Journal of Alzheimer's Disease - Volume 92, issue 4

Authors: Loughman, Amy | Adler, Christina J. | Macpherson, Helen

Article Type: Review Article

Abstract: Advancing age is recognized as the primary risk factor for Alzheimer’s disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which …the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk. Show more

Keywords: Alzheimer’s disease, dementia, healthy lifestyle, microbiota, oral health, periodontal diseases

DOI: 10.3233/JAD-220760

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1111-1129, 2023

Authors: Shah, Jay | Rahman Siddiquee, Md Mahfuzur | Krell-Roesch, Janina | Syrjanen, Jeremy A. | Kremers, Walter K. | Vassilaki, Maria | Forzani, Erica | Wu, Teresa | Geda, Yonas E.

Article Type: Review Article

Abstract: There is a growing interest in the application of machine learning (ML) in Alzheimer’s disease (AD) research. However, neuropsychiatric symptoms (NPS), frequent in subjects with AD, mild cognitive impairment (MCI), and other related dementias have not been analyzed sufficiently using ML methods. To portray the landscape and potential of ML research in AD and NPS studies, we present a comprehensive literature review of existing ML approaches and commonly studied AD biomarkers. We conducted PubMed searches with keywords related to NPS, AD biomarkers, machine learning, and cognition. We included a total of 38 articles in this review after excluding some irrelevant …studies from the search results and including 6 articles based on a snowball search from the bibliography of the relevant studies. We found a limited number of studies focused on NPS with or without AD biomarkers. In contrast, multiple statistical machine learning and deep learning methods have been used to build predictive diagnostic models using commonly known AD biomarkers. These mainly included multiple imaging biomarkers, cognitive scores, and various omics biomarkers. Deep learning approaches that combine these biomarkers or multi-modality datasets typically outperform single-modality datasets. We conclude ML may be leveraged to untangle the complex relationships of NPS and AD biomarkers with cognition. This may potentially help to predict the progression of MCI or dementia and develop more targeted early intervention approaches based on NPS. Show more

Keywords: Alzheimer’s disease, cognition, deep learning, machine learning, neuropsychiatric symptoms

DOI: 10.3233/JAD-221261

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1131-1146, 2023

Authors: Dingle, Sara E. | Bujtor, Melissa S. | Milte, Catherine M. | Bowe, Steven J. | Daly, Robin M. | Torres, Susan J.

Article Type: Review Article

Abstract: Background: Dementia prevention is a global health priority, and there is emerging evidence to support associations between individual modifiable health behaviors and cognitive function and dementia risk. However, a key property of these behaviors is they often co-occur or cluster, highlighting the importance of examining them in combination. Objective: To identify and characterize the statistical approaches used to aggregate multiple health-related behaviors/modifiable risk factors and assess associations with cognitive outcomes in adults. Methods: Eight electronic databases were searched to identify observational studies exploring the association between two or more aggregated health-related behaviors and cognitive outcomes in …adults. Results: Sixty-two articles were included in this review. Fifty articles employed co-occurrence approaches alone to aggregate health behaviors/other modifiable risk factors, eight studies used solely clustering-based approaches, and four studies used a combination of both. Co-occurrence methods include additive index-based approaches and presenting specific health combinations, and whilst simple to construct and interpret, do not consider the underlying associations between co-occurring behaviors/risk factors. Clustering-based approaches do focus on underlying associations, and further work in this area may aid in identifying at-risk subgroups and understanding specific combinations of health-related behaviors/risk factors of particular importance in the scope of cognitive function and neurocognitive decline. Conclusion: A co-occurrence approach to aggregating health-related behaviors/risk factors and exploring associations with adult cognitive outcomes has been the predominant statistical approach used to date, with a lack of research employing more advanced statistical methods to explore clustering-based approaches. Show more

Keywords: Clustering, co-occurrence, cognition, combined, health behaviors, lifestyle

DOI: 10.3233/JAD-221034

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1147-1171, 2023

Authors: Xu, Yunlong | Zheng, Fuxiang | Zhong, Qi | Zhu, Yingjie

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include …improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, ketogenic diet, ketone body, ketone bodies therapy, neuroinflammation, tau protein

DOI: 10.3233/JAD-230002

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1173-1198, 2023

Authors: Jehu, Deborah A. | Davis, Jennifer C. | Gill, Jessica | Oke, Olabamibo | Liu-Ambrose, Teresa

Article Type: Systematic Review

Abstract: Background: People living with dementia (PWD) are at a heightened risk for falls. However, the effects of exercise on falls in PWD are unclear. Objective: To conduct a systematic review of randomized controlled trials (RCTs) examining the efficacy of exercise to reduce falls, recurrent falls, and injurious falls relative to usual care among PWD. Methods: We included peer-reviewed RCTs evaluating any exercise mode on falls and related injuries among medically diagnosed PWD aged ≥55years (international prospective register of systematic reviews (PROSPERO) ID:CRD42021254637). We excluded studies that did not solely involve PWD and were not the primary …publication examining falls. We searched the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register and grey literature on 08/19/2020 and 04/11/2022; topical categories included dementia, exercise, RCTs, and falls. We evaluated the risk of bias (ROB) using the Cochrane ROB Tool-2 and study quality using the Consolidated Standards of Reporting Trials. Results: Twelve studies were included (n  = 1,827; age = 81.3±7.0 years; female = 59.3%; Mini-Mental State Examination = 20.1±4.3 points; intervention duration = 27.8±18.5 weeks; adherence = 75.5±16.2%; attrition = 21.0±12.4%). Exercise reduced falls in two studies [Incidence Rate Ratio (IRR) range = 0.16 to 0.66; fall rate range: intervention = 1.35–3.76 falls/year, control = 3.07–12.21 falls/year]; all other studies (n  = 10) reported null findings. Exercise did not reduce recurrent falls (n  = 0/2) or injurious falls (n  = 0/5). The RoB assessment ranged from some concerns (n  = 9) to high RoB (n  = 3); no studies were powered for falls. The quality of reporting was good (78.8±11.4%). Conclusion: There was insufficient evidence to suggest that exercise reduces falls, recurrent falls, or injurious falls among PWD. Well-designed studies powered for falls are needed. Show more

Keywords: Dementia, exercise, fall risk, falls, injury, older adults, recurrent, secondary prevention, systematic review

DOI: 10.3233/JAD-221038

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1199-1217, 2023

Authors: Golas, Angela C. | Salwierz, Patrick | Rajji, Tarek K. | Bowie, Christopher R. | Butters, Meryl A. | Fischer, Corinne E. | Flint, Alastair J. | Herrmann, Nathan | Mah, Linda | Mulsant, Benoit H. | Pollock, Bruce G. | Taghdiri, Foad | Wang, Wei | Tartaglia, M. Carmela

Article Type: Short Communication

Abstract: Major depressive disorder (MDD) is a risk factor for Alzheimer’s disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n  = 12), MCI with remitted MDD (MDD+MCI) (n  = 12), and remitted MDD alone (MDD) (n  = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in …MCI patients with AD(-) biomarkers. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, major depressive disorder, mild neurocognitive disorder

DOI: 10.3233/JAD-221097

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1219-1227, 2023

Authors: Abraham Daniel, Ann | Silzer, Talisa | Sun, Jie | Zhou, Zhengyang | Hall, Courtney | Phillips, Nicole | Barber, Robert

Article Type: Research Article

Abstract: Background: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer’s disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation). Objective: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs. Methods: DNA obtained from peripheral …blood of 551 participants from the Texas Alzheimer’s Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. Results: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p  < 0.05. Three suggestive sites obtained were cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs). Most methylation sites were hypermethylated in CI compared to controls, except cg13529380 which was hypomethylated. Conclusion: The strongest association with CI was at cg13135255 (FDR-adjusted p  = 0.029 in MAs), within the CREBBP gene. Moving forward, identifying additional ethnicity-specific methylation sites may be useful to discern CI risk in MAs. Show more

Keywords: Alzheimer’s disease, epigenetics, methylation, Mexican Americans, mild cognitive impairment

DOI: 10.3233/JAD-221031

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1229-1239, 2023

Authors: Li, Yi | Wang, Jin-zhao | Deng, Yue-ming | Wang, Kun | Yang, Li | Long, Cheng

Article Type: Research Article

Abstract: Background: Amyloid-β protein precursor (AβPP) is enriched in neurons. However, the mechanism underlying AβPP regulation of neuronal activity is poorly understood. Potassium channels are critically involved in neuronal excitability. In hippocampus, A-type potassium channels are highly expressed and involved in determining neuronal spiking. Objective: We explored hippocampal local field potential (LFP) and spiking in the presence and absence of AβPP, and the potential involvement of an A-type potassium channel. Methods: We used in vivo extracellular recording and whole-cell patch-clamp recording to determine neuronal activity, current density of A-type potassium currents, and western blot to detect …changes in related protein levels. Results: Abnormal LFP was observed in AβPP–/– mice, including reduced beta and gamma power, and increased epsilon and ripple power. The firing rate of glutamatergic neurons reduced significantly, in line with an increased action potential rheobase. Given that A-type potassium channels regulate neuronal firing, we measured the protein levels and function of two major A-type potassium channels and found that the post-transcriptional level of Kv1.4, but not Kv4.2, was significantly increased in the AβPP–/– mice. This resulted in a marked increase in the peak time of A-type transient outward potassium currents in both glutamatergic and gamma-aminobutyric acid-ergic (GABAergic) neurons. Furthermore, a mechanistic experiment using human embryonic kidney 293 (HEK293) cells revealed that the AβPP deficiency-induced increase in Kv1.4 may not involve protein-protein interaction between AβPP and Kv1.4. Conclusion: This study suggests that AβPP modulates neuronal firing and oscillatory activity in the hippocampus, and Kv1.4 may be involved in mediating the modulation. Show more

Keywords: A-type transient outward potassium current, Alzheimer’s disease, amyloid-β precursor protein, hippocampus, Kv1.4

DOI: 10.3233/JAD-220606

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1241-1256, 2023

Authors: Mahanna-Gabrielli, Elizabeth | Kuwayama, Sayaka | Tarraf, Wassim | Kaur, Sonya | DeBuc, Delia Cabrera | Cai, Jianwen | Daviglus, Martha L. | Joslin, Charlotte E. | Lee, David J. | Mendoza-Santiesteban, Carlos | Stickel, Ariana M. | Zheng, Diane | González, Hector M. | Ramos, Alberto R.

Article Type: Research Article

Abstract: Background: Visual impairment could worsen sleep/wake disorders and cognitive decline. Objective: To examine interrelations among self-reported visual impairment, sleep, and cognitive decline in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Miami-site. Method: HCHS/SOL Miami-site participants ages 45–74 years (n  = 665) at Visit-1, who returned for cognitive test 7-years later (SOL-INCA). Participants completed the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ), validated sleep questionnaires and test for obstructive sleep apnea (OSA) at Visit-1. We obtained verbal episodic learning and memory, verbal fluency, processing speed, and executive functioning at Visit-1 and at SOL-INCA. Processing speed/executive functioning were …added to SOL-INCA. We examined global cognition and change using a regression-based reliable change index, adjusting for the time lapse between Visit-1 and SOL-INCA. We used regression models to test whether 1) persons with OSA, self-reported sleep duration, insomnia, and sleepiness have an increased risk for visual impairment, 2a) visual impairment is associated with worse cognitive function and/or decline, and 2b) sleep disorders attenuate these associations. Result: Sleepiness (β= 0.04; p  < 0.01) and insomnia (β= 0.04; p  < 0.001) were cross-sectionally associated with visual impairment, adjusting for sociodemographic characteristics, behavioral factors, acculturation, and health conditions. Visual impairment was associated with lower global cognitive function at Visit-1 (β= –0.16; p  < 0.001) and on average 7-years later (β= –0.18; p  < 0.001). Visual impairment was also associated with a change in verbal fluency (β= –0.17; p  < 0.01). OSA, self-reported sleep duration, insomnia, and sleepiness did not attenuate any of the associations. Conclusion: Self-reported visual impairment was independently associated with worse cognitive function and decline. Show more

Keywords: Cognitive decline, health disparities, Hispanic/Latinos, sleep disorders, visual impairment

DOI: 10.3233/JAD-221073

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1257-1267, 2023

Authors: O’Shea, Deirdre M. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Evidence suggests that APOE ɛ4 carriers have worse memory performances compared to APOE ɛ4 non-carriers and effects may vary by sex and age. Estimates of biological age, using DNA methylation may enhance understanding of the associations between sex and APOE ɛ4 on cognition. Objective: To investigate whether associations between APOE ɛ4 status and memory vary according to rates of biological aging, using a DNA methylation age biomarker, in older men and women without dementia. Methods: Data were obtained from 1,771 adults enrolled in the 2016 wave of the Health and Retirement …Study. A series of ANCOVAs were used to test the interaction effects of APOE ɛ4 status and aging rates (defined as 1 standard deviation below (i.e., slow rate), or above (i.e., fast rate) their sex-specific mean rate of aging on a composite measure of verbal learning and memory. Results: APOE ɛ4 female carriers with slow rates of GrimAge had significantly better memory performances compared to fast and average aging APOE ɛ4 female carriers. There was no effect of aging group rate on memory in the female non-carriers and no significant differences in memory according to age rate in either male APOE ɛ4 carriers or non-carriers. Conclusion: Slower rates of aging in female APOE ɛ4 carriers may buffer against the negative effects of the ɛ4 allele on memory. However, longitudinal studies with larger sample sizes are needed to evaluate risk of dementia/memory impairment based on rates of aging in female APOE ɛ4 carriers. Show more

Keywords: Aging, APOE ɛ4, epigenetic clocks, memory

DOI: 10.3233/JAD-221145

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1269-1282, 2023