Journal of Alzheimer's Disease - Volume 90, issue 2

Authors: Hrincu, Viorica | An, Zijian | Joseph, Kenneth | Jiang, Yu Fei | Robillard, Julie M.

Article Type: Review Article

Abstract: Background: Social media is a powerful tool for engaging diverse audiences in dementia research. However, there is little data summarizing current content exchange in this context. Objective: To inform ethical dementia research engagement on social media, we characterized current practices by analyzing public social media posts. Methods: We retrieved Facebook (2-year period, N  = 7,896) and Twitter (1-year period, N  = 9,323) posts containing dementia research-related keywords using manual and machine learning-based search strategies. We performed qualitative and quantitative content and sentiment analyses on random samples (10%) of the posts. Results: Top Facebook users were advocacy …(45%) and health organizations (25%). On Twitter, academics/researchers were the largest user group. Prevention was the most frequently coded theme (Facebook 30%; Twitter 26%), followed by treatment (Facebook 15%; Twitter 18%). Diagnostics had the highest Facebook engagement. Sharing knowledge was the primary form of content exchange (Facebook 63%; Twitter 80%). Most shared journal articles were peer-reviewed and open access. Emotional tone was overall more positive on Facebook. Justice was a prominent ethics topic regarding inequalities related to identity and intersecting modes of marginalization in dementia research. Conclusion: The findings indicate the importance of social media as an engagement tool of current topics in health research and reveal areas of potential for increased engagement. These data can inform consensus-based best practices for ethical social media application in dementia research. Show more

Keywords: Access to information, Alzheimer’s disease, dementia, internet, qualitative research, social media

DOI: 10.3233/JAD-220525

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 447-459, 2022

Authors: Joshi, Mahesh S. | Galvin, James E.

Article Type: Review Article

Abstract: With the expected rise in Alzheimer’s disease and related dementias (ADRD) in the coming decades due to the aging population and a lack of effective disease-modifying treatments, there is a need for preventive strategies that may tap into resilience parameters. A wide array of resilience strategies has been proposed including genetics, socioeconomic status, lifestyle modifications, behavioral changes, and management of comorbid disease. These different strategies can be broadly classified as distinguishing between modifiable and non-modifiable risk factors, some of which can be quantified so that their clinical intervention can be effectively accomplished. A clear shift in research focus from dementia …risk to addressing disease resistance and resilience is emerging that has provided new potential therapeutic targets. Here we review and summarize the latest investigations of resilience mechanisms and methods of quantifying resilience for clinical research. These approaches include identifying genetic variants that may help identify novel pathways (e.g., lipid metabolism, cellular trafficking, synaptic function, inflammation) for therapeutic treatments and biomarkers for use in a precision medicine-like regimen. In addition, innovative structural and molecular neuroimaging analyses may assist in detecting and quantifying pathological changes well before the onset of clinical symptoms setting up the possibility of primary and secondary prevention trials. Lastly, we summarize recent studies demonstrating the study of resilience in caregivers of persons living with dementia may have direct and indirect impact on the quality of care and patient outcomes. Show more

Keywords: Alzheimer’s disease, biomarkers, brain health, cognition, cognitive reserve, dementia, neuroimaging, resilience

DOI: 10.3233/JAD-220755

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 461-473, 2022

Authors: Downey, Jocelyn | Lam, Jacqueline C.K. | Li, Victor O.K. | Gozes, Illana

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents a global health challenge, with an estimated 55 million people suffering from the non-curable disease across the world. While amyloid-β plaques and tau neurofibrillary tangles in the brain define AD proteinopathy, it has become evident that diverse coding and non-coding regions of the genome may significantly contribute to AD neurodegeneration. The diversity of factors associated with AD pathogenesis, coupled with age-associated damage, suggests that a series of triggering events may be required to initiate AD. Since somatic mutations accumulate with aging, and aging is a major risk factor for AD, there is a great potential for …somatic mutational events to drive disease. Indeed, recent data from the Gozes team/laboratories as well as other leading laboratories correlated the accumulation of somatic brain mutations with the progression of tauopathy. In this review, we lay the current perspectives on the principal genetic factors associated with AD and the potential causes, highlighting the contribution of somatic mutations to the pathogenesis of late onset Alzheimer’s disease. The roles that artificial intelligence and big data can play in accelerating the progress of causal somatic mutation markers/biomarkers identification, and the associated drug discovery/repurposing, have been highlighted for future AD and other neurodegenerations, with the aim to bring hope for the vulnerable aging population. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, artificial intelligence, big data, late onset Alzheimer’s disease, somatic mutations, tau

DOI: 10.3233/JAD-220643

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 475-493, 2022

Authors: Xu, Chang | Zhao, Li | Dong, Chunbo

Article Type: Review Article

Abstract: The number of patients with Alzheimer’s disease (AD) and non-Alzheimer’s disease (non-AD) has drastically increased over recent decades. The amyloid cascade hypothesis attributes a vital role to amyloid-β protein (Aβ) in the pathogenesis of AD. As the main pathological hallmark of AD, amyloid plaques consist of merely the 42 and 40 amino acid variants of Aβ (Aβ42 and Aβ40 ). The cerebrospinal fluid (CSF) biomarker Aβ42/40 has been extensively investigated and eventually integrated into important diagnostic tools to support the clinical diagnosis of AD. With the development of highly sensitive assays and technologies, blood-based Aβ42/40 , which was …obtained using a minimally invasive and cost-effective method, has been proven to be abnormal in synchrony with CSF biomarker values. This paper presents the recent progress of the CSF Aβ42/40 ratio and plasma Aβ42/40 for AD as well as their potential clinical application as diagnostic markers or screening tools for dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, plasma

DOI: 10.3233/JAD-220673

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 495-512, 2022

Authors: Rai, Harleen Kaur | Kernaghan, David | Schoonmade, Linda | Egan, Kieren J. | Pot, Anne Margriet

Article Type: Systematic Review

Abstract: Background: Dementia poses significant and sustained challenges to global society. Diagnosis can lead to increased feelings of loneliness and social isolation. People with dementia living alone are particularly at risk. Considering the growing number of technologies proposed to aid people with dementia address social isolation and loneliness, we reviewed the existing literature. Objective: To collate and summarize current evidence for digital technologies to prevent social isolation and loneliness for people with dementia. Methods: Following the PRISMA guidelines, we systematically searched five databases to identify studies of digital technologies designed to support or prevent social isolation or …loneliness for people with dementia. Pre-specified outcomes included social isolation, loneliness, and quality of life. We used deductive thematic analysis to synthesize the major themes emerging from the studies. Results: Ten studies met our inclusion criteria where all studies reported improvements in quality of life and seven reported benefits regarding social inclusion or a reduction in loneliness. Technologies were varied across purpose, delivery format, theoretical models, and levels of personalization. Two studies clearly described the involvement of people with dementia in the study design and five technologies were available outside the research context. Conclusion: There is limited— but increasing— evidence that technologies hold potential to improve quality of life and reduce isolation/loneliness for people with dementia. Results presented are largely based in small-scale research studies. Involvement of people with dementia was limited and few research concepts are reaching implementation. Closer collaboration with people with dementia to provide affordable, inclusive, and person-centered solutions is urgently required. Show more

Keywords: Dementia, digital technology, loneliness, quality of life, social isolation

DOI: 10.3233/JAD-220438

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 513-528, 2022

Authors: Khezri, Mohammad Rafi | Esmaeili, Ayda | Ghasemnejad-Berenji, Morteza

Article Type: Research Article

Abstract: In recent years, the association between the activity of platelets and risk of Alzheimer’s disease (AD) risk has been noticed in numerous studies. However, there in no investigations on the role of specific intracellular pathways to explain this connection. The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is one of the main regulators of cell survival which regulates cellular responses to environmental changes. This pathway also regulates the activity of platelets, and its aberrant activity has been linked to platelet dysfunction in different pathologies. On the other hand, the PI3K/AKT pathway regulates amyloid-β (Aβ) production through regulation of amyloid-β protein precursor (AβPP), …BACE-1, ADAMs, and γ -secretase. In addition, alterations in the activity of all of these factors in platelets has been shown in AD-related pathologies. Therefore, this paper aims to introduce the PI3K/AKT pathway as a molecular inducer of platelet dysfunction during aging and AD progression. Show more

Keywords: Alzheimer’s disease, amyloid, PI3K/AKT, platelet

DOI: 10.3233/JAD-220663

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 529-534, 2022

Authors: Palmer, Jacqueline A. | Kaufman, Carolyn S. | Vidoni, Eric D. | Honea, Robyn A. | Burns, Jeffrey M. | Billinger, Sandra A.

Article Type: Short Communication

Abstract: Sex as a biological variable appears to contribute to the multifactorial etiology of Alzheimer’s disease. We tested sex-based interactions between cerebrovascular function and APOE4 genotype on resistance and resilience to brain pathology and cognitive executive dysfunction in cognitively-normal older adults. Female APOE4 carriers had higher amyloid-β deposition yet achieved similar cognitive performance to males and female noncarriers. Further, female APOE4 carriers with robust cerebrovascular responses to exercise possessed lower amyloid-β. These results suggest a unique cognitive resilience and identify cerebrovascular function as a key mechanism for resistance to age-related brain pathology in females with high genetic vulnerability …to Alzheimer’s disease. Show more

Keywords: Aging, Apolipoproteins E, amyloid, cardiovascular system, cerebrovascular circulation, cognition, female, hemodynamics, ultrasound

DOI: 10.3233/JAD-220359

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 535-542, 2022

Authors: Vipin, Ashwati | Koh, Chen Ling | Wong, Benjamin Yi Xin | Zailan, Fatin Zahra | Tan, Jayne Yi | Soo, See Ann | Satish, Vaynii | Kumar, Dilip | Wang, Brian Zhiyang | Ng, Adeline Su Lyn | Chiew, Hui Jin | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Short Communication

Abstract: We examined amyloid-tau-neurodegeneration biomarker effects on cognition in a Southeast-Asian cohort of 84 sporadic young-onset dementia (YOD; age-at-onset <65 years) patients. They were stratified into A+N+, A– N+, and A– N– profiles via cerebrospinal fluid amyloid-β1–42 (A), phosphorylated-tau (T), MRI medial temporal atrophy (neurodegeneration– N), and confluent white matter hyperintensities cerebrovascular disease (CVD). A, T, and CVD effects on longitudinal Mini-Mental State Examination (MMSE) were evaluated. A+N+ patients demonstrated steeper MMSE decline than A– N+ (β = 1.53; p  = 0.036; CI 0.15:2.92) and A– N– (β = 4.68; p  = 0.001; CI 1.98:7.38) over a mean follow-up of 1.24 years. Within A– N+, T– …CVD+ patients showed greater MMSE decline compared to T+CVD– patients (β = – 2.37; p  = 0.030; CI – 4.41:– 0.39). A+ results in significant cognitive decline, while CVD influences longitudinal cognition in the A– sub-group. Show more

Keywords: ATN profile, cognition, longitudinal, Southeast Asian cohort, young-onset dementia

DOI: 10.3233/JAD-220448

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 543-551, 2022

Authors: Crockett, Rachel A. | Hsu, Chun Liang | Dao, Elizabeth | Tam, Roger | Eng, Janice J. | Handy, Todd C. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) are associated with impaired cognition and increased falls risk. Resistance training (RT) is a promising intervention to reduce WMH progression, improve executive functions, and reduce falls. However, the underlying neurobiological process by which RT improves executive functions and falls risk remain unclear. We hypothesized that: 1) RT reduces the level of WMH-related disruption to functional networks; and 2) reduced disruption to the sensorimotor and attention networks will be associated with improved executive function and reduced falls risk. Objective: Investigate the impact of 52 weeks of RT on WMH-related disruption to functional networks. …Methods: Thirty-two older females (65–75 years) were included in this exploratory analysis of a 52-week randomized controlled trial. Participants received either twice-weekly RT or balance and tone training (control). We used lesion network mapping to assess changes in WMH-related disruption to the sensorimotor, dorsal attention, and ventral attention networks. Executive function was measured using the Stroop Colour-Word Test. Falls risk was assessed using the Physiological Profile Assessment (PPA) and the foam sway test. Results: RT significantly reduced the level of WMH-related disruption to the sensorimotor network (p  = 0.012). Reduced disruption to the dorsal attention network was associated with improvements in Stroop performance (r  = 0.527, p  = 0.030). Reduced disruption to the ventral attention network was associated with reduced PPA score (r  = 0.485, p  = 0.049) Conclusion: RT may be a promising intervention to mitigate WMH-related disruption to the sensorimotor network. Additionally, reducing disruption to the dorsal and ventral attention networks may contribute to improved executive function and reduced falls risk respectively. Show more

Keywords: Cognition, executive functions, exercise, falls risk, functional connectivity, resistance training

DOI: 10.3233/JAD-220142

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 553-563, 2022

Authors: Dentoni, Giacomo | Naia, Luana | Portal, Benjamin | Leal, Nuno Santos | Nilsson, Per | Lindskog, Maria | Ankarcrona, Maria

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) research has relied on mouse models overexpressing human mutant A βPP ; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL -F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment. Objective: In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL -F embryos, especially to identify early mitochondrial alterations in this model. …Methods: Primary cultures of AppNL -F neurons kept in culture for 12–15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death. Results: We detected higher levels of Aβ42 released from AppNL -F neurons as compared to wild-type neurons. AppNL -F neurons, also displayed an increased Aβ42 /Aβ40 ratio, similar to adult AppNL -F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL -F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function. Conclusion: We show that widespread mitochondrial alterations can be detected in AppNL -F neurons in vitro , where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations. Show more

Keywords: Alzheimer’s disease, AppNL-F knock-in mice, mitochondria, mitochondria-ER contact sites, synapses

DOI: 10.3233/JAD-220383

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 565-583, 2022