62 research outputs found
APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases
A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer’s disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated β-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies
Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer\u27s Symposium
The Alzheimer\u27s Association hosted the second Latinos & Alzheimer\u27s Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer\u27s disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD
Cognitive performance in asymptomatic carriers of mutations R1031C and R141C in CADASIL
CADASIL is the most common hereditary cause of repeated ischemic strokes, and has also been identified as a model of pure vascular dementia. The objective of this study was to establish the cognitive performance of asymptomatic carriers with the mutations R1031C and R141C. This observational cross-sectional analytical study divided subjects into three groups: asymptomatic carriers of the R1031C mutation (n = 39), asymptomatic carries of the R141C mutation (n = 8) and non-carriers (n = 50). Statistically significant differences were found (p <0.05) between the group of the R1031C mutation and the non-carriers in constructional praxis, executive function and abstract reasoning. For the R141C mutation, scores below expected values in executive function and mental calculation were observed. It is concluded that asymptomatic carriers of the two mutations showed low performance in working memory, mental abstraction and processing speed, which could be associated with preclinical cognitive biomarkers preceding the presentation of the first vascular event
Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease: A Retrospective Cohort Study
Data from an autosomal dominant Alzheimer disease (ADAD) kindred were used to track the longitudinal trajectory of cognitive decline associated with preclinical ADAD and explore factors that may modify the rate of cognitive decline
Initial investigation of test-retest reliability of home-to-home teleneuropsychological assessment in healthy, English-speaking adults
Prior teleneuropsychological research has assessed the reliability between in-person and remote administration of cognitive assessments. Few, if any, studies have examined the test-retest reliability of cognitive assessments conducted in sequential clinic-to-home or home-to-home teleneuropsychological evaluations - a critical issue given the state of clinical practice during the COVID-19 pandemic. This study examined this key psychometric question for several cognitive tests administered over repeated videoconferencing visits 4-6 months apart in a sample of healthy English-speaking adults. A total of 44 participants (ages 18-75) completed baseline and follow-up cognitive testing 4-6 months apart. Testing was conducted in a home-to-home setting over HIPAA-compliant videoconferencing meetings on participants' audio-visual enabled laptop or desktop computers. The following measures were repeated at both virtual visits: the Controlled Oral Word Association Test (FAS), Category Fluency (Animals), and Digit Span Forward and Backward from the Wechsler Adult Intelligence Scale, Fourth Edition. Intraclass correlation coefficients (ICC), Pearson correlations, root mean square difference (RMSD), and concordance correlation coefficients (CCC) were calculated as test-retest reliability metrics, and practice effects were assessed using paired-samples t-tests. Some tests exhibited small practice effects, and test-retest reliability was marginal or worse for all measures except FAS, which had adequate reliability (based on ICC and r). Reliability estimates with RMSD suggested that change within +/- 1 SD on these measures may reflect typical test-retest variability. The included cognitive measures exhibited questionable reliability over repeated home-to-home videoconferencing evaluations. Future teleneuropsychology test-retest reliability research is needed with larger, more diverse samples and in clinical populations.F31 AG062158 - NIA NIH HHS; R01 AG054671 - NIA NIH HHS; R01 AG066823 - NIA NIH HHSAccepted manuscrip
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White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia
Background
To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity.
Methods
This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.
Results
The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.
Conclusions
The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms
Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.
We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease
Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the Second Latinos and Alzheimer's Symposium
The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD
World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia
© 2020 The Authors. Alzheimer\u27s & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer\u27s Association Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer\u27s disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at-risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies
Perspectives on ethnic and racial disparities in Alzheimer\u27s disease and related dementias: Update and areas of immediate need
Alzheimer\u27s disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer\u27s Association International Society to Advance Alzheimer\u27s Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise “state-of-the-science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations. © 2018 The Author
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