Journal of Alzheimer's Disease - Volume 93, issue 1

Authors: Fillenbaum, Gerda G. | Mohs, Richard

Article Type: Review Article

Abstract: Background: In 1986, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) was mandated to develop a brief neuropsychological assessment battery (CERAD-NAB) for AD, for uniform neuropsychological assessment, and information aggregation. Initially used across the National Institutes of Aging-funded Alzheimer’s Disease Research Centers, it has become widely adopted wherever information is desired on cognitive status and change therein, particularly in older populations. Objective: Our purpose is to provide information on the multiple uses of the CERAD-NAB since its inception, and possible further developments. Methods: Since searching on “CERAD neuropsychological assessment battery” or similar terms missed …important information, “CERAD” alone was entered into PubMed and SCOPUS, and CERAD-NAB use identified from the resulting studies. Use was sorted into major categories, e.g., psychometric information, norms, dementia/differential dementia diagnosis, epidemiology, intervention evaluation, genetics, etc., also translations, country of use, and alternative data gathering approaches. Results: CERAD-NAB is available in ∼20 languages. In addition to its initial purpose assessing AD severity, CERAD-NAB can identify mild cognitive impairment, facilitate differential dementia diagnosis, determine cognitive effects of naturally occurring and experimental interventions (e.g., air pollution, selenium in soil, exercise), has helped to clarify cognition/brain physiology-neuroanatomy, and assess cognitive status in dementia-risk conditions. Surveys of primary and tertiary care patients, and of population-based samples in multiple countries have provided information on prevalent and incident dementia, and cross-sectional and longitudinal norms for ages 35–100 years. Conclusion: CERAD-NAB has fulfilled its original mandate, while its uses have expanded, keeping up with advances in the area of dementia. Show more

Keywords: Alzheimer’s disease, CERAD, CERAD Plus, Consortium to Establish a Registry for Alzheimer’s Disease, epidemiological surveys, incidence, neuropsychological assessment, norms, prevalence

DOI: 10.3233/JAD-230026

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 1-27, 2023

Authors: Hendrie, Hugh C.

Article Type: Article Commentary

Abstract: The 1980s saw an upsurge of research in Alzheimer’s disease (AD). The necessity of standardized assessment batteries became apparent, leading to the development of standardized instruments, such as the CERAD, the CAMDEX, the CSI ’D’, and later the TOOLBOX. The advent of new biological markers has led to speculation in the research community about the necessity for these instruments. As the association of biomarkers with subsequent clinical dementia remains unclear, assessment batteries are still necessary, especially with growing evidence that prodromal symptoms of AD may not be cognitive decline but emotional or behavioral symptoms. Inclusion of ethnic minority groups is …also essential. Show more

Keywords: Alzheimer’s disease, biological markers, ethnic minority representation, standardized assessment tools

DOI: 10.3233/JAD-230215

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 29-32, 2023

Authors: Hook, Gregory | Kindy, Mark | Hook, Vivian

Article Type: Review Article

Abstract: The lysosomal cysteine protease cathepsin B (CTSB) has been suggested as a biomarker for Alzheimer’s disease (AD) because elevated serum CTSB in AD patients has been found to correlate with cognitive dysfunction. Furthermore, CTSB gene knockout (KO) in non-transgenic and transgenic AD animal models showed that elimination of CTSB improved memory deficits. However, conflicting CTSB KO results on amyloid-β (Aβ) pathology in transgenic AD models have been reported. The conflict is resolved here as likely being due to the different hAβPP transgenes used in the different AD mouse models. CTSB gene KO reduced wild-type (Wt) β-secretase activity, brain …Aβ, pyroglutamate-Aβ, amyloid plaque, and memory deficits in models that used cDNA transgenes expressing hAβPP isoform 695. But in models that used mutated mini transgenes expressing hAβPP isoforms 751 and 770, CTSB KO had no effect on Wt β-secretase activity and slightly increased brain Aβ. All models expressed the AβPP transgenes in neurons. These conflicting results in Wt β-secretase activity models can be explained by hAβPP isoform specific cellular expression, proteolysis, and subcellular processing. CTSB KO had no effect on Swedish mutant (Swe) β-secretase activity in hAβPP695 and hAβPP751/770 models. Different proteolytic sensitivities for hAβPP with Wt versus Swe β-secretase site sequences may explain the different CTSB β-secretase effects in hAβPP695 models. But since the vast majority of sporadic AD patients have Wt β-secretase activity, the CTSB effects on Swe β-secretase activity are of little importance to the general AD population. As neurons naturally produce and process hAβPP isoform 695 and not the 751 and 770 isoforms, only the hAβPP695 Wt models mimic the natural neuronal hAβPP processing and Aβ production occurring in most AD patients. Significantly, these CTSB KO findings in the hAβPP695 Wt models demonstrate that CTSB participates in memory deficits and production of pyroglutamate-Aβ (pyroglu-Aβ), which provide rationale for future investigation of CTSB inhibitors in AD therapeutics development. Show more

Keywords: Alzheimer’s disease, amyloid-β, AβPP isoform, β-secretase, cathepsin B, cDNA, gene, memory deficits, mouse models, neuron, promoter

DOI: 10.3233/JAD-221005

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 33-46, 2023

Authors: Umfleet, Laura Glass | Bilder, Robert M. | Loring, David W. | Thames, April | Hampstead, Benjamin M. | Bauer, Russell M. | Drane, Daniel L. | Cavanagh, Lucia

Article Type: Review Article

Abstract: Cognitive screening instruments (CSI) have variable sensitivity and specificity to the cognitive changes associated with dementia syndromes, and the most recent systematic review found insufficient evidence to support the benefit of cognitive screening tools in older adults residing within the community. Consequently, there is a critical need to improve CSI methods, which have not yet incorporated advances in psychometrics, neuroscience, and technology. The primary goal of this article is to provide a framework for transitioning from legacy CSIs to advanced dementia screening measurement. In line with ongoing efforts in neuropsychology and the call for next-generation digital assessment for early detection …of AD, we propose a psychometrically advanced (including application of item response theory methods), automated selective assessment model that provides a framework to help propel an assessment revolution. Further, we present a three-phase model for modernizing CSIs and discuss critical diversity and inclusion issues, current challenges in differentiating normal from pathological aging, and ethical considerations. Show more

Keywords: Alzheimer’s disease, cognitivescreening instruments, dementia, neuropsychology

DOI: 10.3233/JAD-221077

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 47-59, 2023

Authors: Weidung, Bodil | Lövheim, Hugo | Littbrand, Håkan | Wahlin, Johanna | Olofsson, Birgitta | Gustafson, Yngve

Article Type: Research Article

Abstract: Background: Long-increasing dementia incidence and prevalence trends may be shifting. Whether such shifts have reached the very old is unknown. Objective: To investigate temporal trends in the incidence of dementia and cognitive impairment and prevalence of dementia, cognitive impairment, Alzheimer’s disease, vascular dementia, and unclassified dementia among 85-, 90-, and ≥ 95-year-olds in Sweden during 2000–2017. Methods: This study was conducted with Umeå 85 + /Gerontological Regional Database data from 2182 85-, 90-, and ≥ 95-year-olds in Sweden collected in 2000–2017. Using logistic regression, trends in the cumulative 5-year incidences of dementia and cognitive impairment; prevalences of dementia, …cognitive impairment, Alzheimer’s disease, and vascular dementia; and Mini-Mental State Examination thresholds for dementia diagnosis were estimated. Results: Dementia and cognitive impairment incidences decreased in younger groups, which generally showed more-positive temporal trends. The prevalences of overall dementia, cognitive impairment, and Alzheimer’s disease were stable or increasing; longer disease durations and increasing dementia subtype classification success may mask positive changes in incidences. Vascular dementia increased while unclassified dementia generally decreased. Conclusion: The cognitive health of the very old may be changing in the 21st century, possibly indicating a trend break. Show more

Keywords: Aged 80 and over, Alzheimer’s disease, cognition disorders, cohort studies, cross-sectional studies, dementia, epidemiologic studies, longitudinal studies, neurocognitive disorders, vascular dementia

DOI: 10.3233/JAD-220915

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 61-74, 2023

Authors: Grisanti, Stefano Giuseppe | Massa, Federico | Chincarini, Andrea | Pretta, Stefano | Rissotto, Roberto | Serrati, Carlo | Monacelli, Fiammetta | Serafini, Gianluca | Calcagno, Pietro | Brugnolo, Andrea | Pardini, Matteo | Nobili, Flavio | Girtler, Nicola | Schenone, Angelo | Nencioni, Alessio | Amore, Mario | Biffa, Gabriella | Sambuceti, Gianmario | Morbelli, Silvia | Roccatagliata, Luca | Castellan, Lucio | Travalca, Cupillo Beatrice | Castellini, Paola | Fiocca, Roberto | Gaggero, Gabriele | Mandich, Paola | Origone, Paola | Livrari, Barbara

Article Type: Research Article

Abstract: Background: Apathy is a frequent behavioral symptom of Alzheimer’s disease (AD). The Apathy Evaluation Scale (AES) is a tool exploring the perception of apathy by both caregivers (CG-AES) and patients (PT-AES), and the discrepancy in their ratings is a proxy of patients’ disease unawareness. Objective: To assess in a cohort study of patients with amnesic mild cognitive impairment (aMCI) whether apathy and awareness of apathy predict progression to dementia and timing. Methods: From the global AES scores of 110 patients with aMCI and their caregivers, we obtained two principal indices for analysis: 1) ‘Apathy’, the mean …of PT-AES and CG-AES, and 2) ‘Discrepancy’, obtained by subtracting CG-AES from PT-AES. Patients were followed with visits every six months for three years or until dementia. AES indices and the principal demographical/neuropsychological variables were filtered from multicollinearity. The most robust variables entered a logistic regression model and survival analyses (Cox regression, log-rank test of Kaplan-Meier curves) to estimate which predicted the risk and timing of progression, respectively. Results: Sixty patients (54.5%) developed dementia (57 AD) after 6.0–36.0 months, 22 (20%) remained in an MCI stage, and 28 (25.5%) dropped out. ‘Discrepancy’ was a robust and accurate predictor of the risk of progression (AUC = 0.73) and, after binarization according to a computed cutoff, of timing to dementia. Conclusion: A structured evaluation of apathy, both self-assessed and estimated by caregivers, can provide useful information on the risk and timing of progression from aMCI to dementia. The discrepancy between the two estimates is a fairly reliable index for prediction purposes as a proxy of disease unawareness. Show more

Keywords: Alzheimer’s disease, apathy, awareness, dementia discrepancy, mild cognitive impairment

DOI: 10.3233/JAD-220418

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 75-86, 2023

Authors: Moon, Seok Woo | Byun, Min Soo | Yi, Dahyun | Kim, Min Jung | Jung, Joon Hyung | Kong, Nayeong | Jung, Gijung | Ahn, Hyejin | Lee, Jun-Young | Kang, Koung Mi | Sohn, Chul-Ho | Kim, Yu Kyeong | Lee, Dong Young

Article Type: Research Article

Abstract: Background: Ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with Alzheimer’s disease (AD) dementia and related cognitive impairment. Nevertheless, only limited information is available regarding its contribution to brain alterations leading to cognitive decline in late-life. Objective: We aimed to investigate the relationship of ABI with in vivo AD pathologies and cerebrovascular injury in cognitively impaired older adults. Methods: Total 127 cognitively impaired (70 mild cognitive impairment and 57 AD dementia) individuals, who participated in an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessment, …ABI measurement, apolipoprotein E (APOE ) ɛ4 genotyping, and multi-modal brain imaging including [11 C] Pittsburgh Compound B (PiB)-positron emission tomography (PET) and [18 F] fludeoxyglucose (FDG)-PET, and MRI. Results: General linear model analysis showed significant relationship between ABI strata (low ABI: <1.00, normal ABI: 1.00–1.29, and high ABI: ≥1.30) and AD-signature region cerebral glucose metabolism (AD-CM), even after controlling age, sex, clinical dementia rating–sum of box, and APOE ɛ4 positivity (p  = 0.029). Post hoc comparison revealed that low ABI had significantly lower AD-CM than middle and high ABI, while no difference of AD-CM was found between middle and high ABI. There was no significant difference of global Aβ deposition, AD-signature region cortical thickness, and white matter hyperintensity volume between the three ABI strata. Conclusion: Our findings suggest that lower ABI, likely related to atherosclerosis, may contribute to the aggravation of AD-related regional neurodegeneration in cognitively impaired older adults. Show more

Keywords: Alzheimer’s disease, ankle-brachial index, cerebral Aβ deposition, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-220911

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 87-95, 2023

Authors: Schuurmans, Isabel K. | Hoepel, Sanne J.W. | Cecil, Charlotte A.M. | Hillegers, Manon H.J. | Ikram, M. Arfan | Luik, Annemarie I.

Article Type: Research Article

Abstract: Background: Cognitive and brain reserve refer to individual differences that allow some people to better withstand brain pathology than others. Although early life stress has been recognized as a risk factor for low reserve in late life, no research yet has studied this across midlife. Objective: To examine the associations of life stress with brain and cognitive reserve in midlife. Methods: We included 1,232 middle-aged women who participated in the ORACLE Study between 2002-2006). Life stress was calculated as the shared variance of four cumulative stress domains, created from items measured between pregnancy and 10 years …after childbirth. Brain reserve was defined as healthy-appearing brain volume measured with MRI; cognitive reserve as better cognitive functioning than expected based on age, education, and brain MRI measures, using structural equation modelling. Results: More life stress was associated with lower brain (standardized adjusted difference: -0.18 [95% CI 0.25,-0.12]) and cognitive reserve (-0.19 [-0.28,-0.10]). Although, effect sizes were typically smaller, cumulative stress domains were also associated with brain reserve (life events: -0.10 [-0.16,-0.04]; contextual stress: -0.13 [-0.19,-0.07]; parenting-related stress: -0.13[-0.19,-0.07]; interpersonal stress: -0.10 [-0.16,-0.04]) and cognitive reserve (life events: -0.18 [-0.25,-0.11]; contextual stress: -0.15 [-0.10,-0.02]; parenting-related stress: -0.10 [-0.18,-0.03]; interpersonal stress not significant). Conclusion: Women who experience more life stress in midlife were found to have lower reserve. Effects were primarily driven by shared variance across cumulative stress domains, suggesting that focusing on single domains may underestimate effects. The effect of life stress on lower reserve may make women with stress more prone to neurodegenerative disease later in life than women without stress. Show more

Keywords: Cognitive reserve, epidemiology, middle aged, psychological, stress

DOI: 10.3233/JAD-220923

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 97-106, 2023

Authors: Krebs, Christine | Brill, Esther | Minkova, Lora | Federspiel, Andrea | Kellner-Weldon, Frauke | Wyss, Patric | Teunissen, Charlotte E. | van Harten, Argonde C. | Seydell-Greenwald, Anna | Klink, Katharina | Züst, Marc A. | Brem, Anna-Katharine | Klöppel, Stefan

Article Type: Research Article

Abstract: Background: Preclinical Alzheimer’s disease (AD) is one possible cause of subjective cognitive decline (SCD). Normal task performance despite ongoing neurodegeneration is typically considered as neuronal compensation, which is reflected by greater neuronal activity. Compensatory brain activity has been observed in frontal as well as parietal regions in SCD, but data are scarce, especially outside the memory domain. Objective: To investigate potential compensatory activity in SCD. Such compensatory activity is particularly expected in participants where blood-based biomarkers indicated amyloid positivity as this implies preclinical AD. Methods: 52 participants with SCD (mean age: 71.00±5.70) underwent structural and functional …neuroimaging (fMRI), targeting episodic memory and spatial abilities, and a neuropsychological assessment. The estimation of amyloid positivity was based on plasma amyloid-β and phosphorylated tau (pTau181) measures. Results: Our fMRI analyses of the spatial abilities task did not indicate compensation, with only three voxels exceeding an uncorrected threshold at p  < 0.001. This finding was not replicated in a subset of 23 biomarker positive individuals. Conclusion: Our results do not provide conclusive evidence for compensatory brain activity in SCD. It is possible that neuronal compensation does not manifest at such an early stage as SCD. Alternatively, it is possible that our sample size was too small or that compensatory activity may be too heterogeneous to be detected by group-level statistics. Interventions based on the individual fMRI signal should therefore be explored. Show more

Keywords: Blood-based biomarkers, functional MRI, neuronal compensation, episodic memory, spatial abilities, subjective cognitive decline

DOI: 10.3233/JAD-221001

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 107-124, 2023

Authors: Dolcet-Negre, Marta M. | Imaz Aguayo, Laura | García-de-Eulate, Reyes | Martí-Andrés, Gloria | Fernández-Matarrubia, Marta | Domínguez, Pablo | Fernández-Seara, Maria A. | Riverol, Mario

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may represent a preclinical stage of Alzheimer’s disease (AD). Predicting progression of SCD patients is of great importance in AD-related research but remains a challenge. Objective: To develop and implement an ensemble machine learning (ML) algorithm to identify SCD subjects at risk of conversion to mild cognitive impairment (MCI) or AD. Methods: Ninety-nine SCD patients were included. Thirty-two progressed to MCI/AD, while 67 remained stable. To minimize the effect of class imbalance, both classes were balanced, and sensitivity was taken as evaluation metric. Bagging and boosting ML models were developed by …using socio-demographic and clinical information, Mini-Mental State Examination and Geriatric Depression Scale (GDS) scores (feature-set 1a); socio-demographic characteristics and neuropsychological tests scores (feature-set 1b) and regional magnetic resonance imaging grey matter volumes (feature-set 2). The most relevant variables were combined to find the best model. Results: Good prediction performances were obtained with feature-sets 1a and 2. The most relevant variables (variable importance exceeding 20%) were: Age, GDS, and grey matter volumes measured in four cortical regions of interests. Their combination provided the optimal classification performance (highest sensitivity and specificity) ensemble ML model, Extreme Gradient Boosting with over-sampling of the minority class, with performance metrics: sensitivity = 1.00, specificity = 0.92 and area-under-the-curve = 0.96. The median values based on fifty random train/test splits were sensitivity = 0.83 (interquartile range (IQR) = 0.17), specificity = 0.77 (IQR = 0.23) and area-under-the-curve = 0.75 (IQR = 0.11). Conclusion: A high-performance algorithm that could be translatable into practice was able to predict SCD conversion to MCI/AD by using only six predictive variables. Show more

Keywords: Alzheimer’s disease, classification, machine learning, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-221002

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 125-140, 2023