not. Objective: We aimed to study the association of SOB with the level of cognitive performance as well as with the rate of cognitive decline. Methods: We studied 70,203 individuals who participated in the Survey of Health, Aging and Retirement in Europe. Cognition was measured with tests on verbal fluency and immediate and delayed recall. We assessed the association of SOB with the level of cognitive performance …using multiple linear regression and with the rate of cognitive decline using linear mixed-effects models. Results: When compared to individuals born in winter and adjusted for sociodemographic and health-related characteristics, being born in summer was associated with a higher level of delayed recall (B 0.05; 95%CI 0.01 to 0.09) and verbal fluency (B 0.15; 95%CI 0.00 to 0.29) and being born in fall with a higher level of immediate recall (B 0.04; 95%CI 0.01 to 0.08) and verbal fluency (B 0.15; 95%CI 0.01 to 0.29). Individuals born in summer had a higher yearly decline in delayed recall (B –0.005; 95%CI –0.009 to 0.000), while the scores in delayed recall in participants born in spring showed an inverse trend (B 0.005; 95%CI 0.000 to 0.010). Conclusion: Individuals born in winter seem to carry a life-long disadvantage in a lower level of cognitive performance; however, being born in winter does not seem to affect the rate of cognitive decline. Show more

Keywords: Aging, cognition, epidemiology, season of birth, SHARE

DOI: 10.3233/JAD-210289

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1703-1713, 2021

Authors: Frank, Mirjam | Hensel, Jonas | Baak, Lisa | Schramm, Sara | Dragano, Nico | Weimar, Christian | Hoffmann, Per | Nöthen, Markus M. | Erbel, Raimund | Jöckel, Karl-Heinz | Jokisch, Martha | Schmidt, Börge

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ 4 and a genetic sum score of AD-associated risk alleles (GRSAD ) interact with SEP indicators to affect MCI in a population-based cohort. …Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ 4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ 4 and low education on MCI (RERI: 0.52 [95% confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ 4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ 4 expression on MCI, especially among women. Show more

Keywords: Apolipoprotein E4, gene environment interaction, mild cognitive impairment, socioeconomic position

DOI: 10.3233/JAD-210244

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1715-1725, 2021

Authors: Downer, Brian | Chou, Lin-Na | Al Snih, Soham | Barba, Cheyanne | Kuo, Yong-Fang | Raji, Mukaila | Markides, Kyriakos S. | Ottenbacher, Kenneth J.

Article Type: Research Article

Abstract: Background: Hispanic older adults are a high-risk population for Alzheimer’s disease and related dementias (ADRD) but are less likely than non-Hispanic White older adults to have ADRD documented as a cause of death on a death certificate. Objective: To investigate characteristics associated with ADRD as a cause of death among Mexican-American decedents diagnosed with ADRD. Methods: Data came from the Hispanic Established Populations for the Epidemiologic Study of the Elderly, Medicare claims, and National Death Index. Results: The final sample included 853 decedents diagnosed with ADRD of which 242 had ADRD documented as a …cause of death. More health comorbidities (OR = 0.40, 95% CI = 0.28–0.58), older age at death (OR = 1.18, 95% CI = 1.03–1.36), and longer ADRD duration (OR = 1.08, 95% CI = 1.03–1.14) were associated with ADRD as a cause of death. In the last year of life, any ER admission without a hospitalization (OR = 0.45, 95% CI = 0.22–0.92), more physician visits (OR = 0.96, 95% CI = 0.93–0.98), and seeing a medical specialist (OR = 0.46, 95% CI = 0.29–0.75) were associated with lower odds for ADRD as a cause of death. In the last 30 days of life, any hospitalization with an ICU stay (OR = 0.55, 95% CI = 0.36–0.82) and ER admission with a hospitalization (OR = 0.67, 95% CI = 0.48–0.94) were associated with lower odds for ADRD as a cause of death. Receiving hospice care in the last 30 days of life was associated with 1.98 (95% CI = 1.37–2.87) higher odds for ADRD as a cause of death. Conclusion: Under-documentation of ADRD as a cause of death may reflect an underestimation of resource needs for Mexican-Americans with ADRD. Show more

Keywords: Cause of death, health services, hispanic Americans, mortality

DOI: 10.3233/JAD-210361

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1727-1736, 2021

Authors: Mori, Hiroaki | Funahashi, Yu | Yoshino, Yuta | Kumon, Hiroshi | Ozaki, Yuki | Yamazaki, Kiyohiro | Ochi, Shinichiro | Tachibana, Ayumi | Yoshida, Taku | Shimizu, Hideaki | Mori, Takaaki | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: Cyclin-dependent kinase inhibitor 2A (CDKN2A ) is an important gene in cellular senescence and aging. Objective: This study assessed the utility of blood CDKN2A mRNA expression levels and methylation status as a potential biomarker for aging and the pathogenesis of Alzheimer’s disease (AD). Methods: The correlation between CDKN2A mRNA expression levels and age was examined in 45 healthy subjects, after which mRNA expression levels were compared among 46 AD patients, 20 mild cognitive impairment due to AD patients, 21 Parkinson’s disease patients, 21 dementia with Lewy bodies patients, and 55 older healthy …controls. The methylation rates of the second exon of the CDKN2A gene, known to influence its expression levels, was also examined. Results: A significant correlation between CDKN2A mRNA expression levels and age was found (Spearman’s rank correlation coefficient: r  = 0.407, p  = 0.005). CDKN2A mRNA expression levels in blood were significantly decreased in AD patients, although those of healthy controls were significantly increased with age. Further, only in AD patients were CDKN2A mRNA expression levels significantly and positively correlated with methylation rates. Conclusion: Although further research with a larger sample size is needed to elucidate the relationships between CDKN2A gene expression in blood and the development of other neurodegenerative diseases, CDKN2A mRNA expression in blood may be a biomarker for differentiating AD from normal aging and other neurodegenerative diseases. Show more

Keywords: Aging, Alzheimer’s disease, blood, CDKN2A, gene expression

DOI: 10.3233/JAD-210483

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1737-1744, 2021

Authors: Jacob, Louis | Kostev, Karel | Smith, Lee | Oh, Hans | López-Sánchez, Guillermo F. | Shin, Jae Il | Abduljabbar, Adel S. | Haro, Josep Maria | Koyanagi, Ai

Article Type: Research Article

Abstract: Background: Little is known about the relationship between sarcopenia and mild cognitive impairment (MCI) in low- and middle-income countries (LMICs). Objective: This study aimed to investigate this association among community-dwelling adults aged≥65 years from six LMICs. Methods: Cross-sectional, nationally representative data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. These data were obtained in China, Ghana, India, Mexico, Russia, and South Africa in 2007–2010. Participants were considered to have sarcopenia if they had low skeletal muscle mass (i.e., lower skeletal mass index) and a weak handgrip strength. MCI was defined using the …National Institute on Aging-Alzheimer’s Association criteria. Multivariable logistic regression analysis was conducted to assess associations. Results: The final analytical sample consisted of 12,912 individuals aged≥65 years with preservation in functional abilities without stroke (mean [standard deviation] age 72.2 [10.8 ] years; 45.2% males). The overall prevalence of sarcopenia and MCI were 11.3% and 18.1%, respectively. After adjusting for potential confounders, there was a positive association between sarcopenia and MCI in all countries (i.e., odds ratio [OR] > 1) with the exception of South Africa, and the overall estimate was OR = 1.60 (95% confidence interval [CI] = 1.32–1.93) with a low level of between-country heterogeneity (I 2  = 0.0%). Conclusion: There was a positive association between sarcopenia and MCI in this sample of older adults living in LMICs. Causality should be assessed in future longitudinal research, while the utility of sarcopenia as a marker of MCI should also be investigated. Show more

Keywords: Community-dwelling adults, low- and middle-income countries, mild cognitive impairment, multicountry study, sarcopenia

DOI: 10.3233/JAD-210321

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1745-1754, 2021

Authors: Tolea, Magdalena I. | Heo, Jaeyeong | Chrisphonte, Stephanie | Galvin, James E.

Article Type: Research Article

Abstract: Background: Although an efficacious dementia-risk score system, Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) was derived using midlife risk factors in a population with low educational attainment that does not reflect today’s US population, and requires laboratory biomarkers, which are not always available. Objective: Develop and validate a modified CAIDE (mCAIDE) system and test its ability to predict presence, severity, and etiology of cognitive impairment in older adults. Methods: Population consisted of 449 participants in dementia research (N  = 230; community sample; 67.9±10.0 years old, 29.6%male, 13.7±4.1 years education) or receiving dementia clinical services (N  = 219; clinical …sample; 74.3±9.8 years old, 50.2%male, 15.5±2.6 years education). The mCAIDE, which includes self-reported and performance-based rather than blood-derived measures, was developed in the community sample and tested in the independent clinical sample. Validity against Framingham, Hachinski, and CAIDE risk scores was assessed. Results: Higher mCAIDE quartiles were associated with lower performance on global and domain-specific cognitive tests. Each one-point increase in mCAIDE increased the odds of mild cognitive impairment (MCI) by up to 65%, those of AD by 69%, and those for non-AD dementia by > 85%, with highest scores in cases with vascular etiologies. Being in the highest mCAIDE risk group improved ability to discriminate dementia from MCI and controls and MCI from controls, with a cut-off of ≥7 points offering the highest sensitivity, specificity, and positive and negative predictive values. Conclusion: mCAIDE is a robust indicator of cognitive impairment in community-dwelling seniors, which can discriminate well between dementia severity including MCI versus controls. The mCAIDE may be a valuable tool for case ascertainment in research studies, helping flag primary care patients for cognitive testing, and identify those in need of lifestyle interventions for symptomatic control. Show more

Keywords: CAIDE, case discrimination, cognitive impairment, dementia risk scores, dementia screening

DOI: 10.3233/JAD-210269

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1755-1768, 2021

Authors: Kuwar, Ram | Rolfe, Andrew | Di, Long | Blevins, Hallie | Xu, Yiming | Sun, Xuehan | Bloom, George S. | Zhang, Shijun | Sun, Dong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns. Among the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the pathogenesis of AD. Objective: We recently developed a novel class of small molecule inhibitors that selectively target the NLRP3 inflammasome. One of the lead compounds, JC124, …has shown therapeutic efficacy in a transgenic animal model of AD. In this study we tested the preventative efficacy of JC124 in another strain of transgenic AD mice. Methods: In this study, 5-month-old female APP/PS1 and matched wild type mice were treated orally with JC124 for 3 months. After completion of treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins, were assessed. Results: We found that inhibition of NLRP3 inflammasome with JC124 significantly decreased multiple AD pathologies in APP/PS1 mice, including amyloid-β (Aβ) load, neuroinflammation, and neuronal cell cycle re-entry, accompanied by preserved synaptic plasticity with higher expression of pre- and post-synaptic proteins, increased hippocampal neurogenesis, and improved cognitive functions. Conclusion: Our study demonstrates the importance of the NLRP3 inflammasome in AD pathological development, and pharmacological inhibition of NLRP3 inflammasome with small molecule inhibitors represents a potential therapy for AD. Show more

Keywords: Alzheimer’s disease, cell cycle re-entry, cognitive function, neuroinflammation, NLRP3 inflammasome

DOI: 10.3233/JAD-210400

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1769-1783, 2021

Authors: Lotan, Roni | Ganmore, Ithamar | Livny, Abigail | Itzhaki, Nofar | Waserman, Mark | Shelly, Shahar | Zacharia, Moran | Moshier, Erin | Uribarri, Jaime | Beisswenger, Paul | Cai, Weijing | Troen, Aron M. | Beeri, Michal Schnaider

Article Type: Research Article

Abstract: Background: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. Objective: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). Methods: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention …arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. Results: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. Conclusion: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention. Show more

Keywords: Advanced glycation end products, diet, feasibility, mild cognitive impairment, randomized controlled trial, pilot, type 2 diabetes

DOI: 10.3233/JAD-210131

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1785-1795, 2021