Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Liu, Rui | Zhang, Lei | You, Hao

Article Type: Review Article

Abstract: The pathogenesis of Alzheimer’s disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating …BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington’s disease, Parkinson’s disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, branched-chain amino acids, insulin resistance, metabolic neurodegenerative disease, metabolism

DOI: 10.3233/JAD-221147

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Nijskens, Charlotte | Henstra, Marieke | Rhodius-Meester, Hanneke | Yasar, Sevil | van Poelgeest, Eveline | Peters, Mike | Muller, Majon

Article Type: Review Article

Abstract: The number of people living with dementia, such as Alzheimer’s disease, is increasing worldwide. Persons with dementia often have a high risk of atherosclerotic cardiovascular disease and they are therefore theoretically eligible for treatment of hypertension and hyperlipidemia. However, in this population, beneficial and harmful effects of cardiovascular risk management (CVRM) may be different compared to older persons without cognitive impairment. Current CVRM guidelines are based on trials from which persons with dementia were excluded. In this narrative review, we will discuss how current guidelines can be translated to persons with dementia and which aspects should be taken into account …when treating hypertension and hyperlipidemia to prevent major adverse cardiovascular events (MACE). Survival time is significantly shorter in persons with dementia. We therefore suggest that since the main goal of CVRM is prevention of MACE, first of all, the patient’s life expectancy and treatment wishes should be evaluated. Risk assessment tools are to be used with care, as they tend to overestimate the 5- and 10-year risk of MACE and benefit from CVRM in the prevention of MACE in persons with dementia. When the clinician and patient have decided that treatment is initiated or intensified, patients should be closely monitored since they are at high risk for adverse drugs events and overtreatment due to the natural course of blood pressure in persons with dementia. In the event of intolerance or side effects, medication should be switched or withdrawn. For persons with dementia and limited life expectancy, deprescribing should be part of usual care. Show more

Keywords: Alzheimer’s disease, cardiovascular diseases, cardiovascular risk, control, dementia, hypercholesterolemia, hypertension, prevention

DOI: 10.3233/JAD-230019

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Zhang, Kexin | Du, Xinzhe | Gao, Yao | Liu, Sha | Xu, Yong

Article Type: Review Article

Abstract: As the size of the population aged 65 and older continues to grow, the incidence and mortality rates of Alzheimer’s disease (AD) are increasing annually. Unfortunately, current treatments only treat symptoms temporarily and do not alter the patients’ life expectancy or course of AD. Mesenchymal stem cells (MSCs) have shown a certain therapeutic potential in neurodegenerative diseases including AD due to their neuroinflammatory regulation and neuroprotective effects. However, the low survival and homing rates of MSCs after transplantation seriously affect their therapeutic effectiveness. Therefore, appropriate in vitro preconditioning is necessary to increase the survival and homing rates of MSCs …to improve their effectiveness in treating AD. Here we summarize the therapeutic mechanisms of MSCs in AD and the chemical reagents used for the pretreatment of MSCs. Show more

Keywords: Alzheimer’s disease, mesenchymal stem cell, neuroinflammation, neuroprotection, pretreatment

DOI: 10.3233/JAD-221253

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Smith, Carr J. | Ashford, J. Wesson

Article Type: Research Article

Abstract: Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE ) ɛ4/ɛ4 genotype, when the ɛ3 allele mutated from the ancestral ɛ4, which elevates the risk of Alzheimer’s disease. Modern humans living today predominantly carry the ɛ3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ɛ4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection …pressure. Some bacteria can exploit the host’s defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ɛ4 carriers, yet ɛ4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ɛ3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, ɛ4 allele, enteric infections, evolution, immunity, selection

DOI: 10.3233/JAD-221218

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Malhotra, Chetna | Balasubramanian, Ishwarya

Article Type: Research Article

Abstract: Background: Family caregivers make end-of-life (EOL) decisions for persons with severe dementia (PWSDs). It is not known whether the family caregivers’ goals change over time. Objective: Assess caregivers’ EOL care goal for PWSDs and change in these goals over time. Methods: Using a prospective cohort of 215 caregivers of PWSDs, we assessed the proportion of caregivers whose EOL care goal for PWSDs changed between two consecutive time points. Mixed effects multinomial regression models assessed factors associated with caregivers’ EOL care goals for PWSD (maximal, moderate, minimal life extension); and change in EOL care goal from previous …time point. Results: At baseline, 20% of the caregivers had a goal of maximal life extension for their PWSD, and 59% changed their EOL care goal at least once over a period of 16 months. Caregivers of PWSDs with lower quality of life (RR: 1.15, CI: 1.06, 1.24), who expected shorter life expectancy for PWSDs (RR: 10.34, CI: 2.14, 49.99) and who had an advance care planning discussion (RR: 3.52, CI: 1.11, 11.18) were more likely to have a goal of minimal life extension for PWSD. Caregivers with higher anticipatory grief (RR: 0.96, CI: 0.93,1) were more likely to have a goal of maximal life extension. Change in PWSDs’ quality of life and change in caregivers’ anticipatory grief were associated with change in caregivers’ EOL care goals. Conclusion: Caregivers’ EOL care goals for PWSDs change over time with change in PWSD and caregiver related factors. Findings have implications regarding how health care providers can engage with caregivers. Show more

Keywords: Anticipatory grief, caregivers, decision-making, dementia, end-of-life care goals, quality of life, Singapore

DOI: 10.3233/JAD-221161

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023

Authors: Hsiao, Wesley Wei-Wen | Angela, Stefanny | Le, Trong-Nghia | Ku, Chia-Chi | Hu, Po-Sheng | Chiang, Wei-Hung

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a pathological disorder defined by the symptoms of memory loss and deterioration of cognitive abilities over time. Although the etiology is complex, it is mainly associated with the accumulation of toxic amyloid-β peptide (Aβ) aggregates and tau protein-induced neurofibrillary tangles (NFTs). Even now, creating non-invasive, sensitive, specific, and cost-effective diagnostic methods for AD remains challenging. Over the past few decades, polymers, and nanomaterials (e.g., nanodiamonds, nanogold, quantum dots) have become attractive and practical tools in nanomedicine for diagnosis and treatment. This review focuses on current developments in sensing methods such as enzyme-linked immunosorbent assay (ELISA) and …surface-enhanced Raman scattering (SERS) to boost the sensitivity in detecting related biomarkers for AD. In addition, optical analysis platforms such as ELISA and SERS have found increasing popularity among researchers due to their excellent sensitivity and specificity, which may go as low as the femtomolar range. While ELISA offers easy technological usage and high throughput, SERS has the advantages of improved mobility, simple electrical equipment integration, and lower cost. Both portable optical sensing techniques are highly superior in terms of sensitivity, specificity, human application, and practicality, enabling the early identification of AD biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid-β , ELISA, nanomaterials, optical analysis platform, polymers, SERS, tau protein

DOI: 10.3233/JAD-221202

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2023

Authors: Bauernschmidt, Dorothee | Hirt, Julian | Langer, Gero | Meyer, Gabriele | Unverzagt, Susanne | Wilde, Fabian | Wittmann, Janina | Bieber, Anja

Article Type: Systematic Review

Abstract: Background: Information technology can enhance timely and individual support for people with Alzheimer’s disease and other dementias and their informal carers. Objective: To review the effectiveness of technology-based counselling interventions for people with dementia and informal carers. Methods: Randomized controlled trials of remote dementia counselling interventions were included. We searched CINAHL, Cochrane Library, MEDLINE, PsycINFO, and the Web of Science Core Collection (April 2021) in combination with citation tracking and free web searching (October to November 2021). We provide meta-analyses for caregiver depression, burden, and self-efficacy/mastery and structured reporting for other outcomes. The Grading of Recommendations …Assessment, Development and Evaluation approach and the Risk of Bias 2 tool were applied. Results: We included five randomized controlled trials involving 880 participants. Interventions were provided for carers (four studies) or dyads (one study). Carers were predominantly women and were the spouses or children of people with dementia. Counselling was delivered via telephone or videoconference with two to 23 sessions over 1 to 12 months. Control groups received educational and resource materials only, standard (helpline) services, non-directive support, or home visits. Meta-analysis for our primary outcome, depressive symptoms in carers, revealed no statistically significant effect (SMD –0.15; 95% CI –0.40 to 0.10). There were also no significant effects on burden and self-efficacy/mastery. We rated the certainty of evidence as low to very low and all outcomes at an overall high risk of bias. Conclusion: The effectiveness of technology-based counselling interventions for people with dementia and informal carers remains uncertain. Theory-based approaches are needed for the development and evaluation of these interventions. Show more

Keywords: Alzheimer’s disease, counselling, dementia, information technology, remotely delivered intervention

DOI: 10.3233/JAD-221194

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Press, Daniel Zvi | Musaeus, Christian Sandøe | Zhao, Li | Breton, Jocelyn | Shafi, Mouhsin M. | Dai, Weiying | Alsop, David C.

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. Objective: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. Methods: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n  = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random …order in three sessions. Afterwards, the participants underwent ASL-MRI. Results: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. Conclusion: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings. Show more

Keywords: Alzheimer’s disease, arterial spin labeling MRI, epilepsy, epileptiform activity, levetiracetam, randomized controlled trial

DOI: 10.3233/JAD-220614

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023

Authors: Gibbons, Laura E. | Power, Melinda C. | Walker, Rod L. | Kumar, Raj G. | Murphy, Alia | Latimer, Caitlin S. | Nolan, Amber L. | Melief, Erica J. | Beller, Allison | Bogdani, Marika | Keene, Dirk | Larson, Eric B. | Crane, Paul K. | Dams-O’Connor, Kristen

Article Type: Research Article

Abstract: Background: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. Objective: To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. Methods: Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, …for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. Results: TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. Conclusion: TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer’s disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, atrophy, dementia, neuropathology, traumatic brain injury

DOI: 10.3233/JAD-221224

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023

Authors: Pilonieta, Giovanna | Pisu, Maria | Martin, Roy C. | Shan, Liang | Kennedy, Richard E. | Oates, Gabriela | Kim, Young-Il | Geldmacher, David S.

Article Type: Research Article

Abstract: Background: Access to specialists facilitates appropriate Alzheimer’s disease and related dementia (ADRD) medication use and adherence. However, there is little information on the impact of specialists’ availability on ADRD medication adherence, especially in regions of the United States (US) where specialists are scarce, e.g., the Deep South (DS). Objective: To ascertain whether the availability of specialty physicians in the DS and other US regions predicts ADRD medication adherence among community-dwelling older adults Methods: We conducted secondary analyses of claims data for 54,194 Medicare beneficiaries with ADRD in 2013–2015. Medication adherence was measured using the proportion of …days covered (PDC). Multivariable-adjusted Modified Poisson regression was used to examine associations of adherence with physicians’ availability by region. Results: The race/ethnicity distribution was 81.44% white, 9.17% black, 6.24% Hispanic, 2.25% Asian, and 1% other; 71.81% were female, and 42.36% were older than 85 years. Beneficiaries across regions differed in all individual and contextual characteristics except sex and comorbidities. Neurologists and psychiatrists’ availability was not significantly associated with adherence (DS = 1.00, 0.97–1.03 & non-DS = 1.01, 1.00–1.01). Race and having ≥1 specialist visits were associated with a lower risk of adherence in both regions (p  <  0.0001). Advanced age, dual Medicare/Medicaid eligibility, and living in non-large metropolitan areas, were associated with adherence in the non-DS region. Conclusion: Among older Americans with ADRD, a context defined by specialist availability does not affect adherence, but other context characteristics related to socioeconomic status may. Research should further examine the influence of individual and contextual factors on ADRD treatment among older adults. Show more

Keywords: Alzheimer’s disease, medication adherence, Medicare, physician availability, specialist use, socioeconomic factors

DOI: 10.3233/JAD-220620

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023