Journal of Alzheimer's Disease - Volume 91, issue 2

Authors: Rajah Kumaran, Kesevan | Yunusa, Suleiman | Perimal, Enoch | Wahab, Habibah | Müller, Christian P. | Hassan, Zurina

Article Type: Review Article

Abstract: The aging population increases steadily because of a healthy lifestyle and medical advancements in healthcare. However, Alzheimer’s disease (AD) is becoming more common and problematic among older adults. AD-related cases show an increasing trend annually, and the younger age population may also be at risk of developing this disorder. AD constitutes a primary form of dementia, an irreversible and progressive brain disorder that steadily damages cognitive functions and the ability to perform daily tasks. Later in life, AD leads to death as a result of the degeneration of specific brain areas. Currently, the cause of AD is poorly understood, and …there is no safe and effective therapeutic agent to cure or slow down its progression. The condition is entirely preventable, and no study has yet demonstrated encouraging findings in terms of treatment. Identifying this disease’s pathophysiology can help researchers develop safe and efficient therapeutic strategies to treat this ailment. This review outlines and discusses the pathophysiology that resulted in the development of AD including amyloid-β plaques, tau neurofibrillary tangles, neuroinflammation, oxidative stress, cholinergic dysfunction, glutamate excitotoxicity, and changes in neurotrophins level may sound better based on the literature search from Scopus, PubMed, ScienceDirect, and Google Scholar. Potential therapeutic strategies are discussed to provide more insights into AD mechanisms by developing some possible pharmacological agents for its treatment. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cholinergic, neurodegeneration, neuroinflammation, pharmacological agent, tau tangles

DOI: 10.3233/JAD-220666

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 507-530, 2023

Authors: Costa, Tommaso | Manuello, Jordi | Cauda, Franco | Liloia, Donato

Article Type: Short Communication

Abstract: Despite intense research on Alzheimer’s disease, no validated treatment able to reverse symptomatology or stop disease progression exists. A recent systematic review by Kim and colleagues evaluated possible reasons behind the failure of the majority of the clinical trials. As the focus was on methodological factors, no statistical trends were examined in detail. Here, we aim to complete this picture leveraging on Bayesian analysis. In particular, we tested whether the failure of those clinical trials was essentially due to insufficient statistical power or to lack of a true effect. The strong Bayes’ Factor obtained supported the latter hypothesis.

Keywords: Alzheimer’s disease, Bayesian statistics, clinical trial, drug development

DOI: 10.3233/JAD-220942

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 531-535, 2023

Authors: Füllgrabe, Christian

Article Type: Short Communication

Abstract: Cognitive-screening tests are used to detect pathological changes in mental abilities. Many use orally presented instructions and test items. Hence, hearing loss (HL), whose prevalence increases with age, may bias cognitive-test performance in the target population for the screening of dementia due to Alzheimer’s disease. To study the effect of the auditory test format, an impairment-simulation approach was used in normal-hearing listeners to compare performance on the Hopkins Verbal Learning Test, a memory task employed in dementia screening and research, when test items were unprocessed and processed to simulate age-related HL. Immediate verbal recall declined with simulated HL, suggesting that …auditory factors are confounding variables in cognitive assessment and result in the underestimation of cognitive functioning. Show more

Keywords: Age-related hearing loss, Alzheimer’s disease, auditory bias, cognitive assessment, dementia, Hopkins Verbal Learning Test, impairment simulation, screening

DOI: 10.3233/JAD-215695

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 537-541, 2023

Authors: Sullivan, Kevin J. | Griswold, Michael E. | Ghelani, Kunali | Rajesh, Aishwarya | Shrestha, Srishti | Gottesman, Rebecca F. | Knopman, David | Mosley, Thomas H. | Windham, B. Gwen

Article Type: Short Communication

Abstract: At visit 3 (1993–1995) of the ARIC Study, 1.5T brain MRI was completed in 1,881 stroke-free participants (Mean age = 62.9±4.9, 50% Black). Cox regression examined associations between infarct group [infarct-free (referent; n  = 1,611), smaller only (<3 mm; n  = 50), larger only (≥3 mm but <20 mm; n  = 185), both (n  = 35)] and up to 25-year incident dementia (n  = 539). Participants with both infarcts were over 2.5 times more likely to develop dementia [HR = 2.61; 95% CI = 1.44, 4.72]. Smaller only (HR = 1.22; 95% CI = 0.70, 2.13) and larger only (HR = 1.27; 95% CI = 0.92, 1.74) groups showed associations with wide confidence intervals, unsupported statistically. A late midlife infarct profile including …smaller and larger infarcts may represent particular vulnerability to dementia risk. Show more

Keywords: Cerebrovascular disease, cognition, dementia, epidemiology, infarct

DOI: 10.3233/JAD-220746

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 543-549, 2023

Authors: van der Steen, Jenny T. | van Leussen, Carolien A. | Ballentine, Joanne | Gribben, Loretta | Reid, Joanne | Hasson, Felicity | Brazil, Kevin | The, B. Anne-Mei | McLaughlin, Dorry

Article Type: Short Communication

Abstract: Much is known about palliative care needs of persons with dementia and their family. Less is known about how to successfully implement models that address those needs. We present specialist models in the Netherlands (2017-2018) and Northern Ireland (2016-2017) contrasting its evaluations. From implementation failure in the Netherlands compared with successful implementation in Northern Ireland, we learn that recognizing roles and competencies among all involved is essential in developing effective partnership relationships. All of this is facilitated by referral before the end of life and offering various training programs and in-patient and out-patient services and therapies to show benefits early.

Keywords: Dementia, evaluation, health services, hospice care, negative results, palliative care

DOI: 10.3233/JAD-220772

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 551-557, 2023

Authors: Green, Zachary D. | Vidoni, Eric D. | Swerdlow, Russell H. | Burns, Jeffrey M. | Morris, Jill K. | Honea, Robyn A.

Article Type: Research Article

Abstract: Background: First-degree relatives of individuals with late-onset Alzheimer’s disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. Objective: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD …risk. Methods: We used MRI and fMRI to study cognitively healthy individuals (n  = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n  = 31) and early-stage AD (n  = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. Results: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. Conclusion: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD. Show more

Keywords: Alzheimer’s disease, default mode network, family history, hippocampus, maternal, mild cognitive impairment, precuneus, resting state

DOI: 10.3233/JAD-210326

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 559-571, 2023

Authors: Blair, Emilie M. | Reale, Bailey K. | Zahuranec, Darin B. | Forman, Jane | Langa, Kenneth M. | Giordani, Bruno | Fagerlin, Angela | Kollman, Colleen | Whitney, Rachael T. | Levine, Deborah A.

Article Type: Research Article

Abstract: Background: People with mild cognitive impairment (MCI) receive fewer guideline-concordant treatments for cardiovascular disease (CVD) than people with normal cognition (NC). Objective: To understand physician perspectives on why patients with MCI receive fewer CVD treatments than patients with NC. Methods: As part of a mixed-methods study assessing how patient MCI influences physicians’ decision making for acute myocardial infarction (AMI) and stroke treatments, we conducted a qualitative study using interviews of physicians. Topics included participants’ reactions to data that physicians recommend fewer CVD treatments to patients with MCI and reasons why participants think fewer CVD treatments may …be recommended to this patient population. Results: Participants included 22 physicians (8 cardiologists, 7 neurologists, and 7 primary care physicians). Most found undertreatment of CVD in patients with MCI unreasonable, while some participants thought it could be considered reasonable. Participants postulated that other physicians might hold beliefs that could be reasons for undertreating CVD in patients with MCI. These beliefs fell into four main categories: 1) patients with MCI have worse prognoses than NC, 2) patients with MCI are at higher risk of treatment complications, 3) patients’ cognitive impairment might hinder their ability to consent or adhere to treatment, and 4) patients with MCI benefit less from treatments than NC. Conclusion: These findings suggest that most physicians do not think it is reasonable to recommend less CVD treatment to patients with MCI than to patients with NC. Improving physician understanding of MCI might help diminish disparities in CVD treatment among patients with MCI. Show more

Keywords: Aging, cognition, treatment disparities

DOI: 10.3233/JAD-220495

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 573-584, 2023

Authors: Overton, Marieclaire | Sjögren, Benjamin | Elmståhl, Sölve | Rosso, Aldana

Article Type: Research Article

Abstract: Background: As mild cognitive impairment (MCI) is typically used to identify prodromal stages of dementia, it is essential to identify MCI criteria with high diagnostic stability and prediction of dementia. Moreover, further investigation into pinpointing key factors for reversion is required to foresee future prognosis of MCI patients accurately. Objective: To explore disparities in diagnostic stability by examining reversion rates produced by two operationalizations of the MCI definition: the widely applied Petersen criteria and a version of the Neuropsychological (NP) criteria and to identify cognitive, lifestyle, and health related factors for reversion. Methods: MCI was retrospectively …classified in a sample from the Swedish community-based study Good Aging in Skåne with the Petersen criteria (n  = 744, median follow-up = 7.0 years) and the NP criteria (n  = 375, median follow-up, 6.7 years), respectively. Poisson regression models estimated the effect of various factors on the likelihood of incident reversion. Results: Reversion rates were 323/744 (43.4%, 95% confidence intervals (CI): 39.8; 47.0) and 181/375 (48.3% 95% CI: 43.2; 53.5) for the Petersen criteria and NP criteria, respectively. Participants with impairment in a single cognitive domain, regular alcohol consumption, living with someone, older age, and lower body mass index had a higher likelihood of reverting to normal. Conclusion: Reversion rates were similar for Petersen and NP criteria indicating that one definition is not superior to the other regarding diagnostic stability. Additionally, the results highlight important aspects such as multiple domain MCI, cohabitation, and the role of alcohol on predicting the trajectory of those diagnosed with MCI. Show more

Keywords: Aging, dementia, diagnostic criteria, mild cognitive impairment, neuropsychological criteria

DOI: 10.3233/JAD-220597

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 585-601, 2023

Authors: de Crom, Tosca O.E. | Ginos, Bigina N.R. | Oudin, Anna | Ikram, M. Kamran | Voortman, Trudy | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Exposure to air pollution has been suggested to increase the risk of dementia, but studies on this link often lack a detailed screening for dementia and data on important confounders. Objective: To determine the association of exposure to air pollution with the risk of dementia and cognitive decline in the population-based Rotterdam Study. Methods: Between 2009 and 2010, we determined air pollutant concentrations at participants residential addresses using land use regression models. Determined air pollutants include particulate matter <10μ m (PM10 ) and <2.5μ m (PM2.5 ), a proxy of elemental carbon (PM2.5 absorbance), …nitrogen oxide (NOx ), and nitrogen dioxide (NO2 ). As the individual air pollutant levels were highly correlated (r  = 0.71–0.98), we computed a general marker covering all air pollutants based on a principal component analysis. We followed participants up for dementia until 2018 and determined cognitive performance during two subsequent examination rounds. Using Cox and linear mixed models, we related air pollution to dementia and cognitive decline. Results: Of the 7,511 non-demented participants at baseline, 545 developed dementia during a median follow-up of 7 years. The general marker of all air pollutants was not associated with the risk of dementia (hazard ratio [95% confidence interval]: 1.04 [0.95–1.15]), neither were the individual air pollutants. Also, the general marker of all air pollutants or the individual air pollutant levels were not associated with cognitive decline. Conclusion: In this study, we found no clear evidence for an association between exposure to air pollution and the risk of dementia or cognitive decline. Show more

Keywords: Air pollution, Alzheimer’s disease, cognition, dementia, particulate matter, nitrogen oxide

DOI: 10.3233/JAD-220804

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 603-613, 2023

Authors: Fenech, Rachel K. | Hamstra, Sophie I. | Finch, Michael S. | Ryan, Chantal R. | Marko, Daniel M. | Roy, Brian D. | Fajardo, Val A. | MacPherson, Rebecca E.K.

Article Type: Research Article

Abstract: Background: Lithium, a commonly used treatment for bipolar disorder, has been shown to have neuroprotective effects for other conditions including Alzheimer’s disease via the inhibition of the enzyme glycogen synthase kinase-3 (GSK3). However, dose-dependent adverse effects of lithium are well-documented, highlighting the need to determine if low doses of lithium can reliably reduce GSK3 activity. Objective: The purpose of this study was to evaluate the effects of a low-dose lithium supplementation on GSK3 activity in the brain of an early, diet-induced Alzheimer’s disease model. Methods: Male C57BL/6J mice were divided into either a 6-week or 12-week …study. In the 6-week study, mice were fed a chow diet or a chow diet with lithium-supplemented drinking water (10 mg/kg/day) for 6 weeks. Alternatively, in the 12-week study, mice were fed a chow diet, a high-fat diet (HFD), or a HFD with lithium-supplemented drinking water for 12 weeks. Prefrontal cortex and hippocampal tissues were collected for analysis. Results: Results demonstrated reduced GSK3 activity in the prefrontal cortex as early as 6 weeks of lithium supplementation, in the absence of inhibitory phosphorylation changes. Further, lithium supplementation in an obese model reduced prefrontal cortex GSK3 activity as well as improved insulin sensitivity. Conclusion: Collectively, these data provide evidence for low-dose lithium supplementation to inhibit GSK3 activity in the brain. Moreover, these results indicate that GSK3 activity can be inhibited despite any changes in phosphorylation. These findings contribute to an overall greater understanding of low-dose lithium’s ability to influence GSK3 activity in the brain and its potential as an Alzheimer’s disease prophylactic. Show more

Keywords: Alzheimer’s disease, brain, GSK3, insulin, lithium

DOI: 10.3233/JAD-220813

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 615-626, 2023