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Late onset Alzheimer’s disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer’s disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer’s cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10−6), RORA (p = 7.4 × 10−7) and ZNF423 (p = 2.1 × 10−6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer’s disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer’s disease-specific protein network and is likely involved with centrosomes and DNA damage repair. [ABSTRACT FROM AUTHOR]

There is evidence to suggest that social isolation is associated with poor cognitive health, although findings are contradictory. One reason for inconsistency in reported findings may be a lack of consideration of underlying mechanisms that could influence this relationship. Cognitive reserve is a theoretical concept that may account for the role of social isolation and its association with cognitive outcomes in later life. Therefore, we aimed to examine the relationship between social isolation and cognition in later life, and to consider the role of cognitive reserve in this relationship. Baseline and two year follow-up data from the Cognitive Function and Ageing Study–Wales (CFAS-Wales) were analysed. Social isolation was assessed using the Lubben Social Network Scale-6 (LSNS-6), cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and cognitive reserve was assessed using a proxy measure of education, occupational complexity, and cognitive activity. Linear regression modelling was used to assess the relationship between social isolation and cognition. To assess the role of cognitive reserve in this relationship, moderation analysis was used to test for interaction effects. After controlling for age, gender, education, and physically limiting health conditions, social isolation was associated with cognitive function at baseline and two year follow-up. Cognitive reserve moderated this association longitudinally. Findings suggest that maintaining a socially active lifestyle in later life may enhance cognitive reserve and benefit cognitive function. This has important implications for interventions that may target social isolation to improve cognitive function. [ABSTRACT FROM AUTHOR]

Introduction: Increasing longevity means more people will be dying in very old age, but little is known about the preferences of the ‘oldest old’ regarding their care at the end of life. Aims: To understand very old people’s preferences regarding care towards the end of life and attitudes towards dying, to inform policy and practice. Methods: Qualitative data collection for n = 42 population-based cohort study participants aged 95–101 (88% women, 42% in long-term-care): topic-guided interviews with n = 33 participants and n = 39 proxy informants, most with both (n = 30: 4 jointly + separate interviews for 26 dyads). Results: Death was a part of life: these very old people mainly live day-to-day. Most were ready to die, reflecting their concerns regarding quality of life, being a nuisance, having nothing to live for and having lived long enough. Contrasting views were rare exceptions but voiced firmly. Most were not worried about death itself, but concerned more about the dying process and impacts on those left behind; a peaceful and pain-free death was a common ideal. Attitudes ranged from not wanting to think about death, through accepting its inevitable approach to longing for its release. Preferring to be made comfortable rather than have life-saving treatment if seriously ill, and wishing to avoid hospital, were commonly expressed views. There was little or no future planning, some consciously choosing not to. Uncertainty hampered end-of-life planning even when death was expected soon. Some stressed circumstances, such as severe dependency and others’ likely decision-making roles, would influence choices. Carers found these issues harder to raise but felt they would know their older relatives’ preferences, usually palliative care, although we found two discrepant views. Conclusions: This study’s rare data show ≥95-year-olds are willing to discuss dying and end-of-life care but seldom do. Formal documentation of wishes is extremely rare and may not be welcome. Although being “ready to die” and preferring a palliative approach predominated, these preferences cannot be assumed. [ABSTRACT FROM AUTHOR]

Background: Changes in criteria and differences in populations studied and methodology have produced a wide range of prevalence estimates for mild cognitive impairment (MCI). Methods: Uniform criteria were applied to harmonized data from 11 studies from USA, Europe, Asia and Australia, and MCI prevalence estimates determined using three separate definitions of cognitive impairment. Results: The published range of MCI prevalence estimates was 5.0%–36.7%. This was reduced with all cognitive impairment definitions: performance in the bottom 6.681% (3.2%–10.8%); Clinical Dementia Rating of 0.5 (1.8%–14.9%); Mini-Mental State Examination score of 24–27 (2.1%–20.7%). Prevalences using the first definition were 5.9% overall, and increased with age (P < .001) but were unaffected by sex or the main races/ethnicities investigated (Whites and Chinese). Not completing high school increased the likelihood of MCI (P ≤ .01). Conclusion: Applying uniform criteria to harmonized data greatly reduced the variation in MCI prevalence internationally. [ABSTRACT FROM AUTHOR]

Aims: β-amyloid (Aβ) plaques are a key feature of Alzheimer’s disease pathology but correlate poorly with dementia. They are associated with astrocytes which may modulate the effect of Aβ-deposition on the neuropil. This study characterised the astrocyte response to Aβ plaque subtypes, and investigated their association with cognitive impairment. Methods: Aβ plaque subtypes were identified in the cingulate gyrus using dual labelling immunohistochemistry to Aβ and GFAP+ astrocytes, and quantitated in two cortical areas: the area of densest plaque burden and the deep cortex near the white matter border (layer VI). Three subtypes were defined for both diffuse and compact plaques (also known as classical or core-plaques): Aβ plaque with (1) no associated astrocytes, (2) focal astrogliosis or (3) circumferential astrogliosis. Results: In the area of densest burden, diffuse plaques with no astrogliosis (β = -0.05, p = 0.001) and with focal astrogliosis (β = -0.27, p = 0.009) significantly associated with lower MMSE scores when controlling for sex and age at death. In the deep cortex (layer VI), both diffuse and compact plaques without astrogliosis associated with lower MMSE scores (β = -0.15, p = 0.017 and β = -0.81, p = 0.03, respectively). Diffuse plaques with no astrogliosis in layer VI related to dementia status (OR = 1.05, p = 0.025). In the area of densest burden, diffuse plaques with no astrogliosis or with focal astrogliosis associated with increasing Braak stage (β = 0.01, p<0.001 and β = 0.07, p<0.001, respectively), and ApoEε4 genotype (OR = 1.02, p = 0.001 and OR = 1.10, p = 0.016, respectively). In layer VI all plaque subtypes associated with Braak stage, and compact amyloid plaques with little and no associated astrogliosis associated with ApoEε4 genotype (OR = 1.50, p = 0.014 and OR = 0.10, p = 0.003, respectively). Conclusions: Reactive astrocytes in close proximity to either diffuse or compact plaques may have a neuroprotective role in the ageing brain, and possession of at least one copy of the ApoEε4 allele impacts the astroglial response to Aβ plaques. [ABSTRACT FROM AUTHOR]

Background: Three factors commonly used as measures of cognitive lifestyle are education, occupation, and social engagement. This study determined the relative importance of each variable to long term cognitive health in those with and without severe cognitive impairment. Methods: Data came from 12,470 participants from a multi-centre population-based cohort (Medical Research Council Cognitive Function and Ageing Study). Respondents were aged 65 years and over and were followed-up over 16 years. Cognitive states of no impairment, slight impairment, and moderate/severe impairment were defined, based on scores from the Mini-Mental State Examination. Multi-state modelling was used to investigate links between component cognitive lifestyle variables, cognitive state transitions over time, and death. Results: Higher educational attainment and a more complex mid-life occupation were associated with a lower risk of moving from a non-impaired to a slightly impaired state (hazard ratios 0.5 and 0.8), but with increased mortality from a severely impaired state (1.3 and 1.1). More socially engaged individuals had a decreased risk of moving from a slightly impaired state to a moderately/severely impaired state (0.7). All three cognitive lifestyle variables were linked to an increased chance of cognitive recovery back to the non-impaired state. Conclusions: In those without severe cognitive impairment, different aspects of cognitive lifestyle predict positive cognitive transitions over time, and in those with severe cognitive impairment, a reduced life-expectancy. An active cognitive lifestyle is therefore linked to compression of cognitive morbidity in late life. [ABSTRACT FROM AUTHOR]

Introduction: Each person having access to needed health services, of sufficient quality, and without suffering financial hardship, defined as universal health coverage (UHC) by the World Health Organization, is critical to improve population health, particularly for vulnerable populations. UHC requires multisectoral collaboration and good governance, and this will require buy-in of key stakeholders; but their views are under-documented. The aim of this stakeholder analysis was to explore the awareness and perceptions of UHC by health care workers (HCWs) in Uganda., Methods: A mixed-methods study was conducted based on primary data from HCWs including an online QualtricsXM survey of 274 HCWs (from a database of persons who had received training at an academic institution), 23 key informant semi-structured interviews, and one eight-person focus group discussion. Data was collected from February to April 2022. Microsoft Excel and R Programme were used for quantitative analyses and NVivo version 12 for qualitative analyses., Results: HCWs attributed a high level of importance to UHC in Uganda. Participants discussed national communication and management practices, organisational roles, health financing and power dynamics, health care demand and the impact of and learnings from COVID-19. Four main themes-each with related sub-themes-emerged from the interview data providing insights into: (1) communication, (2) organisation, (3) power, and (4) trust., Conclusion: There is a critical need for better communication of UHC targets by policymakers to improve understanding at a grassroots level. Results indicated that ensuring trust among the population through transparency in metrics and budgets, strong accountability measures, awareness of local cultural sensitivities, sensitisation of the UHC concept and community inclusion will be essential for a multisectoral roll out of UHC. Further provision of quality health services, a harmonisation of efforts, increased domestic health financing and investment of HCWs through fair remuneration will need to underpin the delivery of UHC., Competing Interests: All authors declare no competing interests., (Copyright: © 2024 Ifeagwu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls., Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci., Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.