Journal of Alzheimer's Disease - Volume 101, issue 2

Authors: Wei, Wenyan | Jiang, Ying | Hu, Guizhen | He, Yanfang | Chen, Huiyi

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including …disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations— bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission– fusion dynamics, mitochondrial degradation, and mitochondrial movement— underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis. Show more

Keywords: Alzheimer’s disease, aging, mitochondria, molecular therapy

DOI: 10.3233/JAD-240092

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 379-396, 2024

Authors: Giudicessi, Averi | McDowell, Celina Pluim | Martinez, Jairo E. | Baena, Ana | Vila-Castelar, Clara | Norton, Daniel | Aguirre-Acevedo, Daniel C. | Tirado, Victoria | Bocanegra, Yamile | Guzman-Velez, Edmarie | Lopera, Francisco | Cronin-Golomb, Alice | Quiroz, Yakeel T.

Article Type: Review Article

Abstract: Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer’s disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1 ) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods: We reviewed and integrated the published research, analyzing …studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD. Show more

Keywords: Alzheimer’s disease, autosomal dominant Alzheimer’s disease, cognitive measures, cognitive outcomes, dementia, early detection, familial AD, preclinical AD

DOI: 10.3233/JAD-240360

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 397-415, 2024

Authors: Yao, Yirou | Zhu, Shun | Ni, Jingnian | Wei, Mingqing | Li, Ting | Long, Siwei | Shi, Jing | Tian, Jinzhou

Article Type: Systematic Review

Abstract: Background: As a natural antioxidant, uric acid has neuroprotective effects. The association between uric acid levels and dementia risk was reported by previous studies. However, recently published studies showed that the relationship between uric acid and dementia risk might be heterogeneous in dementia subtypes. Objective: This study aimed to clarify the relationship between hyperuricemia (or gout) and dementia. Methods: The PubMed and Web of Science databases were systematically searched up to April 2024 to identify relevant studies. A meta-analysis was conducted using hazard ratios (HR) or odds ratios (OR) and 95% confidence interval (CI) as pooled …indicators. Heterogeneity between the studies was examined using Cochran’s Q statistic and I2 statistic. Subgroup analyses were conducted for gender and age. Stratification analysis, sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Publication bias was assessed by funnel plot and Egger’s test. Results: A total of 11 studies met the inclusion criteria including 2,928,152 participants were abstracted. Hyperuricemia (or gout) did not reduce the overall risk of dementia (OR/HR = 0.92, 95% CI: 0.81–1.05) and vascular dementia (OR/HR = 0.74, 95% CI: 0.53–1.05), but may have a protective effect against Alzheimer’s disease (OR/HR = 0.82, 95% CI: 0.70–0.96). Subgroup analysis showed that a lower risk of dementia was observed in men (OR/HR = 0.83, 95% CI: 0.77–0.90) and patients whose age under 65 (OR/HR = 0.83, 95% CI: 0.72–0.95). Conclusions: Patients with gout or hyperuricemia have a low risk of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, dementia, gout, hyperuricemia, meta-analysis, uric acid

DOI: 10.3233/JAD-240076

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 417-427, 2024

Authors: Jann, Kay | Cen, Steven | Santos, Mariella | Aksman, Leon | Wijesinghe, Dilmini | Zhang, Ru | Lynch, Kirsten | Ringman, John M. | Wang, Danny J.

Article Type: Short Communication

Abstract: Reduced functional magnetic resonance imaging (fMRI)-complexity in Alzheimer’s disease (AD) progression has been demonstrated and found to be associated with tauopathy and cognition. However, association of fMRI-complexity with amyloid and influence of genetic risk (APOE ɛ 4) remain unknown. Here we investigate the association between fMRI-complexity, tau-PET, and amyloid-PET as well as influence of APOE genotype using multivariate generalized linear models. We show that fMRI-complexity has a strong association with tau but not amyloid deposition and that the presence of an APOE ɛ 4 allele enhances this effect. Thus fMRI-complexity provides a surrogate marker of impaired brain …functionality in AD progression. Show more

Keywords: Alzheimer’s disease, amyloid, APOE, fMRI-complexity, tau

DOI: 10.3233/JAD-240459

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 429-435, 2024

Authors: Silva-Rudberg, Jason A. | Mecca, Adam P.

Article Type: Article Commentary

Abstract:  Magnetic resonance imaging (MRI)-based diffusion methods can quantify water molecule diffusion within tissues and are used to measure microstructural changes due to neurodegeneration. In a recent issue of the Journal of Alzheimer ’s Disease , Nakaya et al. report on the “Assessment of Gray Matter Microstructural Alterations in Alzheimer’s Disease by Free Water Imaging”. This study and others indicate that MRI diffusion methods, including free water imaging and diffusion tensor imaging, can reveal gray matter microstructural changes present in many AD-affected brain regions. These techniques are a valuable tool for multi-modal and longitudinal imaging studies that can offer insights into …AD neurobiology. Show more

Keywords: Alzheimer’s disease, diffusion imaging, diffusion tensor imaging, free water imaging

DOI: 10.3233/JAD-240673

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 437-439, 2024

Authors: Oliveira, Fabricio Ferreira de

Article Type: Article Commentary

Abstract: Knowledge of performance in activities of daily living and quality of life is important for management decisions and research endpoints. The use of harmonized scales is essential for objective assessment of both caregivers and patients with dementia with Lewy bodies. Functionality and quality of life are more impaired in dementia with Lewy bodies than in Alzheimer’s disease, mostly due to higher prevalence of behavioral symptoms and motor manifestations in dementia with Lewy bodies. More longitudinal studies are required to assess if causality mediates the associations of clinical features with functional independence and worsened quality of life in these patients.

Keywords: Activities of daily living, Alzheimer’s disease, behavioral symptoms, cognitive disorders, dementia, Lewy body dementia, neurodegenerative diseases, neuropsychiatry, quality of life

DOI: 10.3233/JAD-240676

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 441-443, 2024

Authors: Uh, Kyungjun | Monarch, Kaylynn | Reese, Emily D. | Rodriguez, Katherine | Yoon, Junchul | Spate, Lee D. | Samuel, Melissa S. | Koh, Sehwon | Chen, Paula R. | Jarome, Timothy J. | Allen, Timothy A. | Prather, Randall S. | Lee, Kiho

Article Type: Research Article

Abstract: Background: Presenilin 1 (PSEN1 ) is one of the genes linked to the prevalence of early onset Alzheimer’s disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1 , including those with a deleted exon 9 …(Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1 ΔE9/+ pigs to study their relevance to clinical Alzheimer’s diseases. Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, CRISPR/Cas9, Pig, Presenilin-1

DOI: 10.3233/JAD-231297

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 445-461, 2024

Authors: Nianogo, Roch A. | Hays, Ron D. | Gong, Yufan | Yu, Yu | Ritz, Beate | Duru, O. Kenrik

Article Type: Research Article

Abstract: Background: The mechanisms through which acculturation influences the onset of cognitive impairment and dementia are not well understood, especially among older Hispanics. Objective: To investigate whether inflammation and psycho-behavioral factors mediate the relationship between acculturation and incident dementia among older Mexican Americans. Methods: We analyzed the Sacramento Area Latino Study on Aging (1998–2007, SALSA), a longitudinal study (N  = 1,194) with 10 years of follow-up, and used g-computation for mediation analysis with pooled logistic regression to evaluate whether acculturation (assessed by the Revised Acculturation Rating Scale for Mexican Americans [ARSMA-II]) affected dementia or cognitive impairment but not …dementia (CIND) through inflammation (i.e., interleukin 6 [IL-6], tumor necrosis factor-α (TNF-α ), high-sensitivity C-reactive protein [hs-CRP]), smoking, alcohol consumption, and depressive symptoms. The potential mediators were assessed at baseline. Results: The 10-year average adjusted risk ratio (aRR) for the effect of high U.S. acculturation and dementia/CIND was 0.66, 95% CI (0.36, 1.30). The indirect effects were: IL-6 (aRR = 0.98, 95% CI (0.88, 1.05)); TNF-α (aRR:0.99, 95% CI (0.93, 1.05)); hs-CRP: (aRR = 1.21, 95% CI (0.84, 1.95)); current smoking: aRR = 0.97, 95% CI (0.84, 1.16); daily/weekly alcohol consumption (aRR = 1.00, 95% CI (0.96, 1.05)); and depressive symptom score (aRR = 1.03, 95% CI (0.95, 1.26)). Hs-CRP yielded a proportion mediated of -26%, suggesting that hs-CRP could suppress the potential effect of high U.S. acculturation. The other factors explored resulted in little to no mediation. Conclusions: The effect of acculturation on time to incident dementia/CIND varied over time. Our study suggests that inflammation could suppress the effect between high U.S. acculturation and dementia risk. Show more

Keywords: Acculturation, Alzheimer’s disease, causal inference, dementia, disparities, inflammation, mediation, Mexican, stress

DOI: 10.3233/JAD-231341

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 463-473, 2024

Authors: Kreshpa, Wendy | Raffa, Stefano | Girtler, Nicola | Brugnolo, Andrea | Mattioli, Pietro | Orso, Beatrice | Calizzano, Francesco | Arnaldi, Dario | Peira, Enrico | Chincarini, Andrea | Tagliafico, Luca | Monacelli, Fiammetta | Calcagno, Pietro | Serafini, Gianluca | Gotta, Fabio | Mandich, Paola | Pretta, Stefano | Del Sette, Massimo | Sofia, Luca | Sambuceti, Gianmario | Morbelli, Silvia | Schenone, Angelo | Massa, Federico | Pardini, Matteo | Argenti, Lucia | Biffa, Gabriella | Bosinelli, Francesca | Bozzo, Giulia | Castellan, Lucio | Castellini, Paola | Colombo, Barbara | Gandoglia, Ilaria | Giacomini, Gabriele | Lombardo, Lorenzo | Losa, Mattia | Mancini, Raffaele | Murialdo, Alessandra | Nencioni, Alessio | Nozza, Paolo | Origone, Paola | Pelagotti, Virginia | Roccatagliata, Luca

Article Type: Research Article

Abstract: Background: Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective: To explore the [18 F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods: We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) …for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results: DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions: Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations. Show more

Keywords: Alzheimer’s disease, apathy, awareness, dementia, [18F]FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-240430

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 475-485, 2024

Authors: Zhang, Qinghua | Zhao, Shicheng | Feng, Jianli | Wang, Shanshan | Song, Lin | Han, Qi | Cong, Lin | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Little is known about the associations of hearing loss, hippocampal volume, and motoric cognitive risk syndrome (MCR) in older adults. Objective: We aimed to investigate the associations of hearing loss with MCR and hippocampal volume; and the interaction of hearing loss with hippocampal volume on MCR. Methods: This population-based cross-sectional study included 2,540 dementia-free participants (age≥60 years; 56.5% women) in the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China. Data were collected through face-to-face interviews, clinical examination, and laboratory tests. Hearing function was assessed using pure tone audiometry test. …In the subsample (n  = 661), hippocampal volume was assessed on structural magnetic resonance images. Data were analyzed with logistic regression models. Results: In the total sample, MCR was diagnosed in 246 persons (9.7%). High-frequency hearing loss was significantly associated with an increased likelihood of MCR and slow gait. In the subsample, the restricted cubic spline plots indicated an inverted U-shaped nonlinear relationship between high-frequency hearing performance and hippocampal volume. Moreover, greater hippocampal volume was significantly associated with a deduced likelihood of MCR and subjective cognitive decline (SCD). In addition, there were statistical interactions of high-frequency hearing loss with hippocampal volume on MCR and slow gait (p for interaction < 0.05), such that the associations were statistically significant only among participants free of high-frequency hearing loss. Conclusions: High-frequency hearing loss was associated with an increased likelihood of MCR in older adults. The hippocampus might play a part in the relationship of high-frequency hearing loss and MCR. Show more

Keywords: Aging, Alzheimer’s disease, hearing loss, hippocampal volume, motoric cognitive risk syndrome

DOI: 10.3233/JAD-240522

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 487-498, 2024