Journal of Alzheimer's Disease - Volume 95, issue 2

Authors: Mendez, Mario F.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is an age-related neurocognitive disorder that is epidemic in the elderly population. Currently, there are limited pharmacological interventions, and this has heightened the urgency to identify potential preventable or modifiable risk factors that promote resilience to the neuropathological effects of AD. The regular use of two or more languages is one such factor that may increases cognitive reserve through the long-standing executive control involved in managing multiple languages in the brain. There is also evidence that bilingualism is associated with increased brain reserve or maintenance, particularly in frontal-executive structures and networks. This review examines the current, sometimes …conflicting literature on bi/multilingualism and AD. These studies have confounding variations in the assessment of age of second language onset, language proficiency, language usage, and whether determining incidence of AD or age of symptom onset. Despite these limitations, most publications support the presence of increased frontal-executive reserve that compensates for the development of AD neuropathology and, thereby, delays the emergence of clinical symptoms of dementia by about 4-5 years. Although regularly speaking more than one language does not protect against AD neuropathology, the delay in its clinical expression has a potentially significant impact on the lifelong morbidity from this age-related disease. Learning other languages may be an important modifiable factor for delaying the clinical expression of AD in later life. Show more

Keywords: Alzheimer’s disease, bilingualism, cognition, language, mild cognitive impairment

DOI: 10.3233/JAD-230285

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 363-377, 2023

Authors: Bachman, Shelby L. | Blankenship, Jennifer M. | Busa, Michael | Serviente, Corinna | Lyden, Kate | Clay, Ieuan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia worldwide. Despite the magnitude of AD’s impact on patients, caregivers, and society, nearly all AD clinical trials fail. A potential contributor to this high rate of failure is that established clinical outcome assessments fail to capture subtle clinical changes, entail high burden for patients and their caregivers, and ineffectively address the aspects of health deemed important by patients and their caregivers. AD progression is associated with widespread changes in physical behavior that have impacts on the ability to function independently, which is a meaningful aspect of …health for patients with AD and important for diagnosis. However, established assessments of functional independence remain underutilized in AD clinical trials and are limited by subjective biases and ceiling effects. Digital measures of real-world physical behavior assessed passively, continuously, and remotely using digital health technologies have the potential to address some of these limitations and to capture aspects of functional independence in patients with AD. In particular, measures of real-world gait, physical activity, and life-space mobility captured with wearable sensors may offer value. Additional research is needed to understand the validity, feasibility, and acceptability of these measures in AD clinical research. Show more

Keywords: Alzheimer’s disease, digital measure, drug development, gait, life-space mobility, meaningful aspect of health, physical behavior, physical function, wearable sensor

DOI: 10.3233/JAD-230152

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 379-389, 2023

Authors: Lopes das Neves, Pedro | Durães, João | Silva-Spinola, Anuschka | Lima, Marisa | Leitão, Maria João | Tábuas-Pereira, Miguel | Santana, Isabel | Baldeiras, Inês

Article Type: Short Communication

Abstract: Serum light-chain neurofilaments (sNfL) have been investigated as a potential minimally invasive biomarker that could help in the diagnosis of patients with cognitive symptoms. We assessed the correlation between sNfL and cerebrospinal fluid (CSF) biomarkers (sNfL versus CSF NfL, ρ= 0.70, p  < 0.001), the performance of sNfL in distinguishing controls from patients (controls versus frontotemporal dementia, area under curve 0.86), and sNfL differences in mild cognitive impairment according to amyloid-β (Aβ) deposition (Aβ versus non-Aβ, p  = 0.017). Our results support the role of this biomarker in the screening and risk stratification of patients followed in a neurological consultation of a tertiary …center. Show more

Keywords: Alzheimer’s disease, biomarkers, frontotemporal dementia, mild cognitive impairment, neurofilament light chain

DOI: 10.3233/JAD-221208

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 391-397, 2023

Authors: Macyczko, Jesse R. | Wang, Na | Lu, Wenyan | Jeevaratnam, Suren | Shue, Francis | Martens, Yuka | Liu, Chia-Chen | Kanekiyo, Takahisa | Bu, Guojun | Li, Yonghe

Article Type: Short Communication

Abstract: The prevalence of Alzheimer’s disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aβ than males, and sFRP1 protein levels were positively associated with Aβ42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.

Keywords: AβPP, Alzheimer’s disease, amyloid-β, 5xFAD mice, sex-dependent effects, sFRP1

DOI: 10.3233/JAD-230218

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 399-405, 2023

Authors: Volgman, Annabelle Santos | Engelstein, Erica | Aggarwal, Neelum T.

Article Type: Article Commentary

Abstract: In a recent issue of the Journal of Alzheimer ’s Disease , Zinman et al. investigated the role of sex in the risk of cognitive impairment in 5,969 patients with a stroke or transient ischemic attacks. Using a short validated clinical screening tool, they noted that men had a 34% higher risk of screening positive for post-stroke cognitive impairment after adjusting for age, education, and stroke severity compared to women. This study highlights that more large, prospective, and multicenter studies are needed to evaluate sex-specific changes after a stroke since sex differences exist in many aspects of stroke presentation and …management. Show more

Keywords: Alzheimer’s disease, cognitive impairment, post-stroke cognitive impairment, sex differences, strokes

DOI: 10.3233/JAD-230520

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 407-409, 2023

Authors: Daly, Timothy

Article Type: Editorial

Abstract: The Journal of Alzheimer’s Disease (JAD) is already an established forum for cutting-edge science as well as ethical reflection. But I argue that beyond science and ethics, JAD is also a forum for philosophy in science, and that interdisciplinary researchers asking innovative questions about AD should publish their reflections and findings in JAD.

Keywords: Alzheimer’s disease, ethics, interdisciplinary research, philosophy, philosophy in science, philosophy of science, science

DOI: 10.3233/JAD-230407

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 411-413, 2023

Authors: Bogdan, Anamaria | Fabre, Roxane | Desmidt, Thomas | Golebiowski, Jérôme | Topin, Jérémie | Bethus, Ingrid | Hanon, Olivier | Boutoleau-Bretonniere, Claire | Wagemann, Nathalie | Annweiler, Cédric | Ousset, Pierre-Jean | Godefroy, Olivier | Rouch, Isabelle | Paccalin, Marc | Sukhorukova, Maryana | Gabelle, Audrey | Robert, Gabriel | David, Renaud

Article Type: Research Article

Abstract: Background: Apathy and depression are two early behavioral symptoms in Alzheimer’s disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. Objective: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. Methods: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month …period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. Results: Among individuals with SCD (n  = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n  = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. Conclusion: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely—compared to depression—to be associated with conversion to dementia. Show more

Keywords: Alzheimer’s disease, apathy, behavioral and psychological symptoms, dementia, depression

DOI: 10.3233/JAD-230162

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 415-426, 2023

Authors: Edmunds, Kyle J. | Driscoll, Ira | Hagen, Erika W. | Barnet, Jodi H. | Ravelo, Laurel A. | Plante, David T. | Gaitán, Julian M. | Lose, Sarah R. | Motovylyak, Alice | Bendlin, Barbara B. | Okonkwo, Ozioma C. | Peppard, Paul E.

Article Type: Research Article

Abstract: Background: Emerging evidence suggests that age-related changes in cerebral health may be sensitive to vascular risk modifiers, such as physical activity and sleep. Objective: We examine whether cardiorespiratory fitness modifies the association of obstructive sleep apnea (OSA) severity with MRI-assessed measures of cerebral structure and perfusion. Methods: Using data from a cross-sectional sample of participants (n  = 129, 51% female, age range 49.6-85.3 years) in the Wisconsin Sleep Cohort study, we estimated linear models of MRI-assessed total and regional gray matter (GM) and white matter (WM) volumes, WM hyperintensity (WMH:ICV ratio), total lesion volume, and arterial spin …labeling (ASL) cerebral blood flow (CBF), using an estimated measure of cardiorespiratory fitness (CRF) and OSA severity as predictors. Participants’ sleep was assessed using overnight in-laboratory polysomnography, and OSA severity was measured using the apnea-hypopnea index (AHI), or the mean number of recorded apnea and hypopnea events per hour of sleep. The mean±SD time difference between PSG data collection and MRI data collection was 1.7±1.5 years (range: [0, 4.9 years]). Results: OSA severity was associated with reduced total GM volume (β=-0.064; SE = 0.023; p  = 0.007), greater total WM lesion volume (interaction p  = 0.023), and greater WMHs (interaction p  = 0.017) in less-fit subjects. Perfusion models revealed significant differences in the association of AHI and regional CBF between fitness groups (interaction ps < 0.05). Conclusion: This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging in late-middle age to older adults. Show more

Keywords: Alzheimer’s disease, cardiorespiratory fitness, cerebral perfusion, gray matter, obstructive sleep apnea, white matter

DOI: 10.3233/JAD-220910

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 427-435, 2023

Authors: Jann, Kay | Boudreau, Julia | Albrecht, Daniel | Cen, Steven Y. | Cabeen, Ryan P. | Ringman, John M. | Wang, Danny J.J.

Article Type: Research Article

Abstract: Background: Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimer’s disease (AD). Complexity of rs-fMRI has been demonstrated to decrease with cognitive decline in AD. Objective: We hypothesize that the rs-fMRI complexity provides an index for tau-related neuronal injury and cognitive decline in the AD process. Methods: Data was obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study. Associations between tau-PET and rs-fMRI complexity were calculated. Potential pathways relating complexity to cognitive function mediated through tau-PET were assessed …by path analysis. Results: We found significant negative correlations between rs-fMRI complexity and tau-PET in medial temporal lobe of both cohorts, and associations of rs-fMRI complexity with cognitive scores were mediated through tau-PET. Conclusion: The association of rs-fMRI complexity with tau-PET and cognition, suggests that a reduction in complexity is indicative of tau-related neuropathology and cognitive decline in AD processes. Show more

Keywords: Alzheimer’s disease, complexity, multi scale entropy, rs-fMRI, tau-PET

DOI: 10.3233/JAD-220851

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 437-451, 2023

Authors: Dion, Catherine | Tanner, Jared J. | Libon, David J. | Price, Catherine C.

Article Type: Research Article

Abstract: Background: Greater cardiovascular burden and peripheral inflammation are associated with dysexecutive neuropsychological profiles and a higher likelihood of conversion to vascular dementia. The digital clock drawing test (dCDT) is useful in identifying neuropsychological dysfunction related to vascular etiology. However, the specific cognitive implications of the combination of cardiovascular risk, peripheral inflammation, and brain integrity remain unknown. Objective: We aimed to examine the role of cardiovascular burden, inflammation, and MRI-defined brain integrity on dCDT latency and graphomotor metrics in older adults. Methods: 184 non-demented older adults (age 69±6, 16±3 education years, 46% female, 94% white) completed dCDT, …vascular assessment, blood draw, and brain MRI. dCDT variables of interest: total completion time (TCT), pre-first hand latency, digit misplacement, hour hand distance from center, and clock face area. Cardiovascular burden was calculated using the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation markers included interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha, and high sensitivity C-reactive protein. Brain integrity included bilateral entorhinal cortex volume, lateral ventricular volume, and whole brain leukoaraiosis. Results: FSRP-10, peripheral inflammation, and brain integrity explained an additional 14.6% of the variance in command TCT, where FSRP-10 was the main predictor. FSRP-10, inflammatory markers, and brain integrity explained an additional 17.0% in command digit misplacement variance, with findings largely driven by FSRP-10. Conclusion: Subtle graphomotor behavior operationalized using dCDT metrics (i.e., TCT and digit misplacement) is partly explained by cardiovascular burden, peripheral inflammation, and brain integrity and may indicate vulnerability to a disease process. Show more

Keywords: Alzheimer’s disease, cardiovascular diseases, cognition, heart disease risk factors, inflammation

DOI: 10.3233/JAD-221011

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 453-467, 2023