Journal of Alzheimer's Disease - Volume 87, issue 1

Authors: Shi, Yun | Bao, Qianqian | Chen, Weidong | Wang, Lei | Peng, Daiyin | Liu, Jie | Liu, Qing | Zhang, Yanchun | Ji, Zhaojie | Shen, Aizong

Article Type: Review Article

Abstract: Cognitive dysfunction, the major clinical manifestation of Alzheimer’s disease (AD), is caused by irreversible progressive neurological dysfunction. With the aging of the population, the incidence of AD is increasing year by year. However, there is neither a simple and accurate early diagnosis method, nor an effective method to alleviate or prevent the occurrence and progression of AD. Extracellular vesicles (EVs) are a number of heterogeneous membrane structures that arise from the endosome system or shed from the plasma membrane. In the brain, almost every kind of cell may have EVs, which are related to cell-cell communication and regulate cellular function. …At present, an increasing body of evidence suggests that EVs play a crucial role in the pathogenesis of AD, and it is of great significance to use them as specific biomarkers and novel therapeutic targets for cognitive impairment in AD. This article reviews the potential role of EVs as diagnostic biomarkers and treatments for cognitive dysfunction in AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, diagnosis biomarkers, extracellular vesicles, therapeutics

DOI: 10.3233/JAD-215666

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 1-15, 2022

Authors: Escobar, Yael-Natalie H. | O’Piela, Devin | Wold, Loren E. | Mackos, Amy R.

Article Type: Review Article

Abstract: The gut microbiota is made up of trillions of microbial cells including bacteria, viruses, fungi, and other microbial bodies and is greatly involved in the maintenance of proper health of the host body. In particular, the gut microbiota has been shown to not only be involved in brain development but also in the modulation of behavior, neuropsychiatric disorders, and neurodegenerative diseases including Alzheimer’s disease. The precise mechanism by which the gut microbiota can affect the development of Alzheimer’s disease is unknown, but the gut microbiota is thought to communicate with the brain directly via the vagus nerve or indirectly through …signaling molecules such as cytokines, neuroendocrine hormones, bacterial components, neuroactive molecules, or microbial metabolites such as short-chain fatty acids. In particular, interventions such as probiotic supplementation, fecal microbiota transfer, and supplementation with microbial metabolites have been used not only to study the effects that the gut microbiota has on behavior and cognitive function, but also as potential therapeutics for Alzheimer’s disease. A few of these interventions, such as probiotics, are promising candidates for the improvement of cognition in Alzheimer ’s disease and are the focus of this review. Show more

Keywords: Alzheimer’s disease, cognition, microbiota-gut-brain axis, mild cognitive impairment

DOI: 10.3233/JAD-215290

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 17-31, 2022

Authors: Morton, Hallie | Basu, Tanisha | Bose, Chhanda | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a devastating illness in elderly individuals, that currently has no known cure. Causal genetic factors only account for 1-2% of AD patients. However, other causal factors are still unknown for a majority of AD patients. Currently, multiple factors are implicated in late-onset AD, including unhealthy diet, physical inactivity, traumatic brain injury, chronic conditions, epigenetic factors, and environmental exposures. Although clinical symptoms of dementia are common to all races and ethnic groups, conditions that lead to dementia are different in terms of lifestyle, genetic profile, and socio-economic conditions. Increasing evidence also suggests that some elderly individuals age …without cognitive impairments in their 60–90s as seen in rural West Texas, while some individuals progress with chronic conditions and cognitive impairments into their 60s. To understand these discriminations, we assessed current literature on demographic features of health in rural West Texas. This paper also outlines our initiated clinical study with a purpose of understanding the factors that allow some individuals to live without cognitive impairments at the age of 60–90 years, whereas others develop deficits in cognitive function around or above 60 years. Our ongoing study hopes to determine the factors that delay aging in some individuals by investigating various aspects including genetics, epigenetics, ethnicity, biology, culture, and lifestyle. This will be achieved by gathering information about participants’ ethnographic profiles, cognitive assessments, blood-profiles, brain scans, and blood-based genomic analyses in relation to lifestyle. The outcomes of our study will provide insights into healthy aging in rural West Texas. Show more

Keywords: Aging, Alzheimer’s disease, cognitive dysfunction, lifestyle, rural health

DOI: 10.3233/JAD-220084

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 33-49, 2022

Authors: Kok, Frédérique K. | van Leerdam, Suzanne L. | de Lange, Elizabeth C.M.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-β plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could …compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and ‘von Economo neurons’. Furthermore, in NDAN brains, binding of Aβ oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD. Show more

Keywords: Alzheimer’s disease, asymptomatic AD, non-demented individuals with AD neuropathology, preclinical AD, resilience

DOI: 10.3233/JAD-210607

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 51-81, 2022

Authors: Kim, C. Kwon | Lee, Yin Rui | Ong, Lynnett | Gold, Michael | Kalali, Amir | Sarkar, Joydeep

Article Type: Review Article

Abstract: Given the acknowledged lack of success in Alzheimer’s disease (AD) drug development over the past two decades, the objective of this review was to derive key insights from the myriad failures to inform future drug development. A systematic and exhaustive review was performed on all failed AD compounds for dementia (interventional phase II and III clinical trials from ClinicalTrials.gov) from 2004 to the present. Starting with the initial ∼2,700 AD clinical trials, ∼550 trials met our initial criteria, from which 98 unique phase II and III compounds with various mechanisms of action met our criteria of a failed compound. The …two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved. Potential contributing methodological factors for the clinical trial failures were categorized into 1) insufficient evidence to initiate the pivotal trials, and 2) pivotal trial design shortcomings. Our evaluation found that rational drug development principles were not always followed for AD therapeutics development, and the question remains whether some of the failed compounds may have shown efficacy if the principles were better adhered to. Several recommendations are made for future AD therapeutic development. The whole database of the 98 failed compounds is presented in the Supplementary Material . Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, clinical trial, dementia, drug development

DOI: 10.3233/JAD-215699

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 83-100, 2022

Authors: Lacorte, Eleonora | Ancidoni, Antonio | Zaccaria, Valerio | Remoli, Giulia | Tariciotti, Leonardo | Bellomo, Guido | Sciancalepore, Francesco | Corbo, Massimo | Lombardo, Flavia L. | Bacigalupo, Ilaria | Canevelli, Marco | Piscopo, Paola | Vanacore, Nicola

Article Type: Systematic Review

Abstract: Background: Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer’s disease (AD). Objective: Our objectives were to identify all registered trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes. Methods: A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library. Results: Overall, 101 studies …were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD –0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD –0.15). Conclusion: Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset. Show more

Keywords: Alzheimer’s disease, amyloid, meta-analysis, mild cognitive impairment, monoclonal antibodies, safety, systematic review, treatment outcome

DOI: 10.3233/JAD-220046

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 101-129, 2022

Authors: Bendstrup, Nathalie | Hejl, Anne-Mette | Salvesen, Lisette

Article Type: Systematic Review

Abstract: Background: It can be challenging to discriminate between progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD). However, a correct diagnosis is a precondition for targeted treatment strategies and proper patient counseling. There has been a growing interest to identify cerebrospinal fluid (CSF) biomarkers, including neurofilament light chain (NfL). Objective: This systematic review evaluates the existing literature on neurofilament light in CSF aiming to validate its utility for differentiating FTD from PSP. Methods: A systematic literature search was conducted. A broad range of synonyms for PSP, NfL, and FTD as well as associated MeSH terms, were combined …and used as keywords when searching. Relevant data were extracted and assessed for risk of bias. Results: Nine studies including a total of 671 patients with FTD, 254 patients with PSP, 523 healthy controls, and 1,771 patients with other disorders were included in the review. Four studies found a significantly higher level of CSF NfL in FTD (n  = 445) compared to PSP (n  = 124); however, in three of these studies the difference was only significant in certain FTD variants. Four studies found no significant difference in CSF NfL between PSP (n  = 98) and FTD (n  = 248). One study found a significantly higher level of NfL in PSP (n  = 33) compared to FTD (n  = 16). Conclusion: In the majority of patients in the studies included in this review, a higher level of NfL in CSF was found in patients with FTD compared to patients with PSP; however, results were inconsistent and prospective studies including large study cohorts are needed. Show more

Keywords: Biomarkers, frontotemporal dementia, neurofilament proteins, progressive supranuclear palsy

DOI: 10.3233/JAD-215616

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 131-140, 2022

Authors: Babulal, Ganesh M. | Chen, Ling | Doherty, Jason M. | Murphy, Samantha A. | Johnson, Ann M. | Roe, Catherine M.

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) studies in cognitively normal (CN) older adults age≥65 suggest depression is associated with molecular biomarkers (imaging and cerebrospinal fluid [CSF]). This study used linear mixed models (covariance pattern model) to assess whether baseline CSF biomarkers (Aβ42 /Aβ40 , t-Tau/Aβ42 , p-Tau/Aβ42 ) predicted changes in non-depressed mood states in CN older adults (N  = 248), with an average of three follow-up years. Participants with higher levels of CSF biomarkers developed more anger, anxiety, and fatigue over time compared to those with more normal levels. Non-depressed mood states in preclinical AD may be a prodrome for neuropsychiatric symptoms in …symptomatic AD. Show more

Keywords: Alzheimer’s disease, anger, anxiety, biomarkers, cerebrospinal fluid, older adults

DOI: 10.3233/JAD-215708

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 141-148, 2022

Authors: Jacus, Jean-Pierre | Voltzenlogel, Virginie | Antoine, Pascal | Cuervo-Lombard, Christine-Vanessa

Article Type: Short Communication

Abstract: Previous studies have reported the major role of apathy in awareness assessment among Alzheimer’s patients using the patient-caregiver discrepancy method, whatever the awareness dimension assessed. Using the Apathy Evaluation Scales among other awareness scales, we report that apathy is the sole awareness dimension distinguishing healthy controls (25), mild (57) and moderate-to-moderately-severe (11) Alzheimer’s patients. A linear regression showed that the Mini-Mental State Examination score used as a risk factor for non-awareness was the only factor associated with awareness of apathy and was the best predictor. This suggests that apathy is the most discriminant dimension for awareness assessment in Alzheimer’s disease.

Keywords: Alzheimer’s disease, apathy, assessment method, awareness

DOI: 10.3233/JAD-215550

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 149-154, 2022

Authors: Mi, Yingxin | Qin, Qi | Xing, Yi | Tang, Yi

Article Type: Short Communication

Abstract: Capgras syndrome (CS) was usually considered a symptom of a functional disorder in the young, most commonly schizophrenia, or an organic disorder in the elderly. The occurrence of CS among early-onset Alzheimer’s disease (EOAD) is extremely rare. We describe a case in which the unrecognition of CS as part of EOAD resulted in a wrong psychiatric diagnosis and inappropriate treatment. This paper aims to acknowledge CS as an early or core manifestation and highlight EOAD as a differential diagnosis of mental disorders in young people, even without a remarkable family history.

Keywords: Alzheimer’s disease, biomarkers, capgras syndrome, early-onset dementia, mental disorders

DOI: 10.3233/JAD-215565

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 155-160, 2022