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BackgroundIt remains unclear whether persistent loneliness is related to brain structures that are associated with cognitive decline and development of Alzheimer's disease (AD). This study aimed to investigate the relationships between different loneliness types, cognitive functioning, and regional brain volumes.MethodsLoneliness was measured longitudinally, using the item from the Center for Epidemiologic Studies Depression Scale in the Framingham Heart Study, Generation 3, with participants' average age of 46·3 ± 8·6 years. Robust regression models tested the association between different loneliness types with longitudinal neuropsychological performance (n = 2,609) and regional magnetic resonance imaging brain data (n = 1,829) (2002-2019). Results were stratified for sex, depression, and Apolipoprotein E4 (ApoE4).FindingsPersistent loneliness, but not transient loneliness, was strongly associated with cognitive decline, especially memory and executive function. Persistent loneliness was negatively associated with temporal lobe volume (β = -0.18, 95%CI [-0.32, -0.04], P = 0·01). Among women, persistent loneliness was associated with smaller frontal lobe (β = -0.19, 95%CI [-0.38, -0.01], P = 0·04), temporal lobe (β = -0.20, 95%CI [-0.37, -0.03], P = 0·02), and hippocampus volumes (β = -0.23, 95%CI [-0.40, -0.06], P = 0·007), and larger lateral ventricle volume (β = 0.15, 95%CI [0.02, 0.28], P = 0·03). The higher cumulative loneliness scores across three exams, the smaller parietal, temporal, and hippocampus volumes and larger lateral ventricle were evident, especially in the presence of ApoE4.InterpretationPersistent loneliness in midlife was associated with atrophy in brain regions responsible for memory and executive dysfunction. Interventions to reduce the chronicity of loneliness may mitigate the risk of age-related cognitive decline and AD.FundingUS National Institute on Aging.

Introduction: As patient and public involvement (PPI) in research has become increasingly common, research‐based recommendations on its principles and impacts have been established. The specifics of conducting PPI are likely to differ when involving different groups. Family/informal carers for those with health conditions or disabilities have a lot to contribute to research, but instances of their involvement have yet to be reviewed. Objective: To systematically review and synthesize studies where family/informal carers have been involved in the research process, to develop an understanding of the benefits, barriers and facilitating factors. Methods: A search of five electronic databases was conducted using a combination of terms relating to carers, involvement and research. A grey literature search, expert consultation and hand‐searching were also used. Following screening, data extraction and quality assessment, a narrative synthesis incorporating thematic analysis was conducted. Findings: A total of 55 studies met the inclusion criteria, with diverse design and participatory approaches. Four themes were identified, relating to the outcomes, challenges, and practicalities of involving carers: (re) building relationships with carers; carers as equals not afterthoughts; carers have unique experiences; carers create change. Full involvement throughout the research was not always possible, due to barriers from the research world and responsibilities of the caring role. The literature demonstrated ways for carers to contribute in ways that suited them, maximizing their impact, while attending to relationships and power imbalances. Conclusion: By summarizing the reported instances of carer involvement in research, this review brings together different examples of how successful research partnerships can be built with carers, despite various challenges. Carers are a heterogeneous group, and participatory approaches should be tailored to specific situations. Wider understanding of the challenges of conducting empowering research with carers, and the resources required to address these, are needed. Patient and Public Involvement: The initial findings and themes were presented to a group of carers who had been involved in research and whose reflections informed the final synthesis. [ABSTRACT FROM AUTHOR]

Loneliness is an experience resulting from a perceived discrepancy between expected and actual social relationships. Although this discrepancy is widely considered the "core mechanism" of loneliness, previous research and interventions have not sufficiently addressed what older adults specifically expect from their social relationships. To address this gap and to help situate research on older adults' loneliness within broader life span developmental theories, we propose a theoretical framework that outlines six key social relationship expectations of older adults based on research from psychology, gerontology, and anthropology: availability of social contacts, receiving care and support, intimacy and understanding, enjoyment and shared interests, generativity and contribution, and being respected and valued. We further argue that a complete understanding of loneliness across the life span requires attention to the powerful impacts of contextual factors (e.g., culture, functional limitations, social network changes) on the expression and fulfillment of older adults' universal and age-specific relationship expectations. The proposed Social Relationship Expectations Framework may fruitfully inform future loneliness research and interventions for a heterogeneous aging population. [ABSTRACT FROM AUTHOR]

Older adults contribute vast amounts of care to society, yet it remains unclear how unpaid productive activities relate to loneliness. The objective of this systematic review is to synthesise the evidence for associations between midlife and older people's unpaid productive activities (i.e., spousal and grandparental caregiving, volunteering) and loneliness. Peer-reviewed observational articles that investigated the association between loneliness and caregiving or volunteering in later life (>50 years) were searched on electronic databases (Ovid MEDLINE, Embase, PsychInfo and Global Health) from inception until July 2021. Studies were analysed using narrative synthesis and assessed for methodological quality applying the Newcastle Ottawa Scale. A total of 28 articles from 21 countries with 191,652 participants were included (52.5% women). Results were separately discussed for the type of unpaid productive activity, namely, general caregiving (N = 10), spousal caregiving (N = 7), grandparental caregiving (N = 7), and volunteering (N = 6). Risk of bias assessments revealed a moderate to high quality of included studies. Loneliness was positively associated with spousal caregiving but negatively associated with caregiving to grandchildren and volunteering. Grandparental caregiving and volunteering may be promising avenues for reducing loneliness in older age. Future studies will need to distinguish between different types of caregiving and volunteering and explore more complex longitudinal designs with diverse samples to investigate causal relationships with loneliness. Spousal caregiving is associated with more loneliness Grandparental caregiving and volunteering are associated with less loneliness There is a lack of longitudinal evidence from lower- and middle-income countries [ABSTRACT FROM AUTHOR]

Introduction: C‐Reactive protein (CRP) and monocyte chemoattractant protein‐1 (MCP‐1) are both implicated in the peripheral proinflammatory cascade and blood‒brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP‐1 level exerts different effects on the AD risk depending on the genotypes. Methods: Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed. Results: An elevated blood MCP‐1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA‐DRB1) rs9271192‐AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50–6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59–6.53, p = 0.001). In contrast, among HLA‐DRB1 rs9271192‐AA and APOE ε4 noncarriers, blood MCP‐1 levels were not associated with these phenotypes. Discussion: Since HLA‐DRB1 and APOE are expressed in the BBB, blood MCP‐1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA‐DRB1 rs9271192‐AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways. [ABSTRACT FROM AUTHOR]

Older people's care provision is structurally undervalued, posing a threat to social connectedness and healthy aging. Thus, the question arises of how older people's care provision can be valued in diverse economies. By addressing this question, this article proposes a novel perspective by shedding light on the value of contributions older people provide to society, which in turn promote their own well-being. By highlighting evolutionary and proximal motives for older people to provide care, this article advances the theoretical understanding of the benefits of caregiving in the global aging context, going beyond previous successful aging approaches. These new directions aim to center older people's needs while accounting for their care provisions to fruitfully inform policymaking. Finally, the main challenge remaining for future work is to create adequate and valuable opportunities for older people to provide care as Homines curans. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMB) increase the risk for Alzheimer disease. Current neuroimaging methods that are used to detect CMB are costly and not always accessible., Objective: This study aimed to explore whether the digital clock-drawing test (DCT) may provide a behavioral indicator of CMB., Methods: In this study, we analyzed data from participants in the Framingham Heart Study offspring cohort who underwent both brain magnetic resonance imaging scans (Siemens 1.5T, Siemens Healthcare Private Limited; T2*-GRE weighted sequences) for CMB diagnosis and the DCT as a predictor. Additionally, paper-based clock-drawing tests were also collected during the DCT. Individuals with a history of dementia or stroke were excluded. Robust multivariable linear regression models were used to examine the association between DCT facet scores with CMB prevalence, adjusting for relevant covariates. Receiver operating characteristic (ROC) curve analyses were used to evaluate DCT facet scores as predictors of CMB prevalence. Sensitivity analyses were conducted by further including participants with stroke and dementia., Results: The study sample consisted of 1020 (n=585, 57.35% female) individuals aged 45 years and older (mean 72, SD 7.9 years). Among them, 64 (6.27%) participants exhibited CMB, comprising 46 with lobar-only, 11 with deep-only, and 7 with mixed (lobar+deep) CMB. Individuals with CMB tended to be older and had a higher prevalence of mild cognitive impairment and higher white matter hyperintensities compared to those without CMB (P<.05). While CMB were not associated with the paper-based clock-drawing test, participants with CMB had a lower overall DCT score (CMB: mean 68, SD 23 vs non-CMB: mean 76, SD 20; P=.009) in the univariate comparison. In the robust multiple regression model adjusted for covariates, deep CMB were significantly associated with lower scores on the drawing efficiency (β=-0.65, 95% CI -1.15 to -0.15; P=.01) and simple motor (β=-0.86, 95% CI -1.43 to -0.30; P=.003) domains of the command DCT. In the ROC curve analysis, DCT facets discriminated between no CMB and the CMB subtypes. The area under the ROC curve was 0.76 (95% CI 0.69-0.83) for lobar CMB, 0.88 (95% CI 0.78-0.98) for deep CMB, and 0.98 (95% CI 0.96-1.00) for mixed CMB, where the area under the ROC curve value nearing 1 indicated an accurate model., Conclusions: The study indicates a significant association between CMB, especially deep and mixed types, and reduced performance in drawing efficiency and motor skills as assessed by the DCT. This highlights the potential of the DCT for early detection of CMB and their subtypes, providing a reliable alternative for cognitive assessment and making it a valuable tool for primary care screening before neuroimaging referral., (©Samia C Akhter-Khan, Qiushan Tao, Ting Fang Alvin Ang, Cody Karjadi, Indira Swetha Itchapurapu, David J Libon, Michael Alosco, Jesse Mez, Wei Qiao Qiu, Rhoda Au. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.07.2024.)

Introduction: C-Reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) are both implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP-1 level exerts different effects on the AD risk depending on the genotypes., Methods: Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed., Results: An elevated blood MCP-1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA-DRB1) rs9271192-AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50-6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59-6.53, p = 0.001). In contrast, among HLA-DRB1 rs9271192-AA and APOE ε4 noncarriers, blood MCP-1 levels were not associated with these phenotypes., Discussion: Since HLA-DRB1 and APOE are expressed in the BBB, blood MCP-1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA-DRB1 rs9271192-AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways., (© 2022 the Alzheimer's Association.)

Background and Objectives: Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer disease (AD) risk only in APOE ε4 allele carriers; the objective of this study was to examine the interactive effects of plasma CRP and APOE genotype on cognition and AD biomarkers., Methods: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., mild cognitive impairment and dementia due to AD); Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Dementia Staging Instrument scores; CSF concentrations of β-amyloid peptide (Aβ 42 ), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes., Results: Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had 1, and 70 (12.4%) had 2 APOE ε 4 alleles. Among only participants who had 2 APOE ε4 alleles, elevated CRP was associated with lower MMSE score at baseline ( β [95% confidence interval] -0.52 [-1.01, -0.12]) and 12-month follow-up (β -1.09 [-1.88, -0.17]) after adjustment for sex, age, and education. The interaction of 2 APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (β = 11.21, SE 3.37, p < 0.001) and p-Tau (β = +2.74, SE 1.14, p < 0.01). Among those who had no APOE ε4 alleles, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at the 12-month follow-up., Discussion: CRP released during peripheral inflammation could be a mediator in APOE ε4-related AD neurodegeneration and serve as a drug target for AD., (© 2021 American Academy of Neurology.)

Background: Loneliness has drawn increasing attention over the past few decades due to rising recognition of its close connection with serious health issues, like dementia. Yet, researchers are failing to find solutions to alleviate the globally experienced burden of loneliness., Purpose: This review aims to shed light on possible reasons for why interventions have been ineffective. We suggest new directions for research on loneliness as it relates to precision health, emerging technologies, digital phenotyping, and machine learning., Results: Current loneliness interventions are unsuccessful due to (i) their inconsideration of loneliness as a heterogeneous construct and (ii) not being targeted at individuals' needs and contexts. We propose a model for how loneliness interventions can move towards finding the right solution for the right person at the right time. Taking a precision health approach, we explore how transdisciplinary research can contribute to creating a more holistic picture of loneliness and shift interventions from treatment to prevention., Conclusions: We urge the field to rethink metrics to account for diverse intra-individual experiences and trajectories of loneliness. Big data sharing and evolving technologies that emphasize human connection raise hope for realizing our model of precision health applied to loneliness. There is an urgent need for precise, integrated, and theory-driven interventions that focus on individuals' needs and the subjective burden of loneliness in the ageing context., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest regarding the contents of this manuscript.