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

Authors: Bayer, Thomas A. | Jiang, Lan | Erqou, Sebhat | Kunicki, Zachary J. | Singh, Mriganka | Duprey, Matthew | Bozzay, Melanie | McGeary, John E. | Zullo, Andrew R. | Wu, Wen-Chih | Gravenstein, Stefan | Rudolph, James L.

Article Type: Research Article

Abstract: Background: Hospitalization with heart failure (HF) may signal an increased risk of Alzheimer’s disease and related dementias (ADRD). Nursing homes routinely assess cognition but the association of these results with new ADRD diagnosis in a population at high risk of ADRD is not known. Objective: To determine the association between nursing home cognitive assessment results and new diagnosis of dementia after heart failure hospitalization. Methods: This retrospective cohort study included Veterans hospitalized for HF and discharged to nursing homes, from 2010 to 2015, without a prior diagnosis of ADRD. We determined mild, moderate, or severe cognitive …impairment using multiple items of the nursing home admission assessment. We used Cox regression to determine the association of cognitive impairment with new ADRD diagnosis during 365 days of follow-up. Results: The cohort included 7,472 residents, new diagnosis of ADRD occurred in 4,182 (56%). The adjusted hazard ratio of ADRD diagnosis was 4.5 (95% CI 4.2, 4.8) for the mild impairment group, 5.4 (95% CI 4.8, 5.9) for moderate impairment, and 4.0 (95% CI 3.2, 5.0) for severe impairment compared to the cognitively intact group. Conclusion: New ADRD diagnoses occurred in more than half of Veterans with HF admitted to nursing homes for post-acute care. Show more

Keywords: Alzheimer’s disease, cognition, dementia diagnosis, heart failure, multimorbidity, multiple chronic conditions, neurocognitive disorders, nursing homes, veterans

DOI: 10.3233/JAD-221300

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1397-1404, 2023

Authors: Zheng, Yaonan | Li, Tao | Xie, Teng | Zhang, Ying | Liu, Ying | Zeng, Xiangzhu | Wang, Zhijiang | Wang, Luchun | Li, Huizi | Xie, Yuhan | Lv, Xiaozhen | Wang, Jing | Yu, Xin | Wang, Huali

Article Type: Research Article

Abstract: Background: Whether encoding or retrieval failure contributes to memory binding deficit in amnestic mild cognitive impairment (aMCI) has not been elucidated. Also, the potential brain structural substrates of memory binding remained undiscovered. Objective: To investigate the characteristics and brain atrophy pattern of encoding and retrieval performance during memory binding in aMCI. Methods: Forty-three individuals with aMCI and 37 cognitively normal controls were recruited. The Memory Binding Test (MBT) was used to measure memory binding performance. The immediate and delayed memory binding indices were computed by using the free and cued paired recall scores. Partial correlation analysis …was performed to map the relationship between regional gray matter volume and memory binding performance. Results: The memory binding performance in the learning and retrieval phases was worse in the aMCI group than in the control group (F = 22.33 to 52.16, all p  < 0.001). The immediate and delayed memory binding index in the aMCI group was lower than that in the control group (p  < 0.05). The gray matter volume of the left inferior temporal gyrus was positively correlated with memory binding test scores (r  = 0.49 to 0.61, p  < 0.05) as well as the immediate (r  = 0.39, p  < 0.05) and delayed memory binding index (r  = 0.42, p  < 0.05) in the aMCI group. Conclusion: aMCI may be primarily characterized by a deficit in encoding phase during the controlled learning process. Volumetric losses in the left inferior temporal gyrus may contribute to encoding failure. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, controlled learning paradigm, gray matter volume, memory binding, voxel-based morphometry

DOI: 10.3233/JAD-230154

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1405-1415, 2023

Authors: Sušac, Jelena | Vukojević, Jakša | Debogović, Siniša | Bajić, Žarko | Savić, Aleksandar | Đuran, Nataša | Hanževački, Miroslav | Vitezić, Dinko | Mimica, Ninoslav

Article Type: Research Article

Abstract: Background: High heterogeneity exists in estimates of the share of and absolute costs of informal care (IC) for individuals diagnosed with dementia. Objective: To assess the differences in the share of and absolute costs of IC between subpopulations defined by latent profiles of activities of daily living (ADLs), neuropsychiatric symptoms, and global cognitive functioning. Methods: We performed a nested cross-sectional analysis of data collected from 2019–2021 at the Zagreb-Zapad Health Center, Zagreb, Croatia, from a sample of patients and their caregivers. The outcome was the share of costs of IC in the total costs of care …estimated using the Resource Utilization in Dementia questionnaire. We used latent profile analysis of six principal components of the Alzheimer’s Disease Cooperative Study ADLs inventory, Neuropsychiatric Inventory and Mini-Mental State Examination, and conducted the analysis using beta and quantile regression. Results: We enrolled 240 patients with a median age of 74 years; 78% were women. The annual cost for treatment and care for one patient was 11,462 (95% confidence interval 9,947; 12,976) EUR. After the adjustment for covariates, five latent profiles were significantly associated with the share of costs and absolute cost of IC. The adjusted annual costs of IC ranged from 2,157 EUR, with a share of 53% in the first latent profile, to 18,119 EUR, with a share of 78% in the fifth latent profile. Conclusion: The population of patients with dementia was heterogeneous, and there were relatively large differences in the share and absolute costs of IC between particular subpopulations. Show more

Keywords: Alzheimer’s disease, cost of illness, dementia, informal care, latent profile analysis, resource utilization

DOI: 10.3233/JAD-230161

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1417-1430, 2023

Authors: Wei, Jingkai | Xu, Hanzhang | Zhang, Donglan | Tang, Huilin | Wang, Tiansheng | Steck, Susan E. | Divers, Jasmin | Zhang, Jiajia | Merchant, Anwar T.

Article Type: Research Article

Abstract: Background: Hypertension has been identified as a risk factor of dementia, but most randomized trials did not show efficacy in reducing the risk of dementia. Midlife hypertension may be a target for intervention, but it is infeasible to conduct a trial initiating antihypertensive medication from midlife till dementia occurs late life. Objective: We aimed to emulate a target trial to estimate the effectiveness of initiating antihypertensive medication from midlife on reducing incident dementia using observational data. Methods: The Health and Retirement Study from 1996 to 2018 was used to emulate a target trial among non-institutional dementia-free …subjects aged 45 to 65 years. Dementia status was determined using algorithm based on cognitive tests. Individuals were assigned to initiating antihypertensive medication or not, based on the self-reported use of antihypertensive medication at baseline in 1996. Observational analog of intention-to-treat and per-protocol effects were conducted. Pooled logistic regression models with inverse-probability of treatment and censoring weighting using logistic regression models were applied, and risk ratios (RRs) were calculated, with 200 bootstrapping conducted for the 95% confidence intervals (CIs). Results: A total of 2,375 subjects were included in the analysis. After 22 years of follow-up, initiating antihypertensive medication reduced incident dementia by 22% (RR = 0.78, 95% CI: 0.63, 0.99). No significant reduction of incident dementia was observed with sustained use of antihypertensive medication. Conclusion: Initiating antihypertensive medication from midlife may be beneficial for reducing incident dementia in late life. Future studies are warranted to estimate the effectiveness using large samples with improved clinical measurements. Show more

Keywords: Aging, Alzheimer’s disease, antihypertensive medication, causal effect, dementia, emulated target trial, hypertension, midlife

DOI: 10.3233/JAD-230398

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1431-1441, 2023

Authors: Schäfer Hackenhaar, Fernanda | Josefsson, Maria | Nordin Adolfsson, Annelie | Landfors, Mattias | Kauppi, Karolina | Porter, Tenielle | Milicic, Lidija | Laws, Simon M. | Hultdin, Magnus | Adolfsson, Rolf | Degerman, Sofie | Pudas, Sara

Article Type: Research Article

Abstract: Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer’s disease (AD) prediction. Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers. Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse …Partial Least Squares Discriminant Analysis applied at pre- (10–16 years), and post-AD-onset time-points. Results: EAA did not differentiate cases from controls during the follow-up time (p  > 0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p -values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p  = 0.012) in an external cohort (n  = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE ɛ 4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ 4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n  = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs. Show more

Keywords: Alzheimer’s disease, biomarkers, DNA methylation, epigenomics, longitudinal studies

DOI: 10.3233/JAD-230039

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1443-1464, 2023

Authors: Akada, Keishi | Koyama, Noriyuki | Miura, Yuji | Takahashi, Kentaro | Aoshima, Ken

Article Type: Research Article

Abstract: Background: Preserving activities of daily living (ADL) is the key issue for Alzheimer’s disease (AD) patients and their caregivers. Objective: To clarify the ADL level of AD patients at diagnosis and the risk factors associated with decreased ADL during long-term care (≤3 years). Methods: Medical records of AD patients in a Japanese health insurance claims database were analyzed retrospectively to determine ADL using the Barthel Index (BI) and identify the risk factors associated with decreased ADL. Results: A total of 16,799 AD patients (mean age at diagnosis: 83.6 years, 61.5% female) were analyzed. Female …patients were older (84.6 versus 81.9 years; p  < 0.001) and had lower BI (46.8 versus 57.6; p  < 0.001) and body mass index (BMI) (21.0 versus 21.7 kg/m2 ; p  < 0.001) than male patients at diagnosis. Disability (BI≤60) increased at age≥80 years and was significantly higher in females. Complete disability was most frequent for bathing and grooming. Risk factors for decreased ADL were determined separately by sex through comparing the ADL-preserved and ADL-decreased groups using propensity score matching by age and BI and multivariable logistic regression analysis. In males, decreased ADL was significantly associated with BMI < 21.5 kg/m2 , stroke, and hip fracture, and inversely associated with hyperlipidemia. In females, decreased ADL was significantly associated with BMI < 21.5 kg/m2 and vertebral and hip fractures, and inversely associated with lower back pain. Conclusion: AD patients with low BMI, stroke, and fractures had increased risks of decreased ADL; such patients should be identified early and managed appropriately, including rehabilitation to preserve ADL. Show more

Keywords: Activities of daily living, Alzheimer’s disease, baths, body mass index, bone, fractures, stroke

DOI: 10.3233/JAD-230106

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1465-1475, 2023

Authors: Cai, Hong-Yan | Hou, Si-Jia | Wen, Rui | Feng, Qi-Fan | Xi, Yu-Jia | Zhang, Sheng-Xiao | Qiao, Jun | Wu, Mei-Na

Article Type: Research Article

Abstract: Background: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer’s disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. Objective: This study aims to investigate the causal effects of the mTOR signaling targets on AD. Methods: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired …from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer’s Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. Results: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p  = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p  = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p  = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p  > 0.05). Conclusion: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD. Show more

Keywords: Alzheimer’s disease, causal relationships, mammalian target of rapamycin, Mendelian randomization

DOI: 10.3233/JAD-230128

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1477-1485, 2023

Authors: Zhang, Hui-Qin | Chau, Anson C.M. | Shea, Yat-Fung | Chiu, Patrick Ka-Chun | Bao, Yi-Wen | Cao, Peng | Mak, Henry Ka-Fung

Article Type: Research Article

Abstract: Background: Dementia presents a significant burden to patients and healthcare systems worldwide. Early and accurate diagnosis, as well as differential diagnosis of various types of dementia, are crucial for timely intervention and management. However, there is currently a lack of clinical tools for accurately distinguishing between these types. Objective: This study aimed to investigate the differences in the structural white matter (WM) network among different types of cognitive impairment/dementia using diffusion tensor imaging, and to explore the clinical relevance of the structural network. Methods: A total of 21 normal control, 13 subjective cognitive decline (SCD), 40 …mild cognitive impairment (MCI), 22 Alzheimer’s disease (AD), 13 mixed dementia (MixD), and 17 vascular dementia (VaD) participants were recruited. Graph theory was utilized to construct the brain network. Results: Our findings revealed a monotonic trend of disruption in the brain WM network (VaD > MixD > AD > MCI > SCD) in terms of decreased global efficiency, local efficiency, and average clustering coefficient, as well as increased characteristic path length. These network measurements were significantly associated with the clinical cognition index in each disease group separately. Conclusion: These findings suggest that structural WM network measurements can be utilized to differentiate between different types of cognitive impairment/dementia, and these measurements can provide valuable cognition-related information. Show more

Keywords: Alzheimer’s disease, brain network, diffusion tensor imaging, mixed dementia, vascular dementia

DOI: 10.3233/JAD-230341

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1487-1502, 2023

Authors: Glass Umfleet, Laura | Pommy, Jessica | Cohen, Alexander D. | Allen, Margaret | Obarski, Shawn | Mason, Lilly | Berres, Halle | Franczak, Malgorzata | Wang, Yang

Article Type: Research Article

Abstract: Background: Cerebrovascular health plays an important role in cognitive health in older adults. Cerebrovascular reactivity (CVR), a measure of cerebrovascular health, changes in both normal and pathological aging, and is increasingly being conceptualized as contributory to cognitive decline. Interrogation of this process will yield new insights into cerebrovascular correlates of cognition and neurodegeneration. Objective: The current study examines CVR using advanced MRI in prodromal dementia states (amnestic and non-amnestic mild cognitive impairment phenotypes; aMCI and naMCI, respectively) and older adult controls. Methods: CVR was assessed in 41 subjects (20 controls, 11 aMCI, 10 naMCI) using multiband …multi-echo breath-holding task functional magnetic resonance imaging. Imaging data were preprocessed and analyzed using AFNI. All participants also completed a battery of neuropsychological tests. T-tests and ANOVA/ANCOVA analyses were conducted to compare controls to MCI groups on CVR and cognitive metrics. Partial correlation analyses between CVR derived from regions-of-interest (ROIs) and different cognitive functions were conducted. Results: CVR was found to be significantly lower in aMCI and naMCI patients compared to controls. naMCI showed intermediate patterns between aMCI and controls (though aMCI and naMCI groups did not significantly differ). CVR of ROIs were positively correlated with neuropsychological measures of processing speed, executive functioning, and memory. Conclusion: The findings highlight regional CVR differences in MCI phenotypes compared to controls, where aMCI may have lower CVR than naMCI. Our results suggest possible cerebrovascular abnormalities associated with MCI phenotypes. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, cerebrovascular reactivity, dementia, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-221156

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1503-1513, 2023

Authors: Mao, Ming | Wang, Chaoqun | Hou, Tingting | Han, Xiaolei | Liu, Rui | Han, Qi | Dong, Yi | Wang, Jiafeng | Liu, Cuicui | Cong, Lin | Imahori, Yume | Vetrano, Davide Liborio | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Evidence has emerged that altered ventricular electrocardiogram profiles are associated with dementia, but the neuropathological mechanisms underlying their associations are poorly understood. Objective: To investigate the interrelationships of ventricular electrocardiogram profiles with dementia and plasma Alzheimer’s disease (AD) biomarkers among older adults. Methods: This population-based cross-sectional study included 5,153 participants (age ≥65 years; 57.3% women) living in rural communities in China; of these, 1,281 had data on plasma amyloid-β (Aβ)40 , Aβ42 , total-tau, and neurofilament light chain (NfL) protein. The QT, QTc, JT, JTc, QRS intervals, and QRS axis were derived from the 10-second …electrocardiogram recording. The DSM-IV criteria were followed for clinical diagnosis of dementia, the NIA-AA criteria for AD, and the NINDS-AIREN criteria for vascular dementia (VaD). Data were analyzed using general linear models, multinomial logistic models, and restricted cubic splines. Results: Of the 5,153 participants, 299 (5.8%) were diagnosed with dementia, including 194 with AD and 94 with VaD. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with all-cause dementia, AD, and VaD (p  < 0.05). Left QRS axis deviation was significantly associated with all-cause dementia and VaD (p  < 0.01). In the subsample of plasma biomarkers (n  = 1,281), prolonged QT, JT, and JTc intervals were significantly associated with a lower Aβ42 /Aβ40 ratio and higher plasma NfL concentrations (p  < 0.05). Conclusion: Alterations in ventricular repolarization and depolarization are independently associated with all-cause dementia, AD, VaD, and AD plasma biomarkers in older adults (age ≥65 years). Ventricular electrocardiogram parameters may be valuable clinical markers for dementia and the underlying AD pathologies and neurodegeneration. Show more

Keywords: Alzheimer’s disease, dementia, electrocardiogram, neurodegeneration, population-based study

DOI: 10.3233/JAD-230056

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1515-1526, 2023

Authors: Belliart-Guérin, Ghislain | Planche, Vincent

Article Type: Research Article

Abstract: Background: Mnemonic discrimination is the behavioral ability stemming from pattern separation, which is the neural process of establishing independent and non-overlapping new memories. Over the past two decades, its assessment in various populations has contributed to a better conceptual understanding of age-related memory decline. Objective: To assess the clinical relevance of mnemonic discrimination in the memory clinics setting. Methods: This retrospective study was performed in 90 patients with a Mini-Mental State Examination (MMSE)>18 who consulted our memory clinic for the first time. All patients were tested with the Mnemonic Similarity Task, a freely available computerized test. …Global cognitive function, executive function, visuoconstructional abilities, and verbal and visual episodic memory were also collected, together with the diagnosis after the initial clinical assessment (subjective cognitive complaint [SCC], mild cognitive impairment [MCI], or mild dementia). Results: Mnemonic discrimination performance was correlated with global cognitive function, executive function, and visual and verbal episodic memory scores, independent of age. It discriminated patients with SCC from those with MCI (amnestic or non-amnestic) with moderate accuracy (AUC = 0.77-0.78), similar to MMSE and the Frontal Assessment Battery (AUC = 0.74-0.84). Mnemonic discrimination performance did not distinguish between amnestic and non-amnestic MCI and the variability of the measure was important within groups. Conclusion: Mnemonic discrimination performance involves many cognitive domains and discriminates between patients with SCC and MCI with performance equivalent to “paper-and-pencil” screening tests. Further dedicated prospective studies will determine whether this task is of interest beyond research purposes, as a diagnostic or screening tool in primary care. Show more

Keywords: Alzheimer’s disease, episodic memory, hippocampus, memory clinic, mild cognitive impairment, mnemonic discrimination, pattern separation, subjective cognitive complaint

DOI: 10.3233/JAD-230221

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1527-1534, 2023

Authors: Emrani, Sheina | Lamar, Melissa | Price, Catherine C. | Swenson, Rod | Libon, David J. | Baliga, Ganesh

Article Type: Research Article

Abstract: Background: The theory of executive attention (Fuster, 2015) suggests considerable plasticity regarding when specific neurocognitive operations are recruited to bring executive tasks to fruition. Objective: We tested the hypothesis that differing neurocognitive operations are recruited upon the initiation of a response, but that other distinct neurocognitive operations are recruited towards the middle or end of a response. Methods: The Backward Digit Span Test (BDST) was administered to 58 memory clinic patients (MCI, n = 22; no-MCI, n = 36). Latency to generate all correct 5-span responses was obtained. Statistical analyses found that optimal group …classification was achieved using the first and third digit backward. First and third response latencies were analyzed in relation to verbal working memory (WM), visual WM, processing speed, visuospatial operations, naming/lexical access, and verbal episodic memory tests. Results: For the first response, slower latencies were associated with better performance in relation to verbal WM and visuospatial test performance. For the third response, faster latencies were associated with better processing speed and visuospatial test performance. Conclusion: Consistent with the theory of executive attention, these data show that the neurocognitive operations underlying successful executive test performance are not monolithic but can be quite nuanced with differing neurocognitive operations associated with specific time epochs. Results support the efficacy of obtaining time-based latency parameters to help disambiguate successful executive neurocognitive operations in memory clinic patients. Show more

Keywords: Alzheimer’s disease, Boston Process Approach, digit span, executive control, intra-component latency, mild cognitive impairment, temporal organization

DOI: 10.3233/JAD-230288

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1535-1547, 2023

Authors: Tio, Earvin S. | Hohman, Timothy J. | Milic, Milos | Bennett, David A. | Felsky, Daniel

Article Type: Research Article

Abstract: Background: Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer’s disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. Objective: We sought to determine whether a PRS for microglial activation (PRSmic ) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. Methods: First, PRSmic were calculated and optimized in a calibration cohort …(Alzheimer’s Disease Neuroimaging Initiative (ADNI), n  = 450), with resampling. Second, predictive performance of optimal PRSmic was assessed in two independent, population-based cohorts (total n  = 212,237). Finally, we explored associations of PRSmic with a comprehensive set of imaging and fluid AD biomarkers in ADNI. Results: Our PRSmic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance in either external cohort. Some nominal associations were found in ADNI, but with inconsistent effect directions. Conclusion: While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase. Show more

Keywords: Alzheimer’s disease, Canadian Longitudinal Study on Aging, computational modelling, microglial cell, neuroinflammation, polygenic traits, statistical data analysis

DOI: 10.3233/JAD-230434

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1549-1561, 2023

Authors: Gottschalk, William K | Mahon, Scott | Hodgson, Dellila | Barrera, Julio | Hill, Delaney | Wei, Angela | Kumar, Manish | Dai, Kathy | Anderson, Lauren | Mihovilovic, Mirta | Lutz, Michael W. | Chiba-Falek, Ornit

Article Type: Research Article

Abstract: Background: The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer’s disease (LOAD) and other age-related conditions. Objective: Here we developed the first humanized mouse model that contains the entire TOMM40 and APOE genes with all intronic and intergenic sequences including the upstream and downstream regions. Thus, the mouse model carries the human TOMM40 and APOE genes and their intact regulatory sequences. Methods: We generated the APOE -TOMM40 humanized mouse model in which the entire mouse region was replaced with the …human (h)APOE -TOMM40 loci including their upstream and downstream flanking regulatory sequences using recombineering technologies. We then measured the expression of the human TOMM40 and APOE genes in the mice brain, liver, and spleen tissues using TaqMan based mRNA expression assays. Results: We investigated the effects of the ‘523’ polyT genotype (S/S or VL/VL), sex, and age on the human TOMM40- and APOE- mRNAs expression levels using our new humanized mouse model. The analysis revealed tissue specific and shared effects of the ‘523’ polyT genotype, sex, and age on the regulation of the human TOMM40 and APOE genes. Noteworthy, the regulatory effect of the ‘523’ polyT genotype was observed for all studied organs. Conclusion: The model offers new opportunities for basic science, translational, and preclinical drug discovery studies focused on the APOE genomic region in relation to LOAD and other conditions in adulthood. Show more

Keywords: Age, Alzheimer’s disease, Alzheimer’s mouse model, APOE , gene expression, sex, TOMM40

DOI: 10.3233/JAD-230451

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1563-1576, 2023

Authors: Wang, Mengxue | Zhao, Guofeng | Jiang, Ying | Lu, Tong | Wang, Yanjuan | Zhu, Yixin | Zhang, Zhengsheng | Xie, Chunming | Wang, Zan | Ren, Qingguo

Article Type: Research Article

Abstract: Background: Cognitive impairment is the most common clinical manifestation of ischemic leukoaraiosis (ILA), but the underlying neurobiological pathways have not been well elucidated. Recently, it was thought that ILA is a “disconnection syndrome”. Disorganized brain connectome were considered the key neuropathology underlying cognitive deficits in ILA patients. Objective: We aimed to detect the disruption of network hubs in ILA patients using a new analytical method called voxel-based eigenvector centrality (EC) mapping. Methods: Subjects with moderate to severe white matters hyperintensities (Fazekas score ≥3) and healthy controls (HCs) (Fazekas score = 0) were included in the study. The resting-state …functional magnetic resonance imaging and the EC mapping approach were performed to explore the alteration of whole-brain network connectivity in ILA patients. Results: Relative to the HCs, the ILA patients exhibited poorer cognitive performance in episodic memory, information processing speed, and executive function (all ps  < 0.0125). Additionally, compared with HCs, the ILA patients had lower functional connectivity (i.e., EC values) in the medial parts of default-mode network (i.e., bilateral posterior cingulate gyrus and ventral medial prefrontal cortex [vMPFC]). Intriguingly, the functional connectivity strength at the right vMPFC was positively correlated with executive function deficit in the ILA patients. Conclusion: The findings suggested disorganization of the hierarchy of the default-mode regions within the whole-brain network in patients with ILA and advanced our understanding of the neurobiological mechanism underlying executive function deficit in ILA. Show more

Keywords: Brain connectome, default-mode network, eigenvector centrality mapping, executive function, ischemic leukoaraiosis, resting-state fMRI

DOI: 10.3233/JAD-230048

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1577-1586, 2023

Authors: Xu, Yuexuan | Vasiljevic, Eva | Deming, Yuetiva K. | Jonaitis, Erin M. | Koscik, Rebecca L. | Van Hulle, Carol A. | Lu, Qiongshi | Carboni, Margherita | Kollmorgen, Gwendlyn | Wild, Norbert | Carlsson, Cynthia M. | Johnson, Sterling C. | Zetterberg, Henrik | Blennow, Kaj | Engelman, Corinne D.

Article Type: Research Article

Abstract: Background: Genetic scores for late-onset Alzheimer’s disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without APOE were constructed separately based on the significant …SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE , the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms. Show more

Keywords: Aging, Alzheimer’s disease, ApoE, biomarkers, cognition, longitudinal studies

DOI: 10.3233/JAD-230097

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1587-1605, 2023

Authors: Fenton, Laura | Han, S. Duke | DiGuiseppi, Carolyn G. | Fowler, Nicole R. | Hill, Linda | Johnson, Rachel L. | Peterson, Ryan A. | Knoepke, Christopher E. | Matlock, Daniel D. | Moran, Ryan | Karlawish, Jason | Betz, Marian E.

Article Type: Research Article

Abstract: Background: Older adults are faced with many unique and highly consequential decisions such as those related to finances, healthcare, and everyday functioning (e.g., driving cessation). Given the significant impact of these decisions on independence, wellbeing, and safety, an understanding of how cognitive impairment may impact decision making in older age is important. Objective: To examine the impact of mild cognitive impairment (MCI) on responses to a modified version of the Short Portable Assessment of Capacity for Everyday Decision making (SPACED). Methods: Participants were community-dwelling, actively driving older adults (N = 301; M age = 77.1 years, SD = 5.1; 69.4% with …a college degree or higher; 51.2% female; 95.3% White) enrolled in the Advancing Understanding of Transportation Options (AUTO) study. A generalized linear model adjusted for age, education, sex, randomization group, cognitive assessment method, and study site was used to examine the relationship between MCI status and decision making. Results: MCI status was associated with poorer decision making; participants with MCI missed an average of 2.17 times more points on the SPACED than those without MCI (adjusted mean ratio: 2.17, 95% CI: 1.02, 4.61, p  = 0.044). Conclusion: This finding supports the idea that older adults with MCI exhibit poorer decision-making abilities than cognitively normal older adults. It also suggests that older adults with MCI may exhibit poorer decision making across a wide range of decision contexts. Show more

Keywords: Alzheimer’s disease, cognition, decision making, mild cognitive impairment, older adults

DOI: 10.3233/JAD-230222

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1607-1615, 2023

Authors: Cai, Hong-Yan | Yang, Dan | Qiao, Jing | Yang, Jun-Ting | Wang, Zhao-Jun | Wu, Mei-Na | Qi, Jin-Shun | Holscher, Christian

Article Type: Correction

DOI: 10.3233/JAD-239006

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1617-1618, 2023

Authors: Yang, Heyun | Wang, Wei | Jia, Longfei | Qin, Wei | Hou, Tingting | Wu, Qiaoqi | Li, Haitao | Tian, Yuanruhua | Jia, Jianping

Article Type: Correction

DOI: 10.3233/JAD-239007

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1619-1622, 2023