Journal of Alzheimer's Disease - Volume 99, issue 4

Authors: Tavares-Júnior, José Wagner Leonel | Ciurleo, Gabriella Cunha Vieira | Feitosa, Esther de Alencar Araripe Falcão | Oriá, Reinaldo B. | Braga-Neto, Pedro

Article Type: Review Article

Abstract:  The link between long COVID-19 and brain/cognitive impairments is concerning and may foster a worrisome worldwide emergence of novel cases of neurodegenerative diseases with aging. This review aims to update the knowledge, crosstalk, and possible intersections between the Post-COVID Syndrome (PCS) and Alzheimer’s disease (AD). References included in this review were obtained from PubMed searches conducted between October 2023 and November 2023. PCS is a very heterogenous and poorly understood disease with recent evidence of a possible association with chronic diseases such as AD. However, more scientific data is required to establish the link between PCS and AD.

Keywords: Alzheimer’s disease, biomarkers, cognitive impairment, COVID-19, long COVID, post-COVID syndrome

DOI: 10.3233/JAD-231368

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1159-1171, 2024

Authors: Zeng, Baoqi | Tang, Chunbian | Wang, Junjian | Yang, Qingqing | Ren, Qingcuo | Liu, Xiaozhi

Article Type: Research Article

Abstract: Background: Early intervention is essential for meaningful disease modification in Alzheimer’s disease (AD). Objective: We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence. …Results: Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments— ranging from low to high certainty— showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] –0.239, 95% confidence interval [CI] –0.343 to –0.134) and lecanemab (SMD –0.194, 95% CI –0.279 to –0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo. Conclusions: Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD. Show more

Keywords: Alzheimer’s disease, meta-analysis, pharmacology, randomized controlled trial, systematic review, treatment efficacy

DOI: 10.3233/JAD-240161

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1173-1186, 2024

Authors: Slachevsky, Andrea | Grandi, Fabrissio | Thumala, Daniela | Baez, Sandra | Santamaria-García, Hernando | Schmitter-Edgecombe, Maureen | Parra, Mario A.

Article Type: Research Article

Abstract: Dementia is a syndrome characterized by cognitive and neuropsychiatric symptoms associated with progressive functional decline (FD). FD is a core diagnostic criterion for dementia, setting the threshold between its prodromal stages and the full-blown disease. The operationalization of FD continues to generate a great deal of controversy. For instance, the threshold of FD for the diagnosis of dementia varies across diagnostic criteria, supporting the need for standardization of this construct. Moreover, there is a need to reconsider how we are measuring FD to set boundaries between normal aging, mild cognitive impairment, and dementia. In this paper, we propose a multidimensional …framework that addresses outstanding issues in the assessment of FD: i) What activities of daily living (ADLs) are necessary to sustain an independent living in aging? ii) How to assess FD in individuals with suspected neurocognitive disorders? iii) To whom is the assessment directed? and iv) How much does FD differentiate healthy aging from mild and major neurocognitive disorders? Importantly, the To Whom Question introduces a person-centered approach that regards patients and caregivers as active agents in the assessment process of FD. Thus, once impaired ADLs have been identified, patients can indicate how significant such impairments are for them in daily life. We envisage that this new framework will guide future strategies to enhance functional assessment and treatment of patients with dementia and their caregivers. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, disability, functional dependence, functional independence, functional status, person-center care, functional ability

DOI: 10.3233/JAD-230376

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1187-1205, 2024

Authors: Starmans, Naomi Louisa Paula | Kappelle, Laurens Jaap | Muller, Majon | Staals, Julie | Teunissen, Charlotte Elisabeth | Biessels, Geert Jan | van der Flier, Wiesje Maria | Wolters, Frank Johannes

Article Type: Short Communication

Abstract:  Higher blood pressure variability (BPV) predisposes to cognitive decline. To investigate underlying mechanisms, we measured 24-h ambulatory BPV, nocturnal dipping and orthostatic hypotension in 518 participants with vascular cognitive impairment, carotid occlusive disease, heart failure, or reference participants. We determined cross-sectional associations between BPV indices and plasma biomarkers of neuronal injury (neurofilament light chain) and Alzheimer’s disease (phosphorylated-tau-181 and Aβ42 /Aβ40 ). None of the BPV indices were significantly associated with any of the biomarkers. Hence, in patients with diseases along the heart-brain axis, we found no evidence for an association between BPV and selected markers of neuronal injury or …Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, blood pressure, dementia, orthostatic hypotension, tau proteins

DOI: 10.3233/JAD-240119

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1207-1215, 2024

Authors: Yunusa, Ismaeel

Article Type: Article Commentary

Abstract:  The recent Alva et al. Phase 3b study on pimavanserin use in older adults with neurodegenerative diseases (NDDs), specifically including Alzheimer’s disease, vascular dementia, Parkinson’s disease (with or without dementia), frontotemporal dementia, and dementia with Lewy bodies, provides important new data on its safety for managing neuropsychiatric symptoms in this population. This commentary on the study further examines the findings within the broader context of antipsychotic therapy as it has evolved from chlorpromazine to pimavanserin in a continuous search for greater safety. Comparing pimavanserin’s safety and efficacy profile with historical data and regulatory milestones provides a nuanced perspective for clinicians …regarding the significance of the drug’s known advantages over prior antipsychotic treatments. More research is needed to determine the full potential of pimavanserin to improve neuropsychiatric symptoms in older adults with NDDs. Show more

Keywords: Alzheimer’ disease, pimavanserin, safety

DOI: 10.3233/JAD-240274

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1217-1220, 2024

Authors: Przybyszewski, Andrzej W. | Chudzik, Artur

Article Type: Article Commentary

Abstract: There has been a lot of buzz surrounding new drug discoveries that claim to cure Alzheimer’s disease (AD). However, it is crucial to keep in mind that the changes in the brain linked to AD start occurring 20–30 years before the first symptoms arise. By the time symptoms become apparent, many areas of the brain have already been affected. That’s why experts are focusing on identifying the onset of the neurodegeneration processes to prevent or cure AD effectively. Scientists use biomarkers and machine learning methods to analyze AD progressions and estimate them “backward” in time to discover the beginning of …the disease. Show more

Keywords: Alzheimer’s disease, Clinical Dementia Rating SUM of Boxes, cognitive tests, multi-granular computing, rough set theory

DOI: 10.3233/JAD-240231

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1221-1223, 2024

Authors: Churchill, Nicola | Barnes, Deborah E. | Habib, Mina | Nianogo, Roch A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) incidence varies based on demographics, but mid-life risk factor contribution to this variability requires more research. Objective: The purpose of this study is to forecast the 20-year incidence of dementia in the U.S. overall and stratified by race/ethnicity, socioeconomic status (SES), and U.S. geographic region given prior mid-life risk factor prevalence and to examine the extent to which risk factor differences 20 years ago may explain current SES, race/ethnicity, or regional disparities in dementia incidence. Methods: We applied the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) prediction …model to the 2006 wave of the Health and Retirement Study (HRS) in participants aged 45 to 64 to estimate the 20-year risk of incident ADRD. Results: The 20-year risk of dementia among middle-aged Americans was 3.3% (95% CI: 3.2%, 3.4%). Dementia incidence was forecast to be 1.51 (95% CI: 1.32, 1.71) and 1.27 (95% CI: 1.14, 1.44) times that in Hispanic and Non-Hispanic Black individuals respectively compared statistically to Non-Hispanic White individuals given mid-life risk factors. There was a progressive increase in dementia risk from the lowest versus highest SES quintile. For geographic region, dementia incidence was forecast to be 1.17 (95% CI: 1.06, 1.30) and 1.27 (95% CI: 1.14, 1.43) times that in Midwestern and Southern individuals respectively compared statistically to Western individuals. Conclusions: Some disparities in dementia incidence could be explained by differences in mid-life risk factors and may point toward policy interventions designed to lessen the ADRD disease burden through early prevention. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, populations at risk, public health, risk reduction, statistical models

DOI: 10.3233/JAD-231133

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1225-1234, 2024

Authors: Thyrian, Jochen René | Boekholt, Melanie | Biernetzky, Olga | Blotenberg, Iris | Teipel, Stefan | Killimann, Ingo | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Caregivers of people with dementia living at home (CPwDh) are likely to be affected by a range of health problems. However, CPwDh are often regarded as accompanying persons and receive less attention in research and care. Little is known about this population and their needs in Germany. However, better knowledge of CPwDH is needed to design effective interventions. Objective: The objective of this report is to describe the situation of CPwDh and highlight differences based on sex and living situation. Methods: This was a cross-sectional analysis of the psychosocial characteristics of participants in the GAIN …trial, a cluster-randomized, controlled intervention trial investigating the effectiveness of a care management program. A total of n  = 192 CPwDh were recruited in GP offices, memory clinics or through public campaigns in the German federal state of Mecklenburg-Western Pomerania. The inclusion criteria were an age of 18 years or above, being a CPwDh, written informed consent. In a comprehensive digital assessment, psychosocial variables, burden, and care needs were assessed. Results: Partners, women, and people living in the same household represented the majority of caregivers, and their mean number of needs was 8.7. Overall, participants indicated a mild to moderate burden. There are differences in burden based on sex and living situation, with caregivers living with people with dementia showing less burden and different psychosocial demographics. Conclusions: There is a need for interventions to reduce caregivers’ unmet needs in the CPwDh. Such interventions should consider differences in sex and living situation to better address individual caregiver needs. Show more

Keywords: Alzheimer’s disease, caregiver, dementia, intervention, primary care, unmet needs

DOI: 10.3233/JAD-231055

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1235-1242, 2024

Authors: Ilboudo, Yann | Yoshiji, Satoshi | Lu, Tianyuan | Butler-Laporte, Guillaume | Zhou, Sirui | Richards, J. Brent

Article Type: Research Article

Abstract: Background: Observational studies have found that vitamin D supplementation is associated with improved cognition. Further, recent Mendelian randomization (MR) studies have shown that higher vitamin D levels, 25(OH)D, may protect against Alzheimer’s disease. Thus, it is possible that 25(OH)D may protect against Alzheimer’s disease by improving cognition. Objective: We assessed this hypothesis, by examining the relationship between 25(OH)D levels and seven cognitive measurements. Methods: To mitigate bias from confounding, we performed two-sample MR analyses. We used instruments from three publications: Manousaki et al. (2020), Sutherland et al. (2022), and the Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies …Collaboration (2021). Results: Our observational studies suggested a protective association between 25(OH)D levels and cognitive measures. An increase in the natural log of 25(OH)D by 1 SD was associated with a higher PACC score (BetaPACC score  = 0.06, 95% CI = (0.04–0.08); p  = 1.8×10-10 ). However, in the MR analyses, the estimated effect of 25(OH)D on cognitive measures was null. Specifically, per 1 SD increase in genetically estimated natural log of 25(OH)D, the PACC scores remained unchanged in the overall population, (BetaPACC score  = –0.01, 95% CI (–0.06 to 0.03); p  = 0.53), and amongst individuals aged over 60 (BetaPACC score  = 0.03, 95% CI (–0.028 to 0.08); p  = 0.35). Conclusions: In conclusion, our MR study found no clear evidence to support a protective role of increased 25(OH)D concentrations on cognitive performance in European ancestry individuals. However, our study cannot entirely dismiss the potential beneficial effect on PACC for individuals over the age of 60. Show more

Keywords: Aging, Alzheimer’s disease, cognitive dysfunction, databases, genetics, mendelian randomization analysis, observational study, vitamin D deficiency

DOI: 10.3233/JAD-221223

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1243-1260, 2024

Authors: Huang, Xiuxiu | Wang, Jiaxin | Zhang, Shifang | Zhao, Xiaoyan | An, Ran | Lan, Yue | Yi, Ming | Wan, Qiaoqin

Article Type: Research Article

Abstract: Background: Reliable blood biomarkers are crucial for early detection and treatment evaluation of cognitive impairment, including Alzheimer’s disease and other dementias. Objective: To examine whether plasma biomarkers and their combination are different between older people with mild cognitive impairment (MCI) and cognitively normal individuals, and to explore their relations with cognitive performance. Methods: This cross-sectional study included 250 older adults, including 124 participants with MCI, and 126 cognitively normal participants. Plasma brain-derived neurotrophic factor (BDNF), irisin and clusterin were measured, and BDNF/irisin ratio was calculated. Global cognition was evaluated by the Montreal Cognitive Assessment. …Results: Plasma irisin levels, but not BDNF, were significantly different between MCI group and cognitively normal group. Higher irisin concentration was associated with an increased probability for MCI both before and after controlling covariates. By contrast, plasma BDNF concentration, but not irisin, was linearly correlated with cognitive performance after adjusting for covariates. Higher BDNF/irisin ratios were not only correlated with better cognitive performance, but also associated with lower risks of MCI, no matter whether we adjusted for covariates. Plasma BDNF and irisin concentrations increased with aging, whereas BDNF/irisin ratios remained stable. No significant results of clusterin were observed. Conclusions: Plasma BDNF/irisin ratio may be a reliable indicator which not only reflects the odds of the presence of MCI but also directly associates with cognitive performance. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, irisin, mild cognitive impairment, old people, plasma

DOI: 10.3233/JAD-231347

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1261-1271, 2024