Journal of Alzheimer's Disease - Volume 73, issue 1

Authors: Parvand, Mahraz | Rankin, Catharine H.

Article Type: Review Article

Abstract: As we age, our olfactory function declines. In addition to occurring in normal aging, more rapid decrement of olfactory decline has been associated with several neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). It has been argued that since olfactory deficits occur less frequently or are absent in diseases such as progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, olfactory deficits can be used for differential diagnoses of AD and PD. The purpose of this review is to provide a survey of current knowledge about the molecular bases and differential patterns of olfactory deficits present in normal …aging, AD, and PD. As substantial research has been conducted in this area, the majority of the content of this review focuses on articles published in the past decade. We hypothesize that olfactory deficits in normal aging, AD, and PD may have different underlying causes, and propose the use of model organisms with small, tractable nervous systems and/or easy to manipulate genomes to further investigate the cellular mechanisms responsible for these deficits. Show more

Keywords: Aging, Alzheimer’s disease, olfaction, Parkinson’s disease, Smell

DOI: 10.3233/JAD-190636

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 1-21, 2020

Authors: Yare, Katrine | Woodward, Michael

Article Type: Review Article

Abstract: Numerous observational studies have suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and Alzheimer’s disease (AD). However, because of the significant disparity between results, especially those between observational and randomized controlled trials (RCT), this postulate remains unproven. A significant contributing factor to these inconsistencies is the loose use of the generic definitions of estrogens and progestogens with most studies not delineating the clear differences between non-endogenous and endogenously identical (bioidentical) hormones, their molecular binding affinities and actions, and resultant metabolites. This is highlighted by the generalized terminological use of HT, which is often used to encompass …significantly disparate hormonal formulations without clear demarcation. This has impacted and continues to significantly influence interpretations of data, meta-analyses, observational studies, etc., relevant to AD. To progress forward and allow unbiased interpretation, it is no longer acceptable to group HT formulations together as a homogenous group. This will also allow differentiation between compounds that exhibit beneficial actions and those that do not and whether these effects are specific or generalized. The role of the endogenous hormones, 17 beta-oestradiol (E2) and progesterone (P4), in the development of sporadic AD in postmenopausal women is also examined. Show more

Keywords: Alzheimer’s disease, 17 beta-oestradiol, conjugated equine estrogens, hormone therapy, progesterone, progestins

DOI: 10.3233/JAD-190896

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 23-37, 2020

Authors: He, Jin-Ting | Zhao, Xin | Xu, Lei | Mao, Cui-Ying

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and …microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-brain barrier, inflammation, ischemia, metabolic syndrome, oxidative stress, p-tau

DOI: 10.3233/JAD-190764

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 39-58, 2020

Authors: Schnaider, Lee | Arnon, Zohar A. | Gazit, Ehud

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is the most common cause of dementia. Despite substantial investment in research, there are no current effective treatments to prevent or delay the onset and development of AD and the exact molecular mechanism of AD pathogenesis is still not fully understood. Researchers have long suspected that microbial infections may play a role in AD; however, this hypothesis has been greatly overlooked for decades, only recently gaining a traction and recognition within the broad scientific community due to new overwhelming evidence on the association of various pathogenic microbes and AD. Here, we provide our perspective on the significance …of these findings, which shed light on the interplay between molecular self-assembly, neurodegeneration, and antimicrobial peptides, as well as propose an amendment to the amyloid cascade hypothesis. It is important to note that this association does not yet prove a causal link, but these reports warrant a thorough investigation into the microbial infection-AD hypothesis which might in turn deliver the elusive therapeutic target the scientific community has been so desperately searching for. Show more

Keywords: Alzheimer’s disease, antimicrobial peptides, infectious diseases, neurodegeneration, self-assembly

DOI: 10.3233/JAD-190765

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 59-62, 2020

Authors: Emrani, Sheina | Lamar, Melissa | Price, Catherine C. | Wasserman, Victor | Matusz, Emily | Au, Rhoda | Swenson, Rodney | Nagele, Robert | Heilman, Kenneth M. | Libon, David J.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called ‘mixed’ dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called ‘pure’ AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological …underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other. Show more

Keywords: Alzheimer’s disease, episodic memory, executive control, mixed dementia, vascular dementia

DOI: 10.3233/JAD-190654

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 63-71, 2020

Authors: Marcon, Gabriella | Manganotti, Paolo | Tettamanti, Mauro

Article Type: Short Communication

Abstract: The number of people reaching old age is growing dramatically and centenarians are among the fastest growing age groups. Since no epidemiological study on Parkinson’s disease (PD) in this age class is present in the medical literature, we estimated PD prevalence in the Centenari a Trieste (CaT) study. Participating centenarians were examined by a neurologist, who also retrieved their remote and pharmacological anamnesis. Ninety centenarians received a neurological examination. No subject had PD clinical signs. Moreover, none had a previous diagnosis of PD or had taken or was taking anti-Parkinson treatment. This simple but consistent clinical observation permits some physio-pathological …hypotheses. Show more

Keywords: Alpha-synuclein, centenarians, Parkinson’s disease, prevalence

DOI: 10.3233/JAD-190717

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 73-76, 2020

Authors: Newkirk, Lori A. | Dao, Virginia L. | Jordan, Joshua T. | Alving, Loren I. | Davies, Helen D. | Hewett, Linda | Beaudreau, Sherry A. | Schneider, Logan D. | Gould, Christine E. | Chick, Christina F. | Hirst, Rayna B. | Rose, Sophia Miryam Schüssler-Fiorenza | Anker, Lauren A. | Tinklenberg, Jared R. | O’Hara, Ruth

Article Type: Research Article

Abstract: Background: Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services. Objective: To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use. Methods: California Alzheimer’s Disease Center patients with AD (n  = 220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were …also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users. Results: Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p  < 0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p  < 0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services. Conclusion: Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use. Show more

Keywords: Activities of daily living, Alzheimer’s disease, caregiver burnout, dementia, family caregivers, respite care, spouse caregivers, support group

DOI: 10.3233/JAD-190438

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 77-86, 2020

Authors: Hays, Chelsea C. | Zlatar, Zvinka Z. | Meloy, M.J. | Osuna, Jessica | Liu, Thomas T. | Galasko, Douglas R. | Wierenga, Christina E.

Article Type: Research Article

Abstract: Evidence suggests the ɛ 4 allele of the apolipoprotein E (APOE ) gene may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE -related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ 4+, ɛ 4–) on FreeSurfer-derived …CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE , CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ 4+, whereas these relationships were not evident in ɛ 4–. In the rACC, higher CSF tau was associated with higher CTH for both ɛ 4+ and ɛ 4–, and with lower CBF only in ɛ 4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer’s disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ 4+ and a positive relationship in ɛ 4–. Findings suggest the presence of an ɛ 4–related pattern of increased CTH and reduced CBF in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition. Show more

Keywords: Aging, Alzheimer’s disease, APOE , cerebral blood flow, cognition, cognitive decline, grey matter, magnetic resonance imaging, tau proteins

DOI: 10.3233/JAD-190504

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 87-101, 2020

Authors: Tarraf, Wassim | Kaplan, Robert | Daviglus, Martha | Gallo, Linda C. | Schneiderman, Neil | Penedo, Frank J. | Perreira, Krista M. | Lamar, Melissa | Chai, Albert | Vásquez, Priscilla M. | González, Hector M.

Article Type: Research Article

Abstract: Background: Cardiovascular disease is linked to cognitive decline and disorders (e.g., dementia). The evidence is based largely on older non-Latino White cohorts. Objective: Examine the association between global vascular risk and cognitive function among Hispanics/Latinos in the United States. Methods: We used data from a large sample of stroke- and cardiovascular disease-free, middle-aged and older Hispanics/Latinos with diverse backgrounds (n =7,650) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We compared associations between two measures of cardiovascular risk (CVR), the Framingham Cardiovascular Risk Score (FCRS) and the multiethnic Global Vascular Risk Score (GVRS), and cognitive …performance using measures of global and domain specific cognitive function, and tested for modification by sex and age. Results: Higher FCRS and GVRS were associated with lower global cognition and higher probability of low mental status, after covariates adjustment. Both CVR indices were associated with lower performances in learning and memory, verbal fluency, and psychomotor speed. Higher GVRS presented stronger associations with lower cognitive function compared to the FCRS. Women and younger age (45–64 years) exhibited more pronounced associations between higher CVR and worse cognition, particularly so with the GVRS. Discussion: CVR is also a risk for compromised cognitive function and evident in middle-age among Hispanics/Latinos. The multiethnic GVRS, tailored to specific risks based on racial/ethnic background, is feasible to use in primary care settings and can provide important insight on cognitive risk. Even modest shifts in population toward cardiovascular health in the high-risk Hispanic/Latino population can have important positive impacts on healthy cognitive aging. Show more

Keywords: Cardiovascular risk, cognition, HCHS/SOL, Hispanics/Latinos, neuroepidemiology, neuropsychology

DOI: 10.3233/JAD-190830

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 103-116, 2020

Authors: Shimizu, Soichiro | Takenoshita, Naoto | Inagawa, Yuta | Tsugawa, Akito | Hirose, Daisuke | Kaneko, Yoshitsugu | Ogawa, Yusuke | Serisawa, Shuntaro | Sakurai, Shu | Hirao, Kentaro | Kanetaka, Hidekazu | Kanbayashi, Takashi | Imanishi, Aya | Sakurai, Hirofumi | Hanyu, Haruo

Article Type: Research Article

Abstract: Background: Recently, many studies have investigated the association between orexin A and Alzheimer’s disease (AD). However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A levels and cognitive function has not been reported to date. Objective: The aim of this study was to identify whether there is a direct association between the orexinergic system and cognitive function in AD. Methods: For this study, we included 22 patients with AD and 25 …control subjects who underwent general physical, neurological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], Aβ42 , and Aβ42 /Aβ40 ) were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were analyzed. Results: There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores: r  = 0.591, p  = 0.04, MoCA score: r  = 0.571, p  = 0.006) in AD patients. Conclusion: This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for cognitive function In AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid Alzheimer’s disease biomarker, cognitive function, hypocretin 1, orexin A

DOI: 10.3233/JAD-190958

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 117-123, 2020