Journal of Alzheimer's Disease - Volume 95, issue 4

Authors: Gezen-Ak, Duygu | Dursun, Erdinc

Article Type: Review Article

Abstract: Vitamin D is a secosteroid hormone exerting neurosteroid-like properties. Its well-known nuclear hormone receptor, and recently proposed as a mitochondrial transcription factor, vitamin D receptor, acts for its primary functions. The second receptor is an endoplasmic reticulum protein, protein disulfide isomerase A3 (PDIA3), suggested to act as a rapid response. Vitamin D has effects on various systems, particularly through calcium metabolism. Among them, the nervous system has an important place in the context of our subject. Recent studies have shown that vitamin D and its receptors have numerous effects on the nervous system. Neurodegeneration is a long-term process. Throughout a …human life span, so is vitamin D deficiency. Our previous studies and others have suggested that the out-come of long-term vitamin D deficiency (hypovitaminosis D or inefficient utilization of vitamin D), may lead neurons to be vulnerable to aging and neurodegeneration. We suggest that keeping vitamin D levels at adequate levels at all stages of life, considering new approaches such as agonists that can activate vitamin D receptors, and utilizing other derivatives produced in the synthesis process with UVB are crucial when considering vitamin D-based intervention studies. Given most aspects of vitamin D, this review outlines how vitamin D and its receptors work and are involved in neurodegeneration, emphasizing Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, mitochondria, neurodegeneration, vitamin D, vitamin D receptor

DOI: 10.3233/JAD-230214

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1273-1299, 2023

Authors: de la Monte, Suzanne M.

Article Type: Review Article

Abstract: Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer’s disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum …stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures. Show more

Keywords: Aging, Alzheimer’s disease, brain, mTOR, neurodegeneration, neuroinflammation, type 3 diabetes, vascular disease, white matter

DOI: 10.3233/JAD-230555

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1301-1337, 2023

Authors: Adewale, Boluwatife Adeleye | Coker, Motunrayo Mojoyin | Ogunniyi, Adesola | Kalaria, Rajesh N. | Akinyemi, Rufus Olusola

Article Type: Review Article

Abstract: Dementia is a chronic syndrome which is common among the elderly and is associated with significant morbidity and mortality for patients and their caregivers. Alzheimer’s disease (AD), the most common form of clinical dementia, is biologically characterized by the deposition of amyloid-β plaques and neurofibrillary tangles in the brain. The onset of AD begins decades before manifestation of symptoms and clinical diagnosis, underlining the need to shift from clinical diagnosis of AD to a more objective diagnosis using biomarkers. Having performed a literature search of original articles and reviews on PubMed and Google Scholar, we present this review detailing the …existing biomarkers and risk assessment tools for AD. The prevalence of dementia in low- and middle-income countries (LMICs) is predicted to increase over the next couple of years. Thus, we aimed to identify potential biomarkers that may be appropriate for use in LMICs, considering the following factors: sensitivity, specificity, invasiveness, and affordability of the biomarkers. We also explored risk assessment tools and the potential use of artificial intelligence/machine learning solutions for diagnosing, assessing risks, and monitoring the progression of AD in low-resource settings. Routine use of AD biomarkers has yet to gain sufficient ground in clinical settings. Therefore, clinical diagnosis of AD will remain the mainstay in LMICs for the foreseeable future. Efforts should be made towards the development of low-cost, easily administered risk assessment tools to identify individuals who are at risk of AD in the population. We recommend that stakeholders invest in education, research and development targeted towards effective risk assessment and management. Show more

Keywords: Alzheimer’s disease, artificial intelligence, biomarkers, blood, cerebrospinal fluid, low- and middle-income countries, neuroimaging, risk

DOI: 10.3233/JAD-221030

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1339-1349, 2023

Authors: Wojt, Ilsa R | Lau, Edward C.Y | Cairns, Rose | Tan, Edwin C.K

Article Type: Review Article

Abstract: Background: Older people with dementia are at a particularly high risk of poisonings and their subsequent harms. Objective: This review aimed to describe the key agents, incidence, risk factors, and disposition of poisonings in people with dementia reported in the literature. Methods: Medline, Embase, CINAHL, and PsycINFO databases were searched from 1 September 2001 to 1 September 2021. Terms for dementia, poisonings, and older adults formed the search concepts. Quantitative studies published in English, describing poisonings in older people with dementia, including Alzheimer’s disease, were included. Two investigators independently assessed articles for eligibility and extracted relevant …data. A meta-analysis of the incidence of poisonings in people with dementia across studies was performed. Results: Of 4,579 articles, 18 were included for final synthesis. Nervous system medications were implicated in over half of all medicinal poisonings, with anti-dementia agents, benzodiazepines, and opioids the most common classes. The non-medicinal agents frequently associated with poisonings were personal care and household products. The yearly incidence of poisoning varied across definitions of poisoning from 3% for International Classification of Disease-defined poisonings to 43% for adverse drug event-defined poisonings. Several risk factors were identified, including multimorbidity, psychotropic medication use, and living in residential care. Where described, up to one in five poisonings resulted in hospitalisation and in death. Conclusions: Poisonings are common in people with dementia, involving commonly prescribed medications or easily accessible substances. Given the significant outcomes associated, further research is required to better understand these poisonings and improve public health strategies to reduce the occurrence of this preventable harm. Show more

Keywords: Aged, Alzheimer’s disease, dementia, medication errors, poisoning

DOI: 10.3233/JAD-230246

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1351-1370, 2023

Authors: Lehmann, Donald J | Elshorbagy, Amany | Hurley, Michael J

Article Type: Research Article

Abstract: Sporadic Alzheimer’s disease (AD) is a complex, multifactorial disease. We should therefore expect to find many factors involved in its causation. The known neuropathology seen at autopsy in patients dying with AD is not consistently seen in all patients with AD and is sometimes seen in patients without dementia. This suggests that patients follow different paths to AD, with different people having slightly different combinations of predisposing physical, chemical and biologic risk factors, and varying neuropathology. This review summarizes what is known of the biologic and chemical predisposing factors and features in AD. We postulate that, underlying the neuropathology of …AD is a progressive failure of neurons, with advancing age or other morbidity, to rid themselves of entropy, i.e., the disordered state resulting from brain metabolism. Understanding the diverse causes of AD may allow the development of new therapies targeted at blocking the paths that lead to dementia in each subset of patients. Show more

Keywords: Aging, Alzheimer’s disease, entropy, neurodegeneration

DOI: 10.3233/JAD-230295

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1371-1382, 2023

Authors: Verde, Federico | Aiello, Edoardo Nicolò | Adobbati, Laura | Poletti, Barbara | Solca, Federica | Tiloca, Cinzia | Sangalli, Davide | Maranzano, Alessio | Muscio, Cristina | Ratti, Antonia | Zago, Stefano | Ticozzi, Nicola | Frisoni, Giovanni Battista | Silani, Vincenzo

Article Type: Short Communication

Abstract: We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer’s disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order …to recognize AD. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, neurodegeneration, neuropsychology

DOI: 10.3233/JAD-230562

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1383-1399, 2023

Authors: Barba, Lorenzo | Otto, Markus | Abu-Rumeileh, Samir

Article Type: Article Commentary

Abstract: Concomitant Alzheimer’s disease (AD) pathology can be observed in approximately 10–15% of cases with amyotrophic lateral sclerosis (ALS). ALS-AD patients have a higher prevalence of amnestic cognitive disturbances, which may often precede motor symptoms. Cerebrospinal fluid (CSF) AD core biomarkers usually show no or slightly significant changes in ALS, whereas blood phosphorylated tau protein might be increased independently from AD copathology. Neurofilament proteins are consistently elevated in CSF and blood of ALS, but have been poorly investigated in ALS-AD. All these issues should be taken into account when using fluid biomarkers as inclusion criteria or secondary endpoints in clinical trials.

Keywords: Alzheimer’s disease, amyloid-β, amyotrophic lateral sclerosis, biomarker, copathology, neurofilament light chain

DOI: 10.3233/JAD-230900

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1401-1404, 2023

Authors: Amofa-Ho, Priscilla A. | Stickel, Ariana M. | Chen, Ruijia | Kobayashi, Lindsay C. | Glymour, M. Maria | Eng, Chloe W.

Article Type: Research Article

Abstract: Background: The mediating roles of neuropathologies and neurovascular damage in the relationship between early-life education and later-life cognitive function are unknown. Objective: To examine whether Alzheimer’s and neurovascular biomarkers mediate the relationships between education and cognitive functions. Methods: Data were from 537 adults aged 55–94 in the Alzheimer’s Disease Neuroimaging Initiative 3. We tested whether the relationships between education (continuous, years) and cognitive function (memory, executive functioning, and language composites) were mediated by neuroimaging biomarkers (hippocampal volumes, cortical gray matter volumes, meta-temporal tau PET standard uptake value ratio, and white matter hyperintensity volumes). Models were adjusted …for age , race, sex/gender, cardiovascular history, body mass index, depression, and Apolipoprotein E-ɛ 4 status. Results: Hippocampal volumes and white matter hyperintensities partially mediated the relationships between education and cognitive function across all domains (6.43% to 15.72% mediated). The direct effects of education on each cognitive domain were strong and statistically significant. Conclusions: Commonly measured neurobiomarkers only partially mediate the relationships between education and multi-domain cognitive function. Show more

Keywords: Alzheimer’s disease, brain aging, cognitive aging, education, hippocampus, tau, white matter hyperintensities

DOI: 10.3233/JAD-230244

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1405-1416, 2023

Authors: Agarwal, Puja | Ford, Christopher N. | Leurgans, Sue E. | Beck, Todd | Desai, Pankaja | Dhana, Klodian | Evans, Denis A. | Halloway, Shannon | Holland, Thomas M. | Krueger, Kristin R. | Liu, Xiaoran | Rajan, Kumar Bharat | Bennett, David A.

Article Type: Research Article

Abstract: Background: We have limited evidence for the relationship of high sugar intake with dementia risk. Objective: To determine whether high sugar intake is associated with an increased risk of dementia in community-dwelling older adults Methods: This study included 789 participants of the Rush Memory and Aging Project (community-based longitudinal cohort study of older adults free of known dementia at enrollment), with annual clinical assessments and complete nutrient data (obtained by validated food frequency questionnaire). Clinical diagnosis of dementia is based on the criteria of the joint working group of the National Institute of Neurological and Communicative …Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. We used Cox proportional hazard models. Results: 118 participants developed dementia during 7.3±3.8 years of follow-up. Those in the highest quintile of total sugar intake were twice as likely to develop dementia than those in the lowest quintile (Q5 versus Q1:HR=2.10 (95% CI: 1.05, 4.19) when adjusted for age, sex, education, APOE ɛ 4 allele, calories from sources other than sugar, physical activity, and diet score. Higher percent calories from sugar were positively associated with dementia risk (β=0.042, p  = 0.0009). In exploratory analyses, the highest versus lowest quintile of fructose and sucrose in the diet had higher dementia risk by 2.8 (95% CI: 1.38, 5.67) and 1.93 (95% CI: 1.05, 3.54) times, respectively. Conclusions: A higher intake of total sugar or total calories from sugar is associated with increased dementia risk in older adults. Among simple sugars, fructose (e.g., sweetened beverages, snacks, packaged desserts) and sucrose (table sugar in juices, desserts, candies, and commercial cereals) are associated with higher dementia risk. Show more

Keywords: Alzheimer’s disease, dementia, longitudinal, total sugar intake

DOI: 10.3233/JAD-230013

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1417-1425, 2023

Authors: Marcolini, Sofia | Rojczyk, Philine | Seitz-Holland, Johanna | Koerte, Inga K. | Alosco, Michael L. | Bouix, Sylvain

Article Type: Research Article

Abstract: Background: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common in Veterans and linked to behavioral disturbances, increased risk of cognitive decline, and Alzheimer’s disease. Objective: We studied the synergistic effects of PTSD and TBI on behavioral, cognitive, and neuroimaging measures in Vietnam war Veterans. Methods: Data were acquired at baseline and after about one-year from male Veterans categorized into: PTSD, TBI, PTSD+TBI, and Veteran controls without PTSD or TBI. We applied manual tractography to examine white matter microstructure of three fiber tracts: uncinate fasciculus (N  = 91), cingulum (N  = 87), and inferior longitudinal fasciculus …(N  = 95). ANCOVAs were used to compare Veterans’ baseline behavioral and cognitive functioning (N  = 285), white matter microstructure, amyloid-β (N  = 230), and tau PET (N  = 120). Additional ANCOVAs examined scores’ differences from baseline to follow-up. Results: Veterans with PTSD and PTSD+TBI, but not Veterans with TBI only, exhibited poorer behavioral and cognitive functioning at baseline than controls. The groups did not differ in baseline white matter, amyloid-β, or tau, nor in behavioral and cognitive functioning, and tau accumulation change. Progression of white matter abnormalities of the uncinate fasciculus in Veterans with PTSD compared to controls was observed; analyses in TBI and PTSD+TBI were not run due to insufficient sample size. Conclusions: PTSD and PTSD+TBI negatively affect behavioral and cognitive functioning, while TBI does not contribute independently. Whether progressive decline in uncinate fasciculus microstructure in Veterans with PTSD might account for cognitive decline should be further studied. Findings did not support an association between PTSD, TBI, and Alzheimer’s disease pathology based on amyloid and tau PET. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, amyloid-β , diffusion magnetic resonance imaging, follow-up studies, risk factors

DOI: 10.3233/JAD-221304

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1427-1448, 2023