Pages 1-15
Review
Yun Shi, Qianqian Bao, Weidong Chen, Lei Wang, Daiyin Peng, Jie Liu, Qing Liu, Yanchun Zhang, Zhaojie Ji, Aizong Shen (Handling Associate Editor: Daniela Galimberti)
Potential Roles of Extracellular Vesicles as Diagnosis Biomarkers and Therapeutic Approaches for Cognitive Impairment in Alzheimer’s Disease
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.
Pages 17-31
Review
Yael-Natalie H. Escobar*, Devin O’Piela*, Loren E. Wold, Amy R. Mackos
Influence of the Microbiota-Gut-Brain Axis on Cognition in Alzheimer’s Disease
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.
Pages 33-49
Review
Hallie Morton*, Tanisha Basu* Chhanda Bose, P. Hemachandra Reddy *These authors contributed equally to this work.
Impact of Chronic Conditions and Dementia in Rural West Texas: A Healthy Aging Study
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.
Pages 51-81
Review
Frédérique K. Kok*, Suzanne L. van Leerdam*, Elizabeth C.M. de Lange (Handling Associate Editor: Giulio Taglialatela) *These authors contributed equally to this work.
Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer’s Disease Neuropathology
Abstract: Alzheimer’s disease (AD) is the most common form of dementia and typically characterized by the accumulation 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.
Pages 83-100
Review
C. Kwon Kim, Yin Rui Lee, Lynnett Ong, Michael Gold, Amir Kalali, Joydeep Sarkar
Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures
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 99 failed compounds is presented in the Supplementary Material.
Pages 101-129
Systematic Review
Eleonora Lacorte, Antonio Ancidoni, Valerio Zaccaria, Giulia Remoli, Leonardo Tariciotti, Guido Bellomo, Francesco Sciancalepore, Massimo Corbo, Flavia L Lombardo, Ilaria Bacigalupo, Marco Canevelli, Paola Piscopo, Nicola Vanacore
Safety and Efficacy of Monoclonal Antibodies for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials
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 (SMD -0.04). 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.
Pages 131-140
Systematic Review
Nathalie Bendstrup, Anne-Mette Hejl, Lisette Salvesen (Handling Associate Editor: Tommaso Schirinzi)
Neurofilament Light Chain Levels in Frontotemporal Dementia and Progressive Supranuclear Palsy: A 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.
Pages 141-148
Short Communication
Ganesh M. Babulal, Ling Chen, Jason M. Doherty, Samantha A. Murphy, Ann M. Johnson, Catherine M. Roe
Longitudinal Changes in Anger, Anxiety, and Fatigue Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) studies in cognitively normal (CN) older adults aged ≥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.
Pages 149-154
Short Communication
Jean-Pierre Jacus, Virginie Voltzenlogel, Pascal Antoine, Christine-Vanessa Cuervo-Lombard
Apathy Is the Best Dimension to Consider for Awareness Assessment in Alzheimer’s Disease
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.
Pages 155-160
Short Communication
Yingxin Mi*, Qi Qin*, Yi Xing, Yi Tang (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Capgras Syndrome as the Core Manifestation of Early-Onset Alzheimer’s Disease
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.
Pages 161-172
Antonella Marino Gammazza, Vincenzo Restivo, Roberta Baschi, Celeste Caruso Bavisotto, Angelo B. Cefalù, Giulia Accardi, Everly Conway de Macario, Alberto J.L. Macario, Francesco Cappello, Roberto Monastero
Circulating Molecular Chaperones in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabùt Aging Project
Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer's disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education, subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR=1.16, 95% CI 1.04-1.30) and controls (OR=1.12, 95% CI 1.03-1.22), while Hsp70 was significantly higher only in AD (OR=1.84, 95% CI 1.09-3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression.
Pages 173-183
Vera Panzarella*, Rodolfo Mauceri*, Roberta Baschi, Laura Maniscalco, Giuseppina Campisi, Roberto Monastero *These authors contributed equally to this work.
Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabùt Aging Project
Abstract: Background: The relationship between Alzheimer’s disease (AD) and periodontitis has been recently investigated with heterogenous results. Objective: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabùt Aging Project, a community-based cohort study performed in rural community in Sicily, Italy. Methods: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment (aMCI), and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality of life (OHR-QoL) were evaluated. Results: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than for aMCI (p=0.009) and controls (p=0.001). Furthermore, the “M” component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p<0.001) and controls (p<0.001). A Poisson regression model revealed that age (p<0.001), male gender (p=0.001), and AD (p=0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p=0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p=0.004). OHR-QoL scores did not differ among the groups. Conclusion: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum. These data remain to be confirmed in larger population-based cohorts.
Pages 185-195
Domantė Kučikienė, Ana Sofia Costa, Leonie C.P. Banning, Veerle van Gils, Jörg B. Schulz, Inez H.G.B. Ramakers, Frans R.J. Verhey, Stephanie J.B. Vos, Kathrin Reetz (Handling Associate Editor: Julius Popp)
The Role of Vascular Risk Factors in Biomarker-Based AT(N) Groups: A German-Dutch Memory Clinic Study
Abstract: Background: The relation between vascular risk factors (VRFs) and Alzheimer’s disease (AD) is important due to possible pathophysiological association. Objective: To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context. Methods: We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site. Results: We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aβ42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition. Conclusion: VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia.
Pages 197-209
Ying Liu, Pei-Ran Han, Hao Hu, Zuo-Teng Wang, Yu Guo, Ya-Nan Ou, Xi-Peng Cao, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative
A Multi-Dimensional Comparison of Alzheimer’s Disease Neurodegenerative Biomarkers
Abstract: Background: In the 2018 AT(N) framework, neurodegenerative (N) biomarkers plays an essential role in the research and staging of Alzheimer’s disease (AD); however, the different choice of N may result in discordances. Objective: We aimed to compare different potential N biomarkers. Methods: We examined these N biomarkers among 1,238 participants from Alzheimer’s Disease Neuroimaging Initiative (ADNI) in their 1) diagnostic utility, 2) cross-sectional and longitudinal correlations between different N biomarkers and clinical variables, and 3) the conversion risk of different N profiles. Results: Six neurodegenerative biomarkers changed significantly from preclinical AD, through prodromal AD to AD dementia stage, thus they were chosen as the candidate N biomarkers: hippocampal volume (HV), 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), cerebrospinal fluid (CSF), total tau (T-tau), plasma neurofilament light chain (NFL), CSF NFL, and CSF neurogranin (Ng). Results indicated that FDG-PET not only had the greatest diagnostic utility in differentiating AD from controls (area under the curve: FDG-PET, 0.922), but also had the strongest association with cognitive scores. Furthermore, FDG-PET positive group showed the fastest memory decline (hazard ratio: FDG-PET, 3.45), which was also true even in the presence of amyloid-β pathology. Moreover, we observed great discordances between three valuable N biomarkers (FDG-PET, HV, and T-tau). Conclusion: These results underline the importance of using FDG-PET as N in terms of cognitive decline and AD conversion, followed by HV, and could be a great complement to the AT(N) framework.
Pages 211-222
Jing Ning, Shu-Yi Huang, Shi-Dong Chen, Ya-Ru Zhang, Yu-Yuan Huang, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study
Abstract: Background: Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. Objective: Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. Methods: We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. Results: Greater abundance of Ruminococcus (OR, 1.245; 95%CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. Conclusion: Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.
Pages 223-237
Daniel Kreft, Gabriele Doblhammer
Sex and Gender Differences in Environmental Influences on Dementia Incidence in Germany, 2014-2019: An Observational Cohort Study Based on Health Claims Data
Abstract: Background: There is an ongoing debate about whether environmental characteristics influence dementia risk like individual traits do, and whether these differ by sex and gender. Objective: This study examines the influence of regional characteristics on the incidence of dementia and explores sex and gender differences using individual-level health information and regional characteristics. Methods: Using a random sample of 250,000 people aged 70+ insured through Germany’s largest German public health agency, we analyzed quarterly data about diagnoses and place of residence from 2014 to 2019. Using five-digit postal codes, we added data on various dimensions of regional characteristics offered by the INKAR database and the 2011 Census database. We used multilevel survival regressions to tease out regional incidence differences while accounting for spatial clustering. Results: After adjusting for multi-morbidity and relocation-related selection bias, we saw that people living in regions with the highest tertile of income (HR=0.87, p<0.001), and who had the highest tertile of remaining life expectancy at age 60 (HR=0.93, p=0.012) had lower dementia risks. There was no gender difference in the regional income effect, but the effect of education (HR=0.91, p=0.015) was significant only for men and remaining life-expectancy was significant only for women (HR=0.93, p=0.026). Conclusion: Environmental characteristics related to wealth and health resources of a region influence the risk of dementia among the elderly in Germany. This effect is independent of the health profiles of the individuals and differs between the two genders. Health policies need to acknowledge these modifiable risk factors and consider how they affect men and women differently.
Pages 239-246
Samantha L. Tyler, John Maltby, Kevin B. Paterson, Claire V. Hutchinson
Reduced Vision-Related Quality of Life in Dementia: A Preliminary Report
Abstract: Background: Despite experimental evidence for concurrent dementia and visual impairment, there are no currently validated vision-related quality of life measures for use in this population. Objective: To establish the extent to which individuals with mild to moderate dementia self-report visual impairment and determine the efficacy of established vision-related quality of life measures for use in a dementia population. Methods: We compared vision-related quality of life in participants with mild-moderate dementia to healthy (dementia-free) older adults using two existing questionnaire measures already validated for use in older adults. These were the Visual Activities Questionnaire (VAQ) and the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Results: Responses on both the VAQ and VFQ-25 revealed a significant effect of dementia on self-reported vision-related quality of life. Visual impairment in dementia was identified in the domains of color discrimination, disability glare, light/dark adaption, acuity/spatial vision, depth perception, peripheral vision, visual search, and visual processing speed. Factor analysis of the data suggested that existing vision-related quality of life measures, designed for use in older adult populations, are likely to provide a robust means of assessing vision-related quality of life in older adults with dementia. Conclusion: Using existing measures designed for use in older adult populations, we have shown that people with dementia experience reduced vision-related quality of life.
Pages 247-258
Mihai S. Cirstea, Daniel Kliger, Abbey D. MacLellan, Adam C. Yu, Jenna Langlois, Mannie Fan, Seti Boroomand, Faezeh Kharazyan, Robyn G.Y. Hsiung, Brian A. MacVicar, Howard Chertkow, Victor Whitehead, Brett Finlay, Silke Appel-Cresswell
The Oral and Fecal Microbiota in a Canadian Cohort of Alzheimer’s Disease
Abstract: Background: Despite decades of research, our understanding of Alzheimer’s disease (AD) etiology remains incomplete. In recent years, appreciation has grown for potential roles for the microbiota in shaping neurological health. Objective: This study aimed to examine associations between the microbiota and AD in a human cross-sectional cohort. Methods: Forty-five AD patients and 54 matched controls were recruited in Vancouver, Canada. Fecal and oral samples underwent 16S microbiota sequencing. A wide array of demographic and clinical data were collected. Differences between participant groups were assessed, and associations between microbes and clinical variables were examined within the AD population. Results: The gut microbiota of AD patients displayed lower diversity relative to controls, although taxonomic differences were sparse. In contrast, the AD oral microbiota displayed higher diversity, with several taxonomic differences relative to controls, including a lower abundance of the families Streptococcaceae and Actinomycetaceae, and a higher abundance of Weeksellaceae, among others. The periodontitis-associated oral microbe Porphyromonas gingivalis was 5 times more prevalent among patients. No significant associations between gut or oral microbes and cognition were detected, but several correlations existed between microbes and mood disorders and BMI among patients, including a strong positive correlation between Alphaproteobacteria and depression score. Conclusion: The gut microbiota of AD patients was not overtly different from controls, although it displayed lower diversity, an overall marker of microbiota health. The oral microbiota did display marked differences. Cognition was not associated with a microbial signature, but other relevant AD factors including mood and BMI did demonstrate an association.
Pages 259-272
Amalie Clement, Marianne Juul Madsen, Kenneth Kastaniegaard, Ove Wiborg, Ayodeji A. Asuni, Allan Stensballe (Handling Associate Editor: Remy Cardoso)
Chronic Stress Induces Hippocampal Mitochondrial Damage in APPPS1 Model Mice and Wildtype Littermates
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. Despite decades of investigation, the etiology of AD is not fully understood, although emerging evidence suggest that chronic environmental and psychological stress plays a role in the mechanisms and contributes to the risk of developing AD. Thus, dissecting the impact of stress on the brain could improve our understanding of the pathological mechanisms. Objective: We aimed to study the effect of chronic stress on the hippocampal proteome in male APPPS1 transgenic mice and wildtype (WT) littermates. Methods: APPPS1 and WT mice were subjected to 4 weeks of chronic stress followed by 3 weeks of continued diurnal disruption. Hippocampal tissue was used for proteomics analysis using label-free quantitative DIA based LC-MS/MS analysis. Results: We identified significantly up- and downregulated proteins in both APPPS1 and WT mice exposed to chronic stress compared to the control groups. Via interaction network mapping, significant proteins could be annotated to specific pathways of mitochondrial function (oxidative phosphorylation and TCA cycle), metabolic pathways, AD pathway and synaptic functions (long term potentiation). In WT mice, chronic stress showed the highest impact on complex I of the oxidative phosphorylation pathway, while in APPPS1 mice this pathway was compromised broadly by chronic stress. Conclusion: Our data shows that chronic stress and amyloidosis additively contribute to mitochondrial damage in hippocampus. Although these results do not explain all effects of chronic stress in AD, they add to the scientific knowledge on the topic.
Pages 273-284
Alexandre Androuin, Manon Thierry, Susana Boluda, Brainbank NeuroCEB Neuropathology Network, Asha Baskaran, Dominique Langui, Charles Duyckaerts, Marie-Claude Potier, Khalid Hamid El Hachimi, Benoît Delatour, Serge Marty
Alterations of Neuronal Lysosomes in Alzheimer’s Disease and in APPxPS1-KI Mice
Abstract: Background: The cellular and molecular alterations associated with synapse and neuron loss in Alzheimer’s disease (AD) remain unclear. In transgenic mouse models that express mutations responsible for familial AD, neuronal and synaptic losses occur in populations that accumulate fibrillar amyloid-β 42 (Aβ42) intracellularly. Objective: We aimed to study the subcellular localization of these fibrillar accumulations and whether such intraneuronal assemblies could be observed in the human pathology. Methods: We used immunolabeling and various electron microscopy techniques on APP x presenilin1 - knock-in mice and on human cortical biopsies and postmortem samples. Results: We found an accumulation of A fibrils in lipofuscin granule-like organelles in APP x presenilin1 - knock-in mice. Electron microscopy of human cortical biopsies also showed an accumulation of undigested material in enlarged lipofuscin granules in neurons from AD compared to age-matched non-AD patients. However, in those biopsies or in postmortem samples we could not detect intraneuronal accumulations of Aβ fibrils, neither in the lipofuscin granules nor in other intraneuronal compartments. Conclusion: The intralysosomal accumulation of Aβ fibrils in specific neuronal populations in APPxPS1-KI mice likely results from a high concentration of Aβ42 in the endosome-lysosome system due to the high expression of the transgene in these neurons.
Pages 285-304
Xiaonan Wang, Fengjie Li, Qi Gao, Zhen Jiang, Xiayidanmu Abudusaimaiti, Jiangyue Yao, Huiping Zhu
Evaluation of the Accuracy of Cognitive Screening Tests in Detecting Dementia Associated with Alzheimer’s Disease: A Hierarchical Bayesian Latent Class Meta-Analysis
Abstract: Background: Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are neuropsychological tests commonly used by physicians for screening cognitive dysfunction of Alzheimer's disease (AD). Due to different imperfect reference standards, the performance of MoCA and MMSE do not reach consensus. It is necessary to evaluate the consistence and differentiation of MoCA and MMSE in the absence of a gold standard for AD. Objective: We aimed to assess the accuracy of MoCA and MMSE in screening AD without a gold standard reference test. Methods: Studies were identified from PubMed, Web of Science, CNKI, Chinese Wanfang Database, China Science and Technology Journal Database, and Cochrane Library. Our search was limited to studies published in English and Chinese before August 2021. A hierarchical Bayesian latent class model was performed in meta-analysis when the gold standard was absent. Results: A total of 67 studies comprising 5,554 individuals evaluated for MoCA and 76,862 for MMSE were included in this meta-analysis. The pooled sensitivity was 0.934 (95%CI 0.905 to 0.954) for MoCA and 0.883 (95%CI 0.859 to 0.903) for MMSE, while the pooled specificity was 0.899 (95%CI 0.859 to 0.928) for MoCA and 0.903 (95%CI 0.879 to 0.923) for MMSE. MoCA was useful to rule out dementia associated with AD with lower negative likelihood ratio (LR-) (0.074, 95%CI 0.051 to 0.108). MoCA showed better performance with higher diagnostic odds ratio (DOR) (124.903, 95%CI 67.459 to 231.260). Conclusion: MoCA had better performance than MMSE in screening dementia associated with AD from patients with mild cognitive impairment or healthy controls.
Pages 305-315
Commentary
J. Wesson Ashford, Frederick A. Schmitt, Michael F. Bergeron, Peter Bayley, James Clifford, Qun Xu, Xiaolei Liu, Xianbo Zhou, Vinod Kumar, Herman Buschke, Margaret Dean, Sanford I. Finkel, Lee Hyer, George Perry (Handling Editor: Paula Moreira)
Now is the Time to Improve Cognitive Screening and Assessment for Clinical and Research Advancement
Abstract: Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer’s disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.
Pages 317-333
Janne J. Luppi, Deborah N. Schoonhoven, Anne M. van Nifterick, Alida A. Gouw, Arjan Hillebrand, Philip Scheltens, Cornelis J. Stam, Willem de Haan
Oscillatory Activity of the Hippocampus in Prodromal Alzheimer’s Disease: A Source-Space Magnetoencephalography Study
Abstract: Background: In Alzheimer’s disease (AD), oscillatory activity of the human brain slows down. However, oscillatory slowing varies between individuals, particularly in prodromal AD. Cortical oscillatory changes have shown suboptimal accuracy as diagnostic markers. We speculated that focusing on the hippocampus might prove more successful, particularly using magnetoencephalography (MEG) for capturing subcortical oscillatory activity. Objective: We explored MEG-based detection of hippocampal oscillatory abnormalities in prodromal AD patients. Methods: We acquired resting-state MEG data of 18 AD dementia patients, 18 amyloid-β-positive amnestic mild cognitive impairment (MCI, prodromal AD) patients, and 18 amyloid-β-negative persons with subjective cognitive decline (SCD). Oscillatory activity in 78 cortical regions and both hippocampi was reconstructed using beamforming. Between-group and hippocampal-cortical differences in spectral power were assessed. Classification accuracy was explored using ROC curves. Results: The MCI group showed intermediate power values between SCD and AD, except for the alpha range, where it was higher than both (p < 0.05 and p < 0.001). The largest differences between MCI and SCD were in the theta band, with higher power in MCI (p < 0.01). The hippocampi showed several unique group differences, such as higher power in the higher alpha band in MCI compared to SCD (p < 0.05). Classification accuracy (MCI versus SCD) was best for absolute theta band power in the right hippocampus (AUC=0.87). Conclusion: In this MEG study, we detected oscillatory abnormalities of the hippocampi in prodromal AD patients. Moreover, hippocampus-based classification performed better than cortex-based classification. We conclude that a focus on hippocampal MEG may improve early detection of AD-related neuronal dysfunction.
Pages 335-344
Min Cao*, Jing Liu*, Xiaomin Zhang, Tingting Yang, Yaqi Wang, Yuli Hou, Qiao Song, Yuting Cui, Yifei Wang, Peichang Wang *These authors contributed equally to this work.
ABI3 Is a Novel Early Biomarker of Alzheimer’s Disease
Abstract: Background: The Abi3 gene has been suggested to be an important regulator of microglia during Alzheimer’s disease (AD), but the diagnostic power of ABI3 in neurodegenerative disease has rarely been reported. Objective: The aim of this study was to evaluate the diagnostic value of ABI3 in AD patients. Methods: ELISAs were used to measure the ABI3 level in the serum and cerebrospinal fluid (CSF) of AD patients as well as in the serum of APP/PS1 mice. RT-PCR and western blot were further performed to detect the expression levels of ABI3 in peripheral blood mononuclear cells (PBMCs) of AD subjects as well as in the hippocampus and cortical tissue of APP/PS1 mice. The correlation of cognitive ability with ABI3 level was estimated by linear regression analysis. Moreover, the diagnostic value of ABI3 for AD was assessed with ROC analysis. Results: The ABI3 levels all decreased significantly in the serum, CSF, and PBMCs of AD patients and showed a good diagnostic performance. In addition, the ABI3 levels were observed to decrease markedly in the hippocampus from 5-month-old mice, but the dramatic change only appeared in the cortical tissue in the 9-month-old APP/PS1 mice. The ABI3 levels in serum and in the hippocampus of APP/PS1 mice were significantly correlated with cognitive capacity. Conclusion: These results demonstrated that ABI3 in serum, CSF, and PBMCs could be a novel early diagnostic biomarker of AD. Moreover, ABI3 had potential to be a novel tracer marker in hippocampus of early AD.
Pages 345-357
Patrick J. Smith, Andrew Sherwood, Alan L. Hinderliter, Stephanie Mabe, Crystal Tyson, Forgive Avorgbedor, Lana L. Watkins, Pao-Hwa Lin, William E. Kraus, James A. Blumenthal
Cerebrovascular Function, Vascular Risk, and Lifestyle Patterns in Resistant Hypertension
Abstract: Background: Impaired cerebrovascular reactivity (CVR) and blunted cerebral hemodynamic recruitment are thought to be important mechanisms linking hypertension to cerebrovascular and cognitive outcomes. Few studies have examined cardiovascular or dietary correlates of CVR among hypertensives. Objective: To delineate associations between cardiometabolic risk, diet, and cerebrovascular functioning among individuals with resistant hypertension from the TRIUMPH trial (n = 140). Methods: CVR was assessed by examining changes in tissue oxygenation (tissue oxygenation index [TOI] and oxygenated hemoglobin [HBO2]) using functional near-infrared spectroscopy (fNIRS) during a breath holding test, a standardized CVR assessment to elicit a hypercapnic response. Participants also underwent fNIRS during three cognitive challenge tasks. Vascular function was assessed by measurement of brachial artery flow mediated dilation and hyperemic flow response. Cardiometabolic fitness was assessed from peak VO2 on an exercise treadmill test and body mass index. Dietary patterns were quantified using the DASH eating score. Cognitive function was assessed using a 45-minute test battery assessing Executive Function, Processing Speed, and Memory. Results: Greater levels fitness (B = 0.30, p = 0.011), DASH compliance (B = 0.19, p = 0.045), and lower obesity (B = -0.30, p = 0.004), associated with greater changes in TOI, whereas greater flow-mediated dilation (B = 0.19, p = 0.031) and lower stroke risk (B = -0.19, p = 0.049) associated with greater HBO2. Similar associations were found for cerebral hemodynamic recruitment, and associations between CVR and cognition were moderated by duration of hypertension. Conclusion: Impaired CVR elevated cardiometabolic risk, obesity, vascular function, and fitness among hypertensives.
Pages 359-372
Fabricio Ferreira de Oliveira, Paulo Henrique Ferreira Bertolucci, Elizabeth Suchi Chen, Marilia Cardoso Smith
Pharmacogenetic Analyses of Therapeutic Effects of Lipophilic Statins on Cognitive and Functional Changes in Alzheimer’s Disease
Abstract: Background: Pharmacogenetic effects of statins on clinical changes in Alzheimer’s disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism. Objective: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOE ε4 carrier status and lipid-lowering treatment with lipophilic statins. Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year. Results: Considering n=190: 142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOE ε4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOE ε4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G. Conclusion: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOE ε4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants.
Pages 373-390
Gowdame Lakshmanan Dharmaraj*, Fraulein Denise Arigo*, Kimberly A. Young, Ralph Martins, Ricardo L. Mancera*, Prashant Bharadwaj* *These authors contributed equally to this work.
Novel Amylin Analogues Reduce Amyloid-β Cross-Seeding Aggregation and Neurotoxicity
Abstract: Background: Type 2 diabetes related human islet amyloid polypeptide (hIAPP) plays a dual role in Alzheimer’s disease (AD). hIAPP has neuroprotective effects in AD mouse models whereas, high hIAPP concentrations can promote co-aggregation with amyloid-β (Aβ) to promote neurodegeneration. In fact, both low and high plasma hIAPP concentration has been associated with AD. Therefore, non-aggregating hIAPP analogues have garnered interest as a treatment for AD. The aromatic amino acids F23 and I26 in hIAPP have been identified as the key residues involved in self-aggregation and Aβ cross-seeding. Objective: Three novel IAPP analogues with single and double alanine mutations (A1=F23, A2=I26, and A3=F23+I26) were assessed for their ability to aggregate, modulate Aβ oligomer formation, and alter neurotoxicity. Methods: A range of biophysical methods including Thioflavin-T, gel electrophoresis, photo-crosslinking, circular dichroism combined with cell viability assays were utilized to assess protein aggregation and toxicity. Results: All IAPP analogues showed significantly less self-aggregation than hIAPP. Co-aggregated Aβ42-A2 and A3 also showed reduced aggregation compared to Aβ42-hIAPP mixtures. Self- and co-oligomerized A1, A2, and A3 exhibited random coil conformations with reduced beta sheet content compared to hIAPP and Aβ42-hIAPP aggregates. A1 was toxic at high concentrations compared to A2 and A3. However, co-aggregated Aβ42-A1, A2, or A3 showed reduced neurotoxicity compared to Aβ42, hIAPP, and Aβ42-hIAPP aggregates. Conclusion: These findings confirm that hIAPP analogues with non-aromatic residues at positions 23 and 26 have reduced self-aggregation and the ability to neutralize Aβ42 toxicity. This warrants further characterization of their protective effects in pre-clinical AD models.
Pages 391-403
YongSoo Shim, Hyun Jeong Han, Kyung Won Park, Byeong C. Kim, Kee Hyung Park, Mee Young Park, Hee-Jin Kim, So Young Moon, Seong Hye Choi, Kun Woo Park, Dong Won Yang, Soo Jin Yoon, SangYun Kim, Young Chul Youn, Ho Jin Choi, Koung Eun Yoon, Hyun Ju Cho, Seol-Heui Han
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IIb Clinical Study to Evaluate the Safety and Efficacy of DHP1401 in Patients with Mild to Moderate Alzheimer's Disease Treated with Donepezil: DHP1401 Randomized Trial in Mild to Moderate Alzheimer’s Disease (DRAMA)
Abstract: Background: Preclinical studies in transgenic models of Alzheimer's disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects. Objective: To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezil. Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24. Results: A total of 180 patients were randomized to Active 1 (500 mg: n=62), Active 2 (1000 mg: n=53), and control groups (n=65) in 16 sites in Korea. There was no significant difference in the Alzheimer’s Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20-26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks. Conclusion: Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials.
Pages 405-414
Ana Verdelho, Manuel Correia, José Manuel Ferro, Sofia Madureira, Pedro Vilela, Mário Rodrigues, Mariana Borges, Vanessa Oliveira, Ana Catarina Santos, Manuel Gonçalves-Pereira, Helena Santa-Clara (Handling Associate Editor: Daniela Galimberti)
Physical Activity Self-Report Is Not Reliable Among Subjects with Mild Vascular Cognitive Impairment: The AFIVASC Study
Abstract: Background: The World Health Organization (WHO) recommends a minimum of 150 minutes of moderate physical activity per week. Adherence to these recommendations is difficult to assess. Objective: We aimed to evaluate the validity of self-reported physical activity in mild vascular cognitive impairment (mVCI) and whether physical activity was associated with cognitive status, by using baseline data from a randomized controlled trial. Methods: A hundred and four subjects with mVCI were included (mean age 72 years; 51% women). Subjects underwent neurological, physical, and comprehensive neuropsychological assessments. Adherence to WHO physical activity recommendations was evaluated using both self-reported information and objective measures (accelerometry). Results: There was poor agreement (kappa=0.106) between self-report of following WHO recommendations and actually fulfilling them according to accelerometry. Only 16.6% of participants reported following WHO recommendations and displayed compatible values according to the accelerometer. Participants whose accelerometry values confirmed adherence to WHO recommendations had better performance in a global measure of cognition, attention, and mental speed processing. In multiple regression analyses, education and accelerometry values in accordance with WHO recommendations were independently associated with the global measure of cognition, attention, and processing speed, controlling for sex, age, and depressive symptoms. Accelerometry results were not associated with memory and executive functions. Conclusion: In this sample of mVCI subjects, self-reported physical activity displayed poor agreement with accelerometry values, suggesting that objective measures of physical activity are preferable. Physical activity (performed, at least, according to WHO recommendations) was associated with better cognitive performance overall.
Pages 415-432
Xianglin L. Du, Lulu Song, Paul E. Schulz, Hua Xu, Wenyaw Chan
Risk of Developing Alzheimer’s Disease and Related Dementias in Association with Cardiovascular Disease, Stroke, Hypertension, and Diabetes in a Large Cohort of Women with Breast Cancer and with up to 26 Years of Follow-Up
Abstract: Background: No study on the long-term incidence of Alzheimer’s disease (AD) and related dementias (ADRD) has been reported in women with breast cancer by vascular diseases. Objective: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in women with breast cancer. Methods: Study identified 246,686 women diagnosed with breast cancer at age ≥65 years in 1991-2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Women were free of ADRD at the time of cancer diagnosis and followed from 1991 to 2016. Results: Cumulative incidence of AD over 26 years of follow-up varied from 10.7% to 13.6% by CVD, stroke, hypertension, and diabetes. Cumulative incidence of ADRD was higher in those with CVD (40.75%) versus no-CVD (31.32%), stroke (40.24%) versus no-stroke (31.34%), hypertension (33.06%) versus no-hypertension (30.47%), and diabetes (33.38%) versus no-diabetes (31.77%). After adjusting for confounders, those with CVD (hazard ratio:1.30, 95%CI: 1.27-1.33), stroke (1.50,1.47-1.54), hypertension (1.08,1.06-1.09), and diabetes (1.26,1.24-1.29) had significantly higher risks of developing ADRD. Women aged 80-84, and ≥85 had 5- and 7-fold higher risks of AD than those aged 65-69. As compared to white women, black women had a significantly higher risk of AD (1.21, 1.16-1.27), whereas Asians/Pacific-Islanders had a significantly lower risk of AD (0.77, 0.71-0.83). Conclusion: In women with breast cancer, CVD, stroke, hypertension, and diabetes were associated with a significantly higher risk of developing any ADRD combined. The risk of ADRD was higher in black women and lower in Asian/Pacific-Islanders than white women.
Pages 433-441
Roland Nicsanu, Carlo Cervellati, Luisa Benussi, Rosanna Squitti, Roberta Zanardini, Valentina Rosta, Alessandro Trentini, Clarissa Ferrari, Claudia Saraceno, Antonio Longobardi, Sonia Bellini, Giuliano Binetti, Orazio Zanetti, Giovanni Zuliani, Roberta Ghidoni
Increased Serum Beta-Secretase 1 Activity is an Early Marker of Alzheimer’s Disease
Abstract: Background: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-β (Aβ) plaques formation. BACE1 activity is increased in brains of patients with AD and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains. Objective: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of Aβ1-40, Aβ1-42, and Aβ40/42 ratio in serum, known biomarkers of brain amyloidosis. Methods: Serum BACE1 activity and levels of Aβ1-40, Aβ1-42, were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of Aβ1-40, Aβ1-42 were measured with the ultrasensitive Single Molecule Array technology. Results: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04 kU/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than Aβ40/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (>16.67 kU/L). Conclusion: Our results provide new evidence supporting serum/plasma BACE1 activity as an early biomarker of AD.
Pages 443-451
Gábor Ternák, Márton Németh, Martin Rozanovic, Lajos Bogár
Alzheimer’s Disease-Related Dysbiosis Might Be Triggered by Certain Classes of Antibiotics with Time-Lapse: New Insights into the Pathogenesis?
Abstract: Background: Several putative factors are identified in the literature as causative agents or risk factors for the development of Alzheimer’s disease (AD). The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades, but recent studies raised the possible role of dysbiosis in the development of AD, which prevents memory loss. Objective: Finding possible associations between antibiotic consumption patterns and the prevalence of AD in European countries. Methods: Antibiotic consumption (European Centre for Disease Prevention and Control, ECDC) for 1997-2007, 2008-2018, and as the whole 1997-2018 period, has been compared to the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. Results: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the years 1997-2007 (r: 0.37, p: 0.044). A similar association was not observed for the entire 22 years (1997-2018) of the average quinolone consumption, and the years 2008-2018, indicating 10-20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008-2018 showed a strong positive association with AD prevalence (2018) (r: 0.406, p: 0.026) and a positive correlation tendency for the entire 22 years 1997-2018 (r: 0.344, p: 0.063), but none for the years 1997-2007 (r: 0.256, p: 0.241). Conclusion: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD.
Pages 453-461
Somayeh Meysami, Cyrus A. Raji, Mario F. Mendez
Quantified Brain Magnetic Resonance Imaging Volumes Differentiates Behavioral Variant Frontotemporal Dementia from Early-Onset Alzheimer’s Disease
Abstract: Background: The differentiation of behavioral variant frontotemporal dementia (bvFTD) from early-onset Alzheimer’s disease (EOAD) by clinical criteria can be inaccurate. The volumetric quantification of clinically available magnetic resonance (MR) brain scans may facilitate early diagnosis of these neurodegenerative dementias. Objective: To determine if volumetric quantification of brain MR imaging can identify persons with bvFTD from EOAD. Methods: 3D T1 MR brain scans of 20 persons with bvFTD and 45 with EOAD were compared using Neuroreader to measure subcortical, and lobar volumes, and Volbrain for hippocampal subfields. Analyses included: 1) discriminant analysis with leave one out cross-validation; 2) input of predicted probabilities from this process into a receiver operator characteristics (ROC) analysis; and 3) Automated linear regression to identify predictive regions. Results: Both groups were comparable in age and sex with no statistically significant differences in symptom duration. bvFTD had lower volume percentiles in frontal lobes, thalamus, and putamen. EOAD had lower parietal lobe volumes. ROC analyses showed 99.3% accuracy with Neuroreader percentiles and 80.2% with subfields. The parietal lobe was the most predictive percentile. Although there were differences in hippocampal (particularly left CA2-CA3) subfields, it did not add to the discriminant analysis. Conclusion: Percentiles from an MR based volumetric quantification can help differentiate between bvFTD from EOAD in routine clinical care. Use of hippocampal subfield volumes does not enhance the diagnostic separation of these two early-onset dementias.
Pages 463-477
Shu-Yi Huang, Yu-Xiang Yang, Ya-Ru Zhang, Kevin Kuo, Hong-Qi Li, Xue-Ning Shen, Shi-Dong Chen, Ke-Liang Chen, Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Investigating Causal Relations Between Circulating Metabolites and Alzheimer’s Disease: A Mendelian Randomization Study
Abstract: Background: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer’s disease (AD). However, the causal relationships between metabolism and AD are poorly understood. Objective: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. Methods: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. Results: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR]=3.18; 95% confidence interval[CI]: 1.52–6.66, p=0.0022), glycoprotein acetyls (OR=1.21; 95%CI: 1.05–1.39, p=0.0093), total cholesterol (OR=2.73; 95%CI: 1.41-5.30, p=0.0030), and low-density lipoprotein (LDL) cholesterol (OR=2.34; 95%CI: 1.53-3.57, p=0.0001). Whereas glutamine (OR=0.81; 95%CI: 0.71-0.92, p=0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. Conclusion: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.
Pages 479-488
See Ann Soo, Fatin Zahra Zailan, Jayne Yi Tan, Gurveen Kaur Sandhu, Benjamin Yi Xin Wong, Brian Zhiyang Wang, Adeline Su Lyn Ng, Hui Jin Chiew, Kok Pin Ng, Nagaendran Kandiah
Safety and Usefulness of Lumbar Puncture for the Diagnosis and Management of Young-Onset Cognitive Disorders
Abstract: Background: Young-onset cognitive disorders (YOCD) often manifests with complex and atypical presentations due to underlying heterogenous pathologies. Therefore, a biomarker-based evaluation will allow for timely diagnosis and definitive management. Objective: Here, we evaluated the safety and usefulness of cerebrospinal fluid (CSF) sampling through lumbar puncture (LP) in YOCD patients in a tertiary clinical setting. Methods: Patients with mild cognitive impairment (MCI) and mild dementia with age of onset between 45-64 years were evaluated. Patients underwent magnetic resonance imaging and their medial temporal lobe atrophy (MTA) was rated. LP side-effects and the impact of the CSF findings on diagnosis and management were analyzed. Results: 142 patients (53 (37.32%) MCI, 51 (35.92%) dementia of the Alzheimer’s disease [DAT] type, and 38 (26.76%) non-AD type dementia) who underwent LP between 2015 to 2021 were analyzed. Using post-LP results and MTA ratings, 74 (52.11%) patients met the AT(N) criteria for AD. 56 (39.44%) patients (28 out of 53 (50.0%) MCI, 12 out of 51 (21.43%) DAT, and 16 out of 38 (28.57%) non-AD dementia) had a change in diagnosis following LP. 13 (9.15%) patients developed side-effects post-LP (11 (84.62%) patients had headache, 1 (7.69%) patient had backache, and 1 (7.69%) patient had headache and backache). 32 (22.54%) patients had a change in management post-LP, 24 (75.0%) had medication changes, 10 (31.30%) had referrals to other specialists, and 3 (9.40%) was referred for clinical trial with disease modifying interventions. Conclusion: LP is well-tolerated in YOCD and can bring about relevant clinical decisions with regards to the diagnosis and management of this complex clinical condition.
Pages 489-501
Charles F. Murchison, Byron C. Jaeger, Jeff M. Szychowski, Gary R. Cutter, Erik D. Roberson, Richard E. Kennedy
Influence of Subject-Specific Effects in Longitudinal Modelling of Cognitive Decline in Alzheimer’s Disease
Abstract: Background: Accurate longitudinal modelling of cognitive decline is a major goal of Alzheimer’s disease and related dementia (ADRD) research. However, the impact of subject-specific effects is not well characterized and may have implications for data generation and prediction. Objective: This study seeks to address the impact of subject-specific effects, which are a less well-characterized aspect of ADRD cognitive decline, as measured by the Alzheimer’s Disease Assessment Scale’s Cognitive Subscale (ADAS-Cog). Methods: Prediction errors and biases for the ADAS-Cog subscale were evaluated when using only population-level effects, robust imputation of subject-specific effects using model covariances, and directly known individual-level effects fit during modelling as a natural control. Evaluated models included pre specified parameterizations for clinical trial simulation, analogous mixed-effects regression models parameterized directly, and random forest ensemble models. Assessment used a meta-database of Alzheimer’s disease studies with validation in simulated synthetic cohorts. Results: All models observed increases in variance under imputation leading to increased prediction error. Bias decreased with imputation except under the pre-specified parameterization, which increased in the meta-database, but was attenuated under simulation. Known fitted subject effects gave the best prediction results. Conclusion: Subject-specific effects were found to have a profound impact on predicting ADAS-Cog. Reductions in bias suggest imputing random effects assists in calculating results on average, as when simulating clinical trials. However, reduction in error emphasizes population-level effects when attempting to predict outcomes for individuals. Forecasting future observations greatly benefits from using known subject-specific effects.
