Generation and deposition of A43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease

As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid- peptide (A) species, which are released from a C-terminal amyloid precursor protein fragment by -secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the A42 to A40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little A generated by PS1 L435F consists primarily of A43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of A43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found A43-containing plaques in brains of patients with this mutation. The aberrant generation of A43 by this particular mutant provides a direct objection against the presenilin hypothesis

Neuropsychiatric symptoms and the outcome of cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging

Objective Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. We examined associations between NPS and the outcomes of global and domain‐specific cognitive trajectories. Methods In this longitudinal study conducted in the setting of the population‐based Mayo Clinic Study of Aging, 5081 community‐dwelling, nondemented individuals aged ≥50 years (51% males) underwent NPS assessment using Neuropsychiatric Inventory Questionnaire (NPI‐Q), and Beck Depression and Anxiety Inventories (BDI‐II, BAI). Global and domain‐specific (memory, language, attention, and visuospatial skills) cognitive performance was assessed through neuropsychological testing every 15 months. Associations between baseline NPS and trajectories for individual yearly change in cognitive z‐scores were calculated using linear mixed‐effect models. Results Cognition declined regardless of NPS status over the median follow‐up of 4.5 years. Presence of NPS was associated with increased cognitive decline. Differences in annualized change in global cognition z‐scores for participants with NPS compared to without NPS ranged from −0.018 (95% CI −0.032, −0.004; p = 0.011) for irritability to −0.159 (−0.254, −0.065; p = 0.001) for hallucinations. Associations between NPS and annual decline in global cognition were significant for most NPI‐Q‐assessed NPS and clinical depression (BDI‐II≥13). Participants with NPI‐Q‐assessed depression, apathy, nighttime behavior, and clinical depression had greater decline in all domain‐specific z‐scores; presence of delusions and anxiety was associated with more pronounced decline in language, attention and visuospatial skills. Conclusion NPS were associated with a more accelerated cognitive decline. Clinical assessment and potential treatment of NPS is warranted even in a community setting as NPS may impact cognitive decline in nondemented individuals

Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) epsilon 4 status. Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged >= 70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE epsilon 4 carriership did not moderate the association between PA and cognition. Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex

Quantity and quality of mental activities and the risk of incident mild cognitive impairment

Objective To investigate whether timing, number, and frequency of mentally stimulating activities in midlife and late life are associated with the risk of incident mild cognitive impairment (MCI). Methods We conducted a prospective cohort study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, including 2,000 individuals aged ≥70 years who were cognitively unimpaired at baseline and were followed for a median of 5.0 years. Participants completed a self-reported survey on timing, number, and frequency of engagement in 5 mentally stimulating activities (reading books, computer use, social activities, playing games, craft activities) at baseline. Results The risk of incident MCI was significantly reduced for participants who engaged in social activities (hazard ratio [95% confidence interval] 0.80 [0.64–0.99]) and playing games (0.80 [0.66–0.98]) in both late life and midlife combined. Using a computer was associated with a decreased risk regardless of timing (not late life but midlife: 0.52 [0.31–0.88]; late life but not midlife: 0.70 [0.56–0.88]; late life and midlife: 0.63 [0.51–0.79]). Craft activities were associated with a reduced risk of incident MCI only when carried out in late life but not midlife (0.58 [0.34–0.97]). Furthermore, engaging in a higher number of activities in late life was associated with a significantly reduced risk of incident MCI (any 2 activities: 0.72 [0.53–0.99], any 3: 0.55 [0.40–0.77], any 4: 0.44 [0.30–0.65], all 5: 0.57 [0.34–0.96]). Conclusion Engaging in a higher number of mentally stimulating activities, particularly in late life, is associated with a decreased risk of MCI among community-dwelling older persons

Cortical β-amyloid burden, neuropsychiatric symptoms, and cognitive status: the Mayo Clinic Study of Aging

Abstract Neuropsychiatric symptoms (NPS) are a risk factor for cognitive impairment and are associated with cortical β-amyloid (Aβ) deposition. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging to examine the frequency of NPS among cognitively unimpaired (CU) and mild cognitive impairment (MCI) participants who either have normal (A−) or abnormal (A+) Aβ deposition. We also investigated whether combined presence of MCI and amyloid positivity (MCI/A+) is associated with greater odds of having NPS as compared to CU/A− (defined as reference group). Participants were 1627 CU and MCI individuals aged ≥ 50 years (54% males; median age 73 years). All participants underwent NPS assessment (Neuropsychiatric Inventory Questionnaire (NPI-Q); Beck Depression Inventory II (BDI-II); Beck Anxiety Inventory (BAI)) and 11C-PiB-PET. Participants with an SUVR > 1.42 were classified as A+. We conducted multivariable logistic regression analyses adjusted for age, sex, education, and APOE ε4 genotype status. The sample included 997 CU/A−, 446 CU/A+, 78 MCI/A−, and 106 MCI/A+ persons. For most NPS, the highest frequency of NPS was found in MCI/A+ and the lowest in CU/A−. The odds ratios of having NPS, depression (BDI ≥ 13), or anxiety (BAI ≥ 8, ≥ 10) were consistently highest for MCI/A+ participants. In conclusion, MCI with Aβ burden of the brain is associated with an increased risk of having NPS as compared to MCI without Aβ burden. This implies that the underlying Alzheimer’s disease biology (i.e., cerebral Aβ amyloidosis) may drive both cognitive and psychiatric symptoms

Association of non-exercise physical activity in mid- and late-life with cognitive trajectories and the impact of APOE ε4 genotype status: the Mayo Clinic Study of Aging

© 2019, The Author(s). In this study derived from the population-based Mayo Clinic Study of Aging, we investigated whether non-exercise physical activity (PA) was associated with global and domain-specific cognitive trajectories (memory, language, visuospatial skills, attention) and whether the association differed by apolipoprotein E (APOE) ε4 genotype status. We included 2061 community-dwelling individuals aged ≥ 70 years (50.5% males, 26.7% APOE ε4 carriers) who were cognitively unimpaired at baseline and on whom serial cognitive data and self-reported information on non-exercise PA were available. We specifically inquired about non-exercise PA carried out at two time points, i.e., midlife (between 50 and 65 years of age) and late-life (within 1 year prior to assessment) and three intensity levels, i.e., light (e.g., laundry), moderate (e.g., scrubbing floors) and heavy (e.g., hard manual labor). Linear mixed-effect models revealed that engaging in midlife PA of moderate or heavy intensity was associated with significantly less-pronounced decline of z-scores in all cognitive domains. Similarly, participants that engaged in late-life moderate or heavy PA had less decline in visuospatial, attention and global z-scores than non-active peers. These associations varied depending on APOE ε4 carrier status, i.e., APOE ε4 non-carriers but not APOE ε4 carriers that engaged in late-life PA had less decline in cognitive z-scores. In contrast, engaging in midlife PA, irrespective of intensity, was significantly associated with less decline in memory function only among APOE ε4 carriers

Mobility requirements for the Campus Charlottenburg – results of an online survey with TUB members

Der Campus Charlottenburg in der Berliner City West ist Hauptstandort der Technischen Universität Berlin (TUB) und der Universität der Künste Berlin. Um ein besseres Verständnis dafür zu entwickeln, mit welchen Verkehrsmitteln die Anreise zum Campus stattfindet und welche Mobilitätsanforderungen sich daraus für den Campus ergeben, wurde im Oktober 2020 eine Online-Umfrage mit 2.204 Studierenden und Beschäftigten der TUB durchgeführt. Der vorliegende Bericht fasst die zentralen Ergebnisse zusammen und liefert Daten unter anderem zur Anreise zum Campus, zum Zugang zu unterschiedlichen Verkehrsmitteln und zu der Fortbewegung auf dem Campus. Weiterhin liefert die Studie Erkenntnisse zur Änderung des Mobilitätsverhaltens aufgrund der Corona-Pandemie und zu Verbesserungsvorschlägen der Nutzer*innen, um den Fußverkehr, Radverkehr und öffentlichen Personennahverkehr am Campus Charlottenburg zu fördern. Die Umfrage wurde im Rahmen des Forschungsprojekts „MobCC - Entwicklung eines zukunftsweisenden Konzeptes für die nachhaltige Mobilitätsentwicklung des Bezirks Charlottenburg-Wilmersdorf mit Schwerpunkt auf dem Campus Charlottenburg“ durchgeführt. Die Projektleitung lag beim Bezirksamt Charlottenburg-Wilmersdorf, die Verantwortung für die wissenschaftliche Begleitforschung beim Fachgebiet Integrierte Verkehrsplanung der Technischen Universität Berlin.The Campus Charlottenburg in Berlin`s City West is the main location of the Technische Universität Belrin (TUB) and the Berlin University of the Arts. In order to develop a better understanding of the means of transport used to travel to the campus and the resulting mobility requirements for the campus, an online survey was conducted in October 2020 with 2,204 TUB students and employees. This report summarizes the key findings and provides data on, among other things, travel to campus, access to different modes of transportation, and getting around campus. Furthermore, the survey provides insights into changes in mobility behavior due to the Corona pandemic and suggestions by users for improvements to promote walking, cycling and public transport on the Campus Charlottenburg. The survey was conducted as part of the research project “MobCC – Development of a future-proof sustainable mobility concept for the Charlottenburg-Wilmersdorf district with a focus on the Campus Charlottenburg”. The project was managed by the Charlottenburg-Wilmersdorf district office while the Department of Integrated Transport Planning of the Technische Universität Berlin was responsible for the accompanying scientific research.BMBF, 01UV2014, Entwicklung eines zukunftsweisenden Konzeptes für die nachhaltige Mobilitätsentwicklung des Bezirks Charlottenburg-Wilmersdorf mit Schwerpunkt auf dem Campus Charlottenburg (MobCC