Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Zuelsdorff, Megan | Okonkwo, Ozioma C. | Norton, Derek | Barnes, Lisa L. | Graham, Karen L. | Clark, Lindsay R. | Wyman, Mary F. | Benton, Susan F. | Gee, Alexander | Lambrou, Nickolas | Johnson, Sterling C. | Gleason, Carey E.

Article Type: Research Article

Abstract: Background: It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer’s and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. Objective: We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Methods: Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life …event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. Results: African Americans (N = 50) reported more stressful life events than Whites (N = 1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. Conclusions: Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course. Show more

Keywords: African Americans, Alzheimer’s disease, life course, stress

DOI: 10.3233/JAD-190439

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Fuller-Thomson, Esme | Deng, ZhiDi

Article Type: Research Article

Abstract: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease whose clinical presentation mimics that of Alzheimer’s disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what they are …today. Thus, each successive birth cohort entering old age has had less cumulative life exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE. Show more

Keywords: Alzheimer’s disease, FTLD with TDP-43 pathology, lead poisoning, nervous system, TDP-43 proteinopathies, tetraethyl lead

DOI: 10.3233/JAD-190943

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Wang, Longcai | Qiao, Yanchun | Zhang, Haihua | Zhang, Yan | Hua, Jiao | Jin, Shuilin | Liu, Guiyou

Article Type: Research Article

Abstract: Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer’s disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin …D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and to forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents. Show more

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D

DOI: 10.3233/JAD-190713

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

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. Pre-press, no. Pre-press, pp. 1-20, 2019

Authors: Itzhaki, Ruth F.

Article Type: Article Commentary

DOI: 10.3233/JAD-191171

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Yoon, Bora | Choi, Seong Hye | Jeong, Jee Hyang | Park, Kyung Won | Kim, Eun-Joo | Hwang, Jihye | Jang, Jae-Won | Kim, Hee Jin | Hong, Jin Yong | Lee, Jong-Min | Kang, Ju-Hee | Yoon, Soo Jin

Article Type: Research Article

Abstract: Background: Balance impairments are common in patients with Alzheimer’s disease (AD) dementia. Objective: We sought to determine the stage along the AD spectrum during which balance impairments appear and identify factors associated with a decline in balance function. Methods: Our cross-sectional study included 295 participants; 71 were cognitively normal, 96 reported subjective cognitive decline (SCD), 72 had amnestic mild cognitive impairment (MCI), and 56 had AD dementia. The balance and mobility function was assessed using the Timed Up and Go test (TUG) and the One-Leg Standing Test (OLST). Results: Participants in the MCI and …AD dementia groups were older than those in the cognitively normal and SCD groups. TUG and OLST test scores were linearly correlated with Mini-Mental Status Examination-Korean Version score (MMSE-KC). TUG score increased with greater AD spectrum severity (all p  < 0.001), whereas OLST score showed a precipitous impairment starting in the SCD group (all p  < 0.001), even after adjusting for age, sex, MMSE-KC, Geriatric depression scale, and body mass index. Based on subgroup analyses, in females and apolipoprotein E (APOE ) ɛ 4 carriers, there was significant balance/mobility impairment in the SCD group when compared to the CN group. Conclusion: Our results suggest that balance/mobility is related to cognitive function and that balance/mobility impairment can be observed beginning in the SCD stage. Furthermore, CN females and APOE ɛ 4 carriers had better balance and mobility when compared to females and APOE ɛ 4 carriers along the ADD spectrum/with cognitive impairment respectively. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cognition, female, postural balance, subjective cognitive decline

DOI: 10.3233/JAD-190601

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Naismith, Sharon L. | Duffy, Shantel L. | Cross, Nathan | Grunstein, Ron | Terpening, Zoe | Hoyos, Camilla | D’Rozario, Angela | Lagopoulos, Jim | Osorio, Ricardo S. | Shine, James M. | McKinnon, Andrew C.

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea is associated with an increased risk of developing mild cognitive impairment and dementia. Intermittent nocturnal hypoxemia in obstructive sleep apnea is associated with brain changes in key regions that underpin memory. Objective: To determine whether older adults with severe nocturnal hypoxemia would exhibit reduced functional connectivity within these regions, with associated deficits in memory. Methods: Seventy-two participants 51 years and over underwent polysomnography with continuous blood oxygen saturation recorded via oximetry. The oxygen desaturation index (ODI, 3% dips in oxygen levels per hour) was the primary outcome measure. ODI was split into …tertiles, with analyses comparing the lowest and highest tertiles (N = 48). Thirty-five of the 48 participants from these two tertiles had mild cognitive impairment. Participants also underwent resting-state fMRI and comprehensive neuropsychological, medical, and psychiatric assessment. Results: The highest ODI tertile group demonstrated significantly reduced connectivity between the left and right parahippocampal cortex, relative to the lowest ODI tertile group (t(42) = –3.26, p  = 0.041, beta = –1.99).The highest ODI tertile group also had poorer working memory performance. In the highest ODI tertile group only, higher left-right parahippocampal functional connectivity was associated with poorer visual memory recall (between-groups z = –2.93, p  = 0.0034). Conclusions: Older adults with severe nocturnal hypoxemia demonstrate impaired functional connectivity in medial temporal structures, key regions involved in sleep memory processing and implicated in dementia pathophysiology. Oxygen desaturation and functional connectivity in these individuals each relate to cognitive performance. Research is now required to further elucidate these findings. Show more

Keywords: Default mode network, memory, mild cognitive impairment, obstructive sleep apnea

DOI: 10.3233/JAD-190747

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: de Oliveira, Jade | Engel, Daiane F. | de Paula, Gabriela C. | Melo, Helen M. | Lopes, Samantha C. | Ribeiro, Camila Tiefensee | Delanogare, Eslen | Moreira, José Claudio Fonseca | Gelain, Daniel Pens | Prediger, Rui D. | Gabilan, Nelson H. | Moreira, Eduardo Luiz G. | Ferreira, Sergio T. | de Bem, Andreza F.

Article Type: Research Article

Abstract: Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/- ), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer’s disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein …1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/- mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels. Show more

Keywords: Amyloid-β, apoptosis, familial hypercholesterolemia, LDLr-/- mice, memory impairment

DOI: 10.3233/JAD-190742

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Eckerström, Carl | Eckerström, Marie | Göthlin, Mattias | Molinder, Anna | Jonsson, Michael | Kettunen, Petronella | Svensson, Johan | Rolstad, Sindre | Wallin, Anders

Article Type: Research Article

Abstract: Background: Research has shown that mixed dementia is more common than previously believed but little is known of its early stages. Objective: To examine if incipient mixed dementia can be differentiated from incipient Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SVD) using neuropsychological tests, cerebrospinal fluid (CSF) markers, and magnetic resonance imaging markers. Methods: We included 493 patients and controls from the Gothenburg MCI study and used the dementia groups for marker selection (CSF total-tau (T-tau), phospho-tau (P-tau), and amyloid-β42 (Aβ42 ), 11 neuropsychological tests, and 92 regional brain volumes) and to obtain cut-off …values which were then applied to the MCI groups. Results: Incipient mixed dementia was best differentiated from incipient AD by the Word fluency F-A-S test and the Trail making test A. CSF T-tau, P-tau, and Aβ42 differentiated incipient mixed dementia from incipient SVD. Conclusion: Incipient mixed dementia is characterized by an AD-like biomarker profile and an SVD-like cognitive profile. Incipient mixed dementia can be separated from incipient AD and incipient SVD using CSF markers and cognitive testing. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, magnetic resonance imaging, mild cognitive impairment, neuropsychological test, vascular dementia

DOI: 10.3233/JAD-190651

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

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. Pre-press, no. Pre-press, pp. 1-9, 2019