Journal of Alzheimer's Disease - Volume 79, issue 4

Authors: de la Torre, Jack C.

Article Type: Review Article

Abstract: This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer’s disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting …the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor’s active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH. Show more

Keywords: Axonal transport, brain hypoperfusion, cognition, mammalian target of rapamycin, neurofibrillary tangles, tau, vascular hypothesis of Alzheimer’s

DOI: 10.3233/JAD-201165

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1381-1396, 2021

Authors: Magnin, Eloi

Article Type: Review Article

Abstract: Neurodevelopmental and neurodegenerative disorders are both growing major public health topics with similarities and frequent complex interactions with each other. Taking these aspects into account can provide a new point of view on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions during cognitive and behavioral clinical assessments is challenging but might improve diagnostic accuracy and physiopathological understanding. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized precision cognitive medicine.

Keywords: Atypical dementia, neurodegenerative disorders, neurodevelopmental disorders

DOI: 10.3233/JAD-201207

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1397-1407, 2021

Authors: Huang, Lei | Zhang, Yang | Wang, Yongwei | Lan, Yajia

Article Type: Review Article

Abstract: Degenerative dementia, of which Alzheimer’s disease is the most common form, is characterized by the gradual deterioration of cognitive function. The events that trigger and promote degenerative dementia are not clear, and treatment options are limited. Experimental and epidemiological studies have revealed chronic noise exposure (CNE) as a potential risk factor for cognitive impairment and degenerative dementia. Experimental studies have indicated that long-term exposure to noise might accelerate cognitive dysfunction, amyloid-β deposition, and tau hyperphosphorylation in different brain regions such as the hippocampus and cortex. Epidemiological studies are increasingly examining the possible association between external noise exposure and dementia. In …this review, we sought to construct a comprehensive summary of the relationship between CNE, cognitive dysfunction, and degenerative dementia. We also present the limitations of existing evidence as a guide regarding important prospects for future research. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognition, dementia, neuropathology, noise, tau

DOI: 10.3233/JAD-201037

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1409-1427, 2021

Authors: Lao, Kejing | Zhang, Ruisan | Luan, Jing | Zhang, Yuelin | Gou, Xingchun

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors …and transporters to provide a molecular basis for future rational design of anti-AD agents. Show more

Keywords: Aβ receptor, Aβ transporter, EphB2, LilrB2, LRP-1, NgR, p75NTR, PrPc, RAGE

DOI: 10.3233/JAD-200851

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1429-1442, 2021

Authors: Delic, Vedad | Ratliff, Whitney A. | Citron, Bruce A.

Article Type: Review Article

Abstract: An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million Americans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of …inadequate sleep have been shown to cause an increase in amyloidβ and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, post-traumatic stress disorder, sleep deprivation, tau

DOI: 10.3233/JAD-201378

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1443-1449, 2021

Authors: Baril, Andrée-Ann | Beiser, Alexa S. | Redline, Susan | McGrath, Emer R. | Gottlieb, Daniel J. | Aparicio, Hugo | Seshadri, Sudha | Himali, Jayandra J. | Pase, Matthew P.

Article Type: Short Communication

Abstract: Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer’s type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.

Keywords: Alzheimer’s disease, dementia, inflammation, interleukin-6, sleep apnea, sleep-disordered breathing, sleep disorders

DOI: 10.3233/JAD-200545

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1451-1457, 2021

Authors: Kristensen, Rachel Underlien | Jensen-Dahm, Christina | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Studies have shown declining use of potentially inappropriate medication (PIM), medication where risks associated with use outweigh potential benefits in older people. However, the trend in people with dementia remains unknown. Objective: To test the hypothesis that the use of PIM has decreased in people with dementia in line with the declining use in the general older population. Methods: Repeated cross-sectional register-based study of the entire Danish population aged ≥65 years (2000: N = 802,106; 2015: N = 1,056,476). PIM was identified using the Danish “Red-yellow-green list”. Changes in the use of PIM were examined by calculating the annual …prevalence of filling prescriptions for at least one PIM in older people with and without dementia. Characteristics of the study population were examined annually including comorbidity. Results: From 2000 to 2015, the prevalence of PIM use decreased from 54.7%to 43.5%in people with dementia and from 39.5%to 28.8%in people without dementia; the decrease was significant across all age groups and remained so in a sensitivity analysis where antipsychotics were removed. During the same period, comorbidity scores increased in people with and without dementia. Conclusion: The declining use of PIM in people with dementia from 2000 to 2015 parallels the trend in the general older population. The use of PIM decreased despite increasing levels of comorbidity and was not solely attributable to the decreasing use of antipsychotics in people with dementia. However, PIM use remained more widespread in people with dementia who may be more vulnerable to the risks associated with PIM. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, potentially inappropriate medication, time trend

DOI: 10.3233/JAD-200627

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1459-1470, 2021

Authors: Lee, Yang Hyun | Jeon, Seun | Yoo, Han Soo | Chung, Seok Jong | Jung, Jin Ho | Baik, Kyoungwon | Sohn, Young H. | Lee, Phil Hyu | Yun, Mijin | Evans, Alan C. | Ye, Byoung Seok

Article Type: Research Article

Abstract: Background: The relationship among amyloid-β (Aβ) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18 F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer’s disease (AD) and Lewy body disease (LBD). Objective: We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. Methods: A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB …groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18 F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. Results: Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. Conclusion: Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases. Show more

Keywords: Alzheimer’s disease, amyloid, glucose metabolism, lewy body disease

DOI: 10.3233/JAD-201094

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1471-1487, 2021

Authors: Ilango, Sindana D. | Gonzalez, Kevin | Gallo, Linda | Allison, Matthew A. | Cai, Jianwen | Isasi, Carmen R. | Hosgood, Dean H. | Vasquez, Priscilla M. | Zeng, Donglin | Mortamais, Marion | Gonzalez, Hector | Benmarhnia, Tarik

Article Type: Research Article

Abstract: Background: Hispanics/Latinos in the United States are more likely to live in neighborhoods with greater exposure to air pollution and are projected to have the largest increase in dementia among race/ethnic minority groups. Objective: We examined the associations of air pollution with performance on cognitive function tests in Hispanic/Latino adults. Methods: We used data from the San Diego site of the Hispanic Community Health Study/Study of Latinos, an ongoing cohort of Hispanics/Latinos. This analysis focused on individuals ≥45 years of age who completed a neurocognitive battery examining overall mental status, verbal learning, memory, verbal fluency, and …executive function (n  = 2,089). Air pollution (PM2.5 and O3 ) before study baseline was assigned to participants’ zip code. Logistic and linear regression were used to estimate the associations of air pollution on overall mental status and domain-specific standardized test scores. Models accounted for complex survey design, demographic, and socioeconomic characteristics. Results: We found that for every 10μg/m3 increase in PM2.5 , verbal fluency worsened (β: –0.21 [95%CI: –0.68, 0.25]). For every 10 ppb increase in O3 , verbal fluency and executive function worsened (β: –0.19 [95%CI: –0.34, –0.03]; β: –0.01 [95%CI: –0.01, 0.09], respectively). We did not identify any detrimental effect of pollutants on other domains. Conclusion: Although we found suggestions that air pollution may impact verbal fluency and executive function, we observed no consistent or precise evidence to suggest an adverse impact of air pollution on cognitive level among this cohort of Hispanic/Latino adults. Show more

Keywords: Air pollution, cognitive dysfunction, cohort study, dementia, hispanics, latinos, particulate matter, ozone

DOI: 10.3233/JAD-200766

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1489-1496, 2021

Authors: Jobin, Benoît | Zahal, Rayane | Bussières, Eve-Line | Frasnelli, Johannes | Boller, Benjamin

Article Type: Research Article

Abstract: Background: Recently, subjective cognitive decline (SCD) has been considered to be one of the first signs of Alzheimer’s disease (AD). Since this potential early marker is sensitive but not specific to AD, combining it with other markers could ensure higher accuracy when predicting which persons with SCD will convert to AD. Since olfactory dysfunction is observable in both AD and mild cognitive impairment (MCI), it is a promising marker that could help improve the early diagnosis of AD. Objective: The aim of this meta-analysis was to verify whether the presence of SCD is associated with a decrease in …olfactory identification ability. Methods: We collected articles from the following databases: PsychNet, PubMed, Ebsco, and ProQuest using the keywords: “SCD”, “subjective cognitive decline”, “subjective cognitive impairment”, “subjective memory impairment”, “subjective memory decline”, “cognitive complaints”, “memory complaints”, “cognitive concerns”, “memory concerns”, “olfac*” and “smell”. We included articles according to the following criteria: 1) participants aged 50 and over; 2) presence of an SCD group or a conceptual equivalent; 3) presence of a healthy control group with the same age range; and 4) assessment of olfactory identification ability. Results: Five studies met the inclusion criteria. Small and homogeneous effects were observed for olfactory identification alteration in individuals with SCD relative to controls (g  = –0.16, 95% CI [–0.46, 0.14]). Conclusion: Despite the low number of studies included, the findings suggest that odor identification is slightly altered in SCD compared to healthy older adults. This alteration in individuals with SCD could be an early marker of AD. Show more

Keywords: Alzheimer’s disease, biomarker, meta-analysis, olfaction, olfactory identification, smell, subjective cognitive decline

DOI: 10.3233/JAD-201022

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1497-1507, 2021