Journal of Alzheimer's Disease Reports - Volume 4, issue 1

Authors: Migliaccio, Raffaella | Bouzigues, Arabella

Article Type: Article Commentary

Abstract: In dementia research and in clinical practice, the COVID-19 pandemic represents an important challenge, not only for neurological staff and researchers, but above all for patients and their caregivers. It is important that the medical staff demonstrate flexibility, open-mindedness, and humanity when following patients and caregivers. It seems inevitable that caregivers will pay the highest price during this crisis.

Keywords: Caregiver, collateral damage, COVID-19, dementia, lockdown

DOI: 10.3233/ADR-200193

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 231-235, 2020

Authors: Wang, Ge | Li, Wei

Article Type: Research Article

Abstract: Background: Diabetes has been shown as a risk factor for cognitive impairments. However, it is still not clear about the time course of developing abnormal cognition in those with diabetes especially if the morbidity accelerates the cognitive deterioration process. Objective: To study how diabetes is related to the abnormal cognition development. Methods: A retrospective analysis was performed using data collected by the National Alzheimer’s Coordinating Center. Incidence, prevalence, and age at onset (AAO) of either mild cognitive impairment (MCI) or dementia were compared between participants with and without diabetes. Results: During a follow-up period …of more than 10 years, the diabetic group had a higher incidence and prevalence of MCI or dementia than the non-diabetic group. However, the AAO of either MCI or dementia was independent of the diagnosis of diabetes. Conclusion: Although diabetic patients have a higher incidence and prevalence of abnormal cognition than those without diabetes, diabetes does not accelerate the cognitive deterioration process. Show more

Keywords: Abnormal cognition, age at onset, dementia, diabetes, mild cognitive impairment

DOI: 10.3233/ADR-200181

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 237-242, 2020

Authors: Park, Kevin H.J. | Barrett, Tomás

Article Type: Research Article

Abstract: Background: The presence of cell cycle markers in postmortem Alzheimer’s disease (AD) brains suggest a potential role of cell cycle activation in AD. It was shown that cell cycle activation in postmitotic neurons in mice produces Aβ and tau pathologies from endogenous mouse proteins in the absence of AβPP or tau mutations. Objective: In this study, we examined the microglial and astrocytic responses in these mice since neuroinflammation is another key pathological feature in AD. Methods: Our neuronal cell cycle re-entry (NCCR) mouse model are bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. Using this tet-off …system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. TRE-SV40T Tg mice were used as SV40T transgene controls. The animals were examined at following time points: 2, 3, 4, 6, and 12 months of age. The microglia and astrocyte responses in our mice were determined by image analysis and stereology on brain sections immunofluorescently labeled using the following antibodies: Iba1, CD45, CD68, MHCII, and GFAP. Cellular senescent marker p16 was also used in this study. Results: Our NCCR mice demonstrate early and persistent activation of microglia and astrocytes. Additionally, proinflammatory and senescent microglia phenotype and brain leukocyte infiltration is present at 12 months of age. Conclusion: In the absence of FAD gene mutations, our NCCR mice simultaneously display many of the pathological changes associated with AD, such as ectopic neuronal cell cycle re-entry, Aβ and tau pathologies, neuroinflammation, and neurodegeneration. These animals represent a promising alternative AD mouse model. Show more

Keywords: Alzheimer’s disease, amyloid-β, cell cycle, leukocyte infiltration, mouse model, neuroinflammation, senescence, sporadic AD, tau

DOI: 10.3233/ADR-200170

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 243-253, 2020

Authors: Marcum, Zachary A. | Rosenberg, Dori | Barnes, Deborah E. | Yaffe, Kristine | Larson, Eric B.

Article Type: Short Communication

Abstract: We administered a web-based survey to a convenience sample of 561 patients in a large health system to assess patient attitudes toward dementia prevention in the context of designing a multi-domain Alzheimer’s risk reduction intervention. The majority of respondents reported being very concerned about Alzheimer’s disease, wanted to know their personal risk factors, and were highly motivated to make healthy lifestyle changes to lower dementia risk. The areas they were most interested in targeting to reduce dementia risk included physical activity, cognitive stimulation, nutrition, and sleep. These results provided strong support for our conceptual framework to target higher-risk patients with …a personalized risk reduction strategy. Show more

Keywords: Alzheimer’s disease, dementia, patient participation, primary prevention

DOI: 10.3233/ADR-200210

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 255-260, 2020

Authors: Oberman, Klaske | Gouweleeuw, Leonie | Hoogerhout, Peter | Eisel, Ulrich L.M. | van Riet, Elly | Schoemaker, Regien G.

Article Type: Research Article

Abstract: Background: Soluble oligomeric amyloid-β (Aβ), rather than Aβ plaques, seems to be the culprit in Alzheimer’s disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aβ, has been developed. Objective: Study the therapeutic potential of this new vaccine in a mouse model for AD. Methods: J20 mice, overexpressing human amyloid precursor protein, were validated for an AD-like phenotype. Then, J20 mice were vaccinated at 2, 3, and 4 months of age and AD phenotype was evaluated at 6, 9, and 12 months of age; or at 9, 10, and 11 …months with evaluation at 12 months. Effects on Aβ pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aβ (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests. Results: J20 mice displayed age-related Aβ plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aβ, leaving plaque load unaffected. Nevertheless, immunization at young ages prevented working- and short-term spatial memory loss, but deteriorated long-term spatial learning and memory, at 12 months of age. Immunization at later ages did not affect any measured parameter. Conclusion: J20 mice provide a relevant model for AD to study potential anti-Aβ treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aβ pathology. Later vaccination had no effects, but optimal timing may require further investigation. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, vaccine

DOI: 10.3233/ADR-200213

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 261-280, 2020

Authors: Robinson, Andrew C. | Davidson, Yvonne S. | Roncaroli, Federico | Minshull, James | Tinkler, Phillip | Horan, Michael A. | Payton, Antony | Pendleton, Neil | Mann, David M.A.

Article Type: Short Communication

Abstract: While many studies have examined the associations between APOE genotype and mortality, findings have often been conflicting and it remains unclear whether APOE genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between APOE genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the APOE ɛ 4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, …APOE ɛ 2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that APOE genotype influences longevity, especially in cognitively impaired individuals who carry the APOE ɛ 4 allele. Show more

Keywords: Alzheimer’s disease, APOE , cognition, longevity, mortality

DOI: 10.3233/ADR-200203

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 281-286, 2020

Authors: Sato, Kenichiro | Mano, Tatsuo | Suzuki, Kazushi | Toda, Tatsushi | Iwatsubo, Takeshi | Iwata, Atsushi | for Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Although aging is the strongest risk factor for the development of Alzheimer’s disease (AD), it remains uncertain if the blood DNA methylation clock, which reflects the effect of biological aging on DNA methylation (DNAme) status of blood cells, may be used as a surrogate biomarker for AD pathology in the central nervous system (CNS). Objective: We aimed to develop a practical model to predict for A/T/N-based AD biomarkers as the prediction targets using the aging acceleration of blood cells. Methods: We obtained data of North American ADNI study participants (n  = 317) whose blood DNA methylation …microarray (Illumina HumanMethylation EPIC Beadchips) and cerebrospinal fluid (CSF) AD biomarkers (Aβ , t-tau, and p-tau) were recorded simultaneously. Methylation clock was calculated to conduct machine learning, in order to predict binary statuses (+ or –) for A (corresponding to the lowered CSF Aβ ), T (the elevated CSF p-tau), or N (the elevated CSF t-tau). The predictive performance of the models was evaluated by area under curve (AUC) in the test subset within ADNI. Results: Among the 317 included samples, 194 (61.2%) were A+, 247 (77.9%) were T+, and 104 (32.8%) were N+. The degree of blood aging acceleration showed weak positive correlation with the CSF Aβ levels, even after adjustment with APOE genotype and other covariates. However, the contribution of aging acceleration to improve the predictive performance of models was not significant for any of A+, T+, or N+. Conclusion: Our exploratory attempts could not demonstrate the substantial utility of the peripheral blood cells’ methylation clock as a predictor for A/T/N-based CSF biomarkers of AD, and further additional work should be conducted to determine whether the blood DNAme signatures including methylation clock have substantial utility in detecting underlying amyloid, tau or neurodegeneration pathology of AD. Show more

Keywords: Alzheimer’s disease, A/T/N, blood biomarker, DNA methylation, epigenetic clock

DOI: 10.3233/ADR-200205

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 287-296, 2020

Authors: Figueiro, Mariana G. | Sahin, Levent | Kalsher, Michael | Plitnick, Barbara | Rea, Mark S.

Article Type: Research Article

Abstract: Background: Persons with Alzheimer’s disease and related dementias (ADRD) frequently experience sleep–wake (circadian) cycle disturbances that lead them to remain awake at night, causing stress and fatigue for families and caregivers. Light therapy shows promise as a nonpharmacological treatment for regulating sleep in this population. Objective: We investigated the long-term impact of a circadian-effective lighting intervention on sleep, mood, and behavior problems in persons with ADRD. Methods: This 25-week clinical trial administered an all-day lighting intervention to 47 patients with ADRD in 9 senior-care facilities, employing wrist-worn actigraphy measures and standardized measures of sleep quality, mood, …and behavior. Results: The intervention significantly improved Pittsburgh Sleep Quality Index scores, from an estimated mean±SEM of 11.89±0.53 at baseline to 5.36±0.63 at the end of the intervention. Additional improvements were noted for sleep efficiency data from actigraph measurements. The intervention significantly reduced Cornell Scale for Depression in Dementia scores (mean±SEM of 11.36±0.74 at baseline and 4.18±0.88 at the end of the intervention) and Cohen-Mansfield Agitation Inventory scores (mean±SEM of 47.10±1.98 at baseline and 35.33±2.23 at the end of the intervention). Conclusion: A regular circadian-effective daytime lighting intervention can improve sleep at night and reduce depression and agitation in patients with dementia living in controlled environments. More importantly, the positive effects of the tailored lighting intervention on these outcomes appear to be cumulative over time. Show more

Keywords: Alzheimer’s disease and related dementias, circadian system, lighting intervention, mood, rest–activity, sleep

DOI: 10.3233/ADR-200212

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 297-312, 2020

Authors: Ryan, Joanne | Woods, Robyn L. | Britt, Carlene J. | Murray, Anne M. | Shah, Raj C. | Reid, Christopher M. | Wolfe, Rory | Nelson, Mark R. | Orchard, Suzanne G. | Lockery, Jessica E. | Trevaks, Ruth E. | Storey, Elsdon | behalf of the ASPREE Investigator Group on

Article Type: Research Article

Abstract: Background: Processing speed, which can be assessed using the Symbol Digit Modalities Test (SDMT), is central to many brain functions. Processing speed declines with advanced age but substantial impairments are indicative of brain injury or disease. Objective: The purpose of this study was to provide SDMT normative data for older community-dwelling individuals in the U.S. and Australia. Methods: The ASPREE trial recruited 19,114 relatively healthy older men and women in Australia and the U.S. from the general community. All participants were without a diagnosis of dementia and with a Modified Mini-Mental State examination score of 78 …or more at enrolment. The SDMT was administered at baseline as part of a neuropsychological test battery. Results: The median age of participants was 74 years (range 65–99), and 56% were women. The median years of education was 12. Ethno-racial differences in SDMT performance were observed and normative data were thus presented separately for 16,289 white Australians, 1,082 white Americans, 891 African-Americans, and 316 Hispanic/Latinos. There were consistent positive associations found between SDMT and education level, and negative associations between SDMT and age. Mean scores for women were consistently higher than men with the exception of Hispanic/Latinos aged ≥70 years. Conclusion: This study provides comprehensive SDMT normative data for whites (Australian and U.S.), Hispanic/Latinos, and African-Americans, according to gender, age, and education level. These norms can be used clinically as reference standards to screen for cognitive impairments in older individuals. Show more

Keywords: Aging, cognition, impairment, normative data, Symbol Digit Modalities Test

DOI: 10.3233/ADR-200194

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 313-323, 2020

Authors: Olson, Nancy L. | Albensi, Benedict C.

Article Type: Review Article

Abstract: Randomized clinical trials (RCT) involve labor-intensive, highly regulated, and controlled processes intended to transform scientific concepts into clinical outcomes. To be effective and targeted, it is imperative they include those populations who would most benefit from those outcomes. Alzheimer’s disease (AD) is most detrimental to the aging population, and its clinical manifestation is influenced by socio-economic factors such as poverty, poor education, stress, and chronic co-morbidities. Indigenous populations in the United States and Canada are among the minority populations most influenced by poor socio-economic conditions and are prone to the ravages of AD, with Indigenous women carrying the added burden …of exposure to violence, caregiving stresses, and increased risk by virtue of their sex. Race- and sex-based disparities in RCT enrollment has occurred for decades, with Indigenous men and women very poorly represented. In this review, we examined literature from the last twenty years that reinforce these disparities and provide some concrete suggestions and guidelines to increase the enrollment numbers in AD RCT among this vulnerable and poorly represented population. Show more

Keywords: Aboriginal, Alzheimer’s disease, gender, Indian, indigenous, Inuit, Metis, native, randomized clinical trial, sex

DOI: 10.3233/ADR-200214

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 325-344, 2020