Journal of Alzheimer's Disease - Volume 100, issue 2

Article Type: Announcement

DOI: 10.3233/JAD-249013

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 377-378, 2024

Authors: Loeffler, David A.

Article Type: Review Article

Abstract: Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer’s disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across …the capillary endothelia, dissolving Aβ aggregates, and a “peripheral sink” mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-brain barrier, blood-cerebrospinal fluid barrier, experimental approaches, glymphatic drainage, perivascular drainage)

DOI: 10.3233/JAD-240212

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 379-411, 2024

Authors: Candeias, Emanuel | Pereira-Santos, Ana Raquel | Empadinhas, Nuno | Cardoso, Sandra Morais | Esteves, Ana Raquel Fernandes

Article Type: Review Article

Abstract: Accumulating evidence suggests that gut inflammation is implicated in neuroinflammation in Alzheimer’s and Parkinson’s diseases. Despite the numerous connections it remains unclear how the gut and the brain communicate and whether gut dysbiosis is the cause or consequence of these pathologies. Importantly, several reports highlight the importance of mitochondria in the gut-brain axis, as well as in mechanisms like gut epithelium self-renewal, differentiation, and homeostasis. Herein we comprehensively address the important role of mitochondria as a cellular hub in infection and inflammation and as a link between inflammation and neurodegeneration in the gut-brain axis. The role of mitochondria in gut …homeostasis and as well the crosstalk between mitochondria and gut microbiota is discussed. Significantly, we also review studies highlighting how gut microbiota can ultimately affect the central nervous system. Overall, this review summarizes novel findings regarding this cross-talk where the mitochondria has a main role in the pathophysiology of both Alzheimer’s and Parkinson’s disease strengthen by cellular, animal and clinical studies. Show more

Keywords: Alzheimer’s disease, gut-brain axis, gut microbiome metabolites, inflammation, mitochondria, Parkinson’s disease

DOI: 10.3233/JAD-240524

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 413-429, 2024

Authors: Sjaelland, Nikolai S. | Gramkow, Mathias H. | Hasselbalch, Steen G. | Frederiksen, Kristian Steen

Article Type: Systematic Review

Abstract: Background: Portable digital health technologies (DHTs) could help evaluate non-cognitive symptoms, but evidence to support their use in patients with dementia with Lewy bodies (DLB) is uncertain. Objective: 1) To describe portable or wearable DHTs used to obtain digital biomarkers in patients with DLB, 2) to assess the digital biomarkers’ ability to evaluate non-cognitive symptoms, and 3) to assess the feasibility of applying digital biomarkers in patients with DLB. Methods: We systematically searched databases MEDLINE, Embase, and Web of Science from inception through February 28, 2023. Studies assessing digital biomarkers obtained by portable or wearable DHTs …and related to non-cognitive symptoms were eligible if including patients with DLB. The quality of studies was assessed using a modified check list based on the NIH Quality assessment tool for Observational Cohort and Cross-sectional Studies. A narrative synthesis of data was carried out. Results: We screened 4,295 records and included 20 studies. Seventeen different DHTs were identified for assessment of most non-cognitive symptoms related to DLB. No thorough validation of digital biomarkers for measurement of non-cognitive symptoms in DLB was reported. Studies did not report on aspects of feasibility in a systematic way. Conclusions: Knowledge about feasibility and validity of individual digital biomarkers remains extremely limited. Study heterogeneity is a barrier for establishing a broad evidence base for application of digital biomarkers in DLB. Researchers should conform to recommended standards for systematic evaluation of digital biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, digital health, feasibility studies, Lewy body disease, symptom assessment, wearable electronic devices

DOI: 10.3233/JAD-240327

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 431-451, 2024

Authors: Chino, Brenda | López-Sanz, David | Doval, Sandra | Torres-Simón, Lucía | de Frutos Lucas, Jaisalmer | Giménez-Llort, Lydia | Zegarra-Valdivia, Jonathan | Maestú, Fernando

Article Type: Systematic Review

Abstract: Background: Aging is a complex and natural process. The physiological decline related to aging is accompanied by a slowdown in cognitive processes, which begins shortly after individuals reach maturity. These changes have been sometimes interpreted as a compensatory sign and others as a fingerprint of deterioration. Objective: In this context, our aim is to uncover the mechanisms that underlie and support normal cognitive functioning in the brain during the later stages of life. Methods: With this purpose, a systematic literature search was conducted using PubMed, Scopus, and Web of Science databases, which identified 781 potential articles. …After applying inclusion and exclusion criteria, we selected 12 studies that examined the brain oscillations patterns in resting-state conditions associated with cognitive performance in cognitively unimpaired older adults. Results: Although cognitive healthy aging was characterized differently across studies, and various approaches to analyzing brain activity were employed, our review indicates a relationship between alpha peak frequency (APF) and improved performance in neuropsychological scores among cognitively unimpaired older adults. Conclusions: A higher APF is linked with a higher score in intelligence, executive function, and general cognitive performance, and could be considered an optimal, and easy-to-assess, electrophysiological marker of cognitive health in older adults. Show more

Keywords: Aging, alpha peak frequency, Alzheimer’s disease, cognitive performance, cognitively unimpaired, resting-state, systematic review

DOI: 10.3233/JAD-231009

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 453-468, 2024

Authors: Jiménez-Gonzalo, Lucía | Bermejo-Gómez, Isabel

Article Type: Article Commentary

Abstract: Caregiving for a person with dementia is considered a situation of chronic stress, with consequences on caregivers’ physical and psychological health. The usual challenges of dementia care were intensified during the pandemic due to the risk of contagion, social isolation measures, and decrease in healthcare resources. The COVID-19 pandemic increased the stress both in the persons with dementia and their caregivers. This commentary reflects on the long-term effects of the pandemic on caregivers’ mental health, focusing on the study by Olavarría and colleagues and drawing future research lines for culturally diverse family caregivers.

Keywords: Alzheimer’s disease, COVID-19, cross-cultural, dementia caregivers

DOI: 10.3233/JAD-240172

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 469-473, 2024

Authors: Shamsi, Anas | Furkan, Mohammad | Khan, Mohd Shahnawaz | Yadav, Dharmendra Kumar | Shahwan, Moyad

Article Type: Research Article

Abstract: Background: HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) plays a pivotal role as a control enzyme in ketogenesis, and its association with the amyloid-β protein precursor (AβPP) in mitochondria implicates a potential involvement in Alzheimer’s disease (AD) pathophysiology. Objective: Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity. Methods: Exploiting the power of drug repurposing in conjunction with virtual screening and molecular dynamic (MD) simulations against ‘HMGCS2’, we present new in-silico insight into structure-based drug repurposing. Results: The initial molecules were screened for their binding affinity to HMGCS2. …Subsequent interaction analyses and extensive 300 ns MD simulations were conducted to explore the conformational dynamics and stability of HMGCS2 in complex with the screened molecules, particularly Penfluridol and Lurasidone. Conclusions: The study revealed that HMGCS2 forms stable protein-ligand complexes with Penfluridol and Lurasidone. Our findings indicate that Penfluridol and Lurasidone competitively bind to HMGCS2 and warrant their further exploration as potential repurposed molecules for anti-Alzheimer’s drug development. Show more

Keywords: Alzheimer’s disease, drug repurposing, human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2, small molecule inhibitors, virtual screening

DOI: 10.3233/JAD-240376

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 475-485, 2024

Authors: Ramos-Cejudo, Jaime | Scott, Matthew R. | Tanner, Jeremy A. | Pase, Matthew P. | McGrath, Emer R. | Ghosh, Saptaparni | Osorio, Ricardo S. | Thibault, Emma | El Fakhri, Georges | Johnson, Keith A. | Beiser, Alexa | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11 C-Pittsburgh Compound-B (PiB)-PET and 18 F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p  = 0.025). A positive association …between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOE ɛ 4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age. Show more

Keywords: Alzheimer’s disease, amyloid-β, Framingham Heart Study, PET, plasma total tau, tau

DOI: 10.3233/JAD-231320

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 487-494, 2024

Authors: Krizanovic, Nela | Jokisch, Martha | Jöckel, Karl-Heinz | Schmidt, Börge | Stang, Andreas | Schramm, Sara

Article Type: Research Article

Abstract: Background: There are indications for sex-specific differences regarding the association between kallikrein-8 (KLK8) and cognitive impairment in early stages of Alzheimer’s disease for which KLK8 may be an early blood-based biomarker. These may be due to different levels of sex hormones. To correctly interpret KLK8 blood concentrations, sex-specific analyses are needed. Objective: The aim of our exploratory study was to investigate sex-specific differences in blood-based KLK8 in participants of the population-based Heinz Nixdorf Recall study with different cognitive status and the association between KLK8 and sex hormones. Methods: In 290 participants (45% women, 69.7±7.4 years (mean±SD)) …we investigated sex-specific serum KLK8 differences between cognitively unimpaired (CU, 43%) and cognitively impaired (CI) participants and the association between KLK8 and dehydroepiandrosteronsulfate (DHEAS), estradiol and testosterone, using adjusted multiple linear regression. Results: The mean±SD KLK8 was similar for CU men (808.1±729.6 pg/ml) and women (795.9±577.7 pg/ml); adjusted mean-difference [95%-CI]: –95.3 [–324.1;133.5] pg/ml. KLK8 was lower in CI women (783.5±498.7 pg/ml) than men (1048.4±829 pg/ml); –261 [–493.1; –29] pg/ml. In men but not women, there was a weak indication for a positive slope between estradiol (11.9 [–0.4;24.3] pg/ml) and DHEAS (1.4 [–0.5;3.3] pg/ml) with KLK8, while testosterone had no impact. Conclusions: The results suggested a different role for KLK8 in the development of cognitive impairment in men and women, potentially influenced by sex hormones. To use blood KLK8 as an early biomarker, further research on hormonal regulation of KLK8 expression is needed as a part of the investigation of the KLK8 involvement in cognitive impairment and Alzheimer's disease pathology. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, DHEAS, estradiol, Heinz Nixdorf Recall study, kallikrein-8, KLK8, non-amnestic mild cognitive impairment, subjective cognitive decline, testosterone

DOI: 10.3233/JAD-240045

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 495-507, 2024

Authors: Galvin, James E. | Chang, Lun-Ching | Estes, Paul | Harris, Heather M. | Fung, Ernest

Article Type: Research Article

Abstract: Background: Detecting cognitive impairment in clinical practice is challenging as most instruments do not perform well in diverse samples of older adults. These same instruments are often used for eligibility into clinical trials making it difficult to recruit minoritized adults into Alzheimer’s disease (AD) studies. Cognivue Clarity ® is an FDA-cleared computerized 10-minute cognitive screening platform using adaptive psychophysics to detect cognitive impairment. Objective: Test the ability of Cognivue Clarity to measure cognitive performance in a diverse community sample compared with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Methods: This study …enrolled 452 participants across 6 US study sites and completed both Cognivue Clarity device and RBANS. Psychometric properties and exploratory factor analysis of Cognivue Clarity were explored and comparisons against RBANS across different age, sex, education, and ethnoracial groups were conducted. Results: Participants had a mean age of 47.9±16.1 years (range: 18–85), 63.6% were female, 45.9% had ≤12 years of education, 31.2% were African American and 9.2% were Hispanic. Cognivue Clarity had strong internal consistency, test-retest reliability and minimal practice effects. A 4-factor structure (Memory, Attention, Visuomotor, and Discrimination) had excellent goodness-of-fit. Normalizing age effects improved performance. Race and education effects were similar to those seen with RBANS. Cognivue Clarity had strong correlations with RBANS. Conclusions: Our study supports the use of Cognivue Clarity as an easy-to-use, brief, and valid cognitive assessment that measures cognitive performance. In the correct clinical setting, Cognivue Clarity may identify individuals with likely cognitive impairment who could be candidates for AD research studies. Show more

Keywords: Alzheimer’s disease, cognition, cognitive impairment, cognitive testing, neuropsychology

DOI: 10.3233/JAD-240331

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 509-523, 2024