The effect of apolipoprotein E genotype on spatial processing in humans: A meta-analysis and systematic review.

The ε4 allele of the apolipoprotein E (APOE4) gene is an established risk factor for Alzheimer's disease but its impact on cognition in healthy adults across the lifespan is unclear. One cognitive domain that is affected early in the course of Alzheimer's disease is spatial cognition, yet the evidence for APOE-related changes in spatial cognition is mixed. In this meta-analysis we assessed the impact of carrying the APOE4 allele on five subdomains of spatial cognition across the lifespan. We included studies of healthy human participants where an APOE4-carrier group (heterozygous or homozygous) could be compared to a homozygous group of APOE3-carriers. We identified 156 studies in total from three databases (Pubmed, Scopus and Web of Science) as well as through searching cited literature and contacting authors for unpublished data. 122 studies involving 32,547 participants were included in a meta-analysis, and the remaining studies are included in a descriptive review. APOE4 carriers scored significantly lower than APOE3 carriers (θˆ = -.08 [-.14, -.02]) on tests of spatial long-term memory; this effect was very small and was not modulated by age. On other subdomains of spatial cognition (spatial construction, spatial working memory, spatial reasoning, navigation) there were no effects of genotype. Overall, our results demonstrate that the APOE4 allele exerts little influence on spatial cognitive abilities in healthy adults.

Longitudinal Trajectories of Stress and Positive Aspects of Dementia Caregiving: Findings From the IDEAL Programme.

OBJECTIVES: Understanding what influences changes over time in caregiver well-being is important for the development of effective support. This study explores differences in trajectories of caregiver stress and positive aspects of caregiving (PAC). METHODS: Caregivers of community-dwelling individuals with mild-to-moderate dementia at baseline from the IDEAL cohort were interviewed at baseline (n = 1,203), 12 months (n = 917), and 24 months (n = 699). Growth mixture models identified multiple growth trajectories of caregiver stress and PAC in the caregiver population. Associations between study measures and trajectory classes were examined using multinomial logistic regression and mixed-effects models. RESULTS: Mean stress scores increased over time. A 4-class solution was identified: a "high" stable class (8.3%) with high levels of stress, a "middle" class (46.1%) with slightly increasing levels of stress, a "low" class (39.5%) with initial low levels of stress which slightly increased over time, and a small "increasing" class (6.1%) where stress level started low but increased at a steeper rate. Mean PAC scores remained stable over time. A 5-class solution was identified: 3 stable classes ("high," 15.2%; "middle," 67.6%; "low" 9.3%), a small "increasing" (3.4%) class, and 1 "decreasing" class (4.5%). For stable classes, positive ratings on study measures tended to be associated with lower stress or higher PAC trajectories and vice versa. Those with "increasing" stress also had worsening trajectories of several study measures including depression, relationship quality, competence, and ability to cope. DISCUSSION: The findings highlight the importance of identifying caregivers at risk of increased stress and declining PAC and offering them targeted support.

Health conditions in spousal caregivers of people with dementia and their relationships with stress, caregiving experiences, and social networks: longitudinal findings from the IDEAL programme.

OBJECTIVES: Longitudinal evidence documenting health conditions in spousal caregivers of people with dementia and whether these influence caregivers' outcomes is scarce. This study explores type and number of health conditions over two years in caregivers of people with dementia and subgroups based on age, sex, education, hours of care, informant-rated functional ability, neuropsychiatric symptoms, cognition of the person with dementia, and length of diagnosis in the person with dementia. It also explores whether over time the number of health conditions is associated with caregivers' stress, positive experiences of caregiving, and social networks METHODS: Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised spousal caregivers (n = 977) of people with dementia. Self-reported health conditions using the Charlson Comorbidity Index, stress, positive experiences of caregiving, and social network were assessed over two years. Mixed effect models were used RESULTS: On average participants had 1.5 health conditions at baseline; increasing to 2.1 conditions over two years. More health conditions were reported by caregivers who were older, had no formal education, provided 10 + hours of care per day, and/or cared for a person with more neuropsychiatric symptoms at baseline. More baseline health conditions were associated with greater stress at baseline but not with stress over time. Over two years, when caregivers' health conditions increased, their stress increased whereas their social network diminished DISCUSSION: Findings highlight that most caregivers have their own health problems which require management to avoid increased stress and shrinking of social networks.

Comorbid health conditions and their impact on social isolation, loneliness, quality of life, and well-being in people with dementia: longitudinal findings from the IDEAL programme.

BACKGROUND: Most people with dementia have multiple health conditions. This study explores (1) number and type of health condition(s) in people with dementia overall and in relation to age, sex, dementia type, and cognition; (2) change in number of health conditions over two years; and (3) whether over time the number of health conditions at baseline is related to social isolation, loneliness, quality of life, and/or well-being. METHODS: Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised people with dementia (n = 1490) living in the community (at baseline) in Great Britain. Health conditions using the Charlson Comorbidity Index, cognition, social isolation, loneliness, quality of life, and well-being were assessed over two years. Mixed effects modelling was used. RESULTS: On average participants had 1.8 health conditions at baseline, excluding dementia; increasing to 2.5 conditions over two years. Those with vascular dementia or mixed (Alzheimer's and vascular) dementia had more health conditions than those with Alzheimer's disease. People aged ≥ 80 had more health conditions than those aged < 65 years. At baseline having more health conditions was associated with increased loneliness, poorer quality of life, and poorer well-being, but was either minimally or not associated with cognition, sex, and social isolation. Number of health conditions had either minimal or no influence on these variables over time. CONCLUSIONS: People with dementia in IDEAL generally had multiple health conditions and those with more health conditions were lonelier, had poorer quality of life, and poorer well-being.

Long-term impact of the COVID-19 pandemic on the quality of life of people with dementia and their family carers.

INTRODUCTION: Few studies have longitudinally mapped quality of life (QoL) trajectories of newly diagnosed people with dementia and their carers, particularly during coronavirus disease-2019 (COVID-19). METHODS: In a UK cohort study, 261 newly diagnosed people with dementia and 206 family carers were assessed prior to the pandemic (July 2019-March 2020), followed up after the first lockdown (July-October 2020) and then again a year and 2 years later. Latent growth curve modelling examined the level and change of QoL over the four time-points using dementia-specific QoL measures (DEMQOL and C-DEMQOL). RESULTS: Despite variations in individual change scores, our results suggest that generally people with dementia maintained their QoL during the pandemic and experienced some increase towards the end of the period. This contrasted with carers who reported a general deterioration in their QoL over the same period. 'Confidence in future' and 'Feeling supported' were the only carer QoL subscales to show some recovery post-pandemic. DISCUSSION: It is positive that even during a period of global disruption, decline in QoL is not inevitable following the onset of dementia. However, it is of concern that carer QoL declined during this same period even after COVID-19 restrictions had been lifted. Carers play an invaluable role in the lives of people with dementia and wider society, and our findings suggest that, post-pandemic, they may require greater support to maintain their QoL.

Trajectories of cognitive and perceived functional decline in people with dementia: Findings from the IDEAL programme.

INTRODUCTION: Impaired cognition and instrumental activities of daily living (iADL) are key diagnostic features of dementia; however, few studies have compared trajectories of cognition and iADL. METHODS: Participants from the IDEAL study comprised 1537, 1183, and 851 people with dementia, and 1277, 977, and 749 caregivers at baseline, 12 and 24 months, respectively. Addenbrooke's Cognitive Examination-III and Functional Activities Questionnaire were used to measure cognition and iADL, respectively. Scores were converted to deciles. RESULTS: Self-rated iADL declined on average by -0.08 (-0.25, 0.08) decile points per timepoint more than cognition. Informant-rated iADL declined on average by -0.31 (-0.43, -0.18) decile points per timepoint more than cognition. DISCUSSION: Cognition and self-rated iADL declined at a similar rate. Informant-rated iADL declined at a significantly greater rate than cognition. Therefore, either cognition and perceived iADL decline at different rates or informants overestimate increasing iADL difficulties compared to both cognition and self-ratings. HIGHLIGHTS: Self-ratings of the degree of functional difficulties were consistent with cognition Decline in self-rated everyday activities was consistent with cognitive decline Informant-ratings of everyday activities declined more than cognition.

Dyadic perspectives on loneliness and social isolation among people with dementia and spousal carers: findings from the IDEAL programme.

OBJECTIVES: This study aims to investigate the impact of self and partner experiences of loneliness and social isolation on life satisfaction in people with dementia and their spousal carers. METHODS: We used data from 1042 dementia caregiving dyads in the Improving the experience of Dementia and Enhancing Active Life (IDEAL) programme cohort. Loneliness was measured using the six-item De Jong Gierveld loneliness scale and social isolation using the six-item Lubben Social Network Scale. Data were analysed using the Actor-Partner Interdependence Model framework. RESULTS: Self-rated loneliness was associated with poorer life satisfaction for both people with dementia and carers. The initial partner effects observed between the loneliness of the carer and the life satisfaction of the person with dementia and between social isolation reported by the person with dementia and life satisfaction of the carer were reduced to nonsignificance once the quality of the relationship between them was considered. DISCUSSION: Experiencing greater loneliness and social isolation is linked with reduced life satisfaction for people with dementia and carers. However, having a positive view of the quality of the relationship between them reduced the impact of loneliness and social isolation on life satisfaction. Findings suggest the need to consider the experiences of both the person with dementia and the carer when investigating the impact of loneliness and social isolation. Individual interventions to mitigate loneliness or isolation may enhance life satisfaction for both partners and not simply the intervention recipient.

Resilience in caregivers of people with mild-to-moderate dementia: findings from the IDEAL cohort.

OBJECTIVES: A novel model of resilience was tested in caregivers of people with mild-to-moderate dementia and was extended to explore whether including self-efficacy, optimism, and self-esteem improved its predictive value. DESIGN: Cross-sectional. SETTING: Data from the IDEAL cohort were used. PARTICIPANTS: The study comprised 1222 caregivers of people with dementia. MEASUREMENTS: A composite resilience score was calculated from five measures. Multivariable regressions were used to investigate factors associated with resilience. RESULTS: Greater resilience was associated with being older, being male, and caregiving for older people with dementia. Greater resilience was also observed when people with dementia had fewer functional difficulties and/or fewer neuropsychiatric symptoms, there was a stronger dyadic relationship, and the caregiver had fewer social restrictions, less neuroticism, and greater perceived competence. Surprisingly, caregiver self-efficacy, optimism, and self-esteem were unrelated to resilience. CONCLUSION: Caregivers of people with mild-to-moderate dementia generally scored well for resilience. Resilience was associated with both the personal characteristics of caregivers and level of care need among people with dementia. Future work is needed to determine whether the caregivers in this cohort appeared resilient because the care recipients had relatively low care needs and consequently placed fewer demands on caregiver well-being than would be the case where dementia is more advanced.

Emotion-focused dyadic coping styles used by family carers of people with dementia during the COVID-19 pandemic.

Emotional wellbeing of family carers and people with dementia is associated with not only how each individual copes with stress and conflict, but also by how they cope together. Finding ways to positively cope together was particularly important during COVID-19 lockdown restrictions, when other avenues of emotional support were less available. We explored how carers experienced and used emotion-focused dyadic coping styles during the COVID-19 pandemic. In-depth qualitative interviews were conducted during the pandemic with 42 family carers, supplemented by quality of life scores collected both pre- and during the pandemic and household status. Abductive thematic analysis identified five styles of emotion-focused dyadic coping: common, supportive, hostile, disengaged avoidance and protective. The COVID-19 pandemic left many dyads unsupported. While many carers adapted, reporting increases in quality of life and enjoying the extra time with the person with dementia, others experienced dyadic conflict and reductions in quality of life. This variation was associated with dyadic coping styles, including challenges in using 'positive' styles and the protective use of 'negative' disengaged avoidance in the right situations. Dyadic coping styles also differed as a function of whether the dyad lived together. As many people with dementia are supported by an informal carer, considering how they cope together could help us to better support them. We make suggestions for dyadic interventions tailored by co-residency status that could help dyads identify and communicate coping needs, reconnect following avoidance coping, and replenish their coping resources through social support.

Using digital technologies to facilitate social inclusion during the COVID-19 pandemic: Experiences of co-resident and non-co-resident family carers of people with dementia from DETERMIND-C19.

BACKGROUND: The COVID-19 pandemic triggered rapid and unprecedented changes in the use of digital technologies to support people's social inclusion. We examined whether and how co-resident and non-co-resident family carers of people with dementia engaged with digital technologies during this period. METHODS: Throughout November 2020-February 2021, we interviewed 42 family carers of people with dementia from our DETERMIND-C19 cohort. Preliminary analysis was conducted through Framework analysis, followed by an inductive thematic analysis. FINDINGS: Digital technologies served as a Facilitator for social inclusion by enabling carers to counter the effects of the differing restrictions imposed on them so they could remain socially connected and form a sense of solidarity, access resources and information, engage in social and cultural activities and provide support and independence in their caring role. However, these experiences were not universal as carers discussed some Challenges for tech inclusion, which included preferences for face-to-face contact, lack of technological literacy and issues associated with the accessibility of the technology. CONCLUSION: Many of the carers engaged with Information and Communication Technologies, and to a lesser extent Assistive Technologies, during the pandemic. Whilst carers experienced different challenges due to where they lived, broadly the use of these devices helped them realise important facets of social inclusion as well as facilitated the support they provided to the person with dementia. However, to reduce the 'digital divide' and support the social inclusion of all dementia carers, our findings suggest it is essential that services are attuned to their preferences, needs and technological abilities.

Predictors of loneliness during the Covid-19 pandemic in people with dementia and their carers in England: findings from the DETERMIND-C19 study.

OBJECTIVES: To identify factors that predict the risk of loneliness for people with dementia and carers during a pandemic. METHODS: People with dementia and their carers completed assessments before (July 2019-March 2020; 206 dyads) and after (July-October 2020) the first Covid-19 'lockdown' in England. At follow-up, the analytic sample comprised 67 people with dementia and 108 carers. We built a longitudinal path model with loneliness as an observed outcome. Carer type and social contacts at both measurements were considered. Other social resources (quality of relationship, formal day activities), wellbeing (anxiety, psychological wellbeing) and cognitive impairment were measured with initial level and change using latent growth curves. We adjusted for socio-demographic factors and health at baseline. RESULTS: In carers, higher levels of loneliness were directly associated with non-spouse coresident carer type, level and increase of anxiety in carer, more formal day activities, and higher cognitive impairment in the person with dementia. In people with dementia, non-spouse coresident carer type, and higher initial levels of social resources, wellbeing, and cognitive impairment predicted the changes in these factors; this produced indirect effects on social contacts and loneliness. CONCLUSION: Loneliness in the Covid-19 pandemic appears to be shaped by different mechanisms for people with dementia and their carers. The results suggest that carers of those with dementia may prioritize providing care that protects the person with dementia from loneliness at the cost of experiencing loneliness themselves. Directions for the promotion of adaptive social care during the Covid-19 pandemic and beyond are discussed.

Longitudinal Predictors of Informant-Rated Involvement of People with Dementia in Everyday Decision-Making: Findings from the IDEAL Program.

The extent to which people with dementia are involved in everyday decision-making is unclear. We explored informant-rated involvement of people with dementia in everyday decision-making over 2 years and whether functional, behavioral, and psychological factors related to the person with dementia and the caregiver explain variability in involvement of people with dementia in everyday decision-making. We used IDEAL data for 1182 people with dementia and their caregivers. Baseline mean score on the decision-making involvement scale was 31/45; it minimally declined over time. People with dementia who were female, single, and/or whose caregiver was younger had greater involvement in everyday decision-making than those without these characteristics. Better cognition, fewer functional difficulties, fewer neuropsychiatric symptoms, less caregiver stress, and better informant-rated relationship quality were associated with higher involvement in everyday decision-making. Cognitive and functional rehabilitation, and educational resources for caregivers, could prolong involvement of people with dementia in everyday decision-making.

Attitudes toward own aging and cognition among individuals living with and without dementia: findings from the IDEAL programme and the PROTECT study.

BACKGROUND: It is unclear whether people with dementia (PwD) have more negative attitudes toward own aging (ATOA) than people without dementia and what factors influence ATOA among PwD. We investigated whether PwD have more negative ATOA than individuals without dementia and whether cognition and dementia subtype are associated with ATOA in PwD. METHODS: Data from the IDEAL and PROTECT studies were used to compare ATOA between 1502 PwD (mean (SD) age = 76.3 (8.5)) and 6377 individuals without dementia (mean (SD) age = 66.1 (7.1)). Linear regressions and ANOVA were used. RESULTS: PwD reported slightly more negative ATOA than people without dementia; this relationship disappeared after controlling for depression and self-rated health. In PwD more positive ATOA showed negligible associations with better general cognition, memory performance, verbal fluency, and visuospatial ability. However, after adjusting for covariates only better visuospatial ability predicted more positive ATOA. Additional analyses showed that before and after controlling for covariates, individuals with poorer self-reported visual acuity have more negative ATOA. Amongst dementia subtypes, people with Parkinson's disease dementia and dementia with Lewy bodies reported most negative ATOA. CONCLUSIONS: ATOA between PwD and people without dementia do not differ. ATOA in PwD appear to be affected not by cognitive impairment but by other characteristics that vary across dementia subtypes. Among PwD, those with Parkinson's disease dementia and dementia with Lewy bodies may have higher risk of experiencing negative ATOA due to the motor and visual impairments that they experience.

"Living Well" Trajectories Among Family Caregivers of People With Mild-to-Moderate Dementia in the IDEAL Cohort.

OBJECTIVES: Understanding whether and how caregivers' capability to "live well" changes over time, and the factors associated with change, could help target effective caregiver support. METHODS: We analyzed 3 time points (12 months apart) of Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort data from coresident spouse caregivers of community-dwelling individuals who had mild-to-moderate dementia at baseline, using latent growth and growth mixture models. Capability to "live well" was derived from measures of quality of life, well-being, and satisfaction with life. RESULTS: Data from 995 spouse caregivers at Time 1, 780 at Time 2, and 601 at Time 3 were included. The mean "living well" score decreased slightly over time. We identified 3 classes of caregivers: one with higher baseline scores declining slightly over time (Stable; 66.8%), one with low baseline scores remaining stable (Lower Stable; 26.0%), and one with higher baseline scores showing marked decline (Declining; 7.2%). Scores on baseline measures differentiated the Lower Stable, but not the Declining, from the Stable class. Longitudinally, the Declining class was associated with care recipient cognitive decline and increasing hours providing care, as well as caregiver stress and depression. Findings were similar when caregivers with other kin relationships were included. DISCUSSION: The findings indicate the importance of prompt identification of, and support for, caregivers at risk of the declining capability to "live well" and may assist in identifying those caregivers who could benefit most from targeted support.

Night-to-night variation in sleep associates with day-to-day variation in vigilance, cognition, memory, and behavioral problems in Alzheimer's disease.

Introduction: Sleep disturbances are commonly reported in people living with Alzheimer's disease (AD), but it is currently unknown whether night-to-night variation in sleep predicts day-to-day variation in vigilance, cognition, mood, and behavior (daytime measures). Methods: Subjective and objective sleep and daytime measures were collected daily for 2 weeks in 15 participants with mild AD, eight participants with mild cognitive impairment (MCI), and 22 participants with no cognitive impairment (NCI). Associations between daytime measures and four principal components of sleep (duration, quality, continuity, and latency) were quantified using mixed-model regression. Results: Sleepiness, alertness, contentedness, everyday memory errors, serial subtraction, and behavioral problems were predicted by at least one of the components of sleep, and in particular sleep duration and continuity. Associations between variations in sleep and daytime measures were linear or quadratic and often different between participants with AD and those with NCI. Discussion: These findings imply that daytime functioning in people with AD may be improved by interventions that target sleep continuity.

Characteristics of people living with undiagnosed dementia: findings from the CFAS Wales study.

BACKGROUND: Many people living with dementia remain undiagnosed, with diagnosis usually occurring long after signs and symptoms are present. A timely diagnosis is important for the wellbeing of the person living with dementia and the family, allowing them to plan and have access to support services sooner. The aim of this study was to identify demographic characteristics and neuropsychiatric symptoms associated with being undiagnosed, which may help clinicians be more aware of signs that could be indicative of early-stage or undetected dementia. METHODS: This cross-sectional study uses data from waves 1 and 2 (two years apart) of the Cognitive Function and Ageing Studies Wales (CFAS Wales). CFAS Wales participants were included who had a study assessment of dementia, as determined by the Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT) algorithm and by expert assessment, and who had had their primary care records checked for a clinical diagnosis of dementia. We identified 19 people with a diagnosis of dementia and 105 people living with undiagnosed dementia, and explored demographic characteristics and the presence or absence of a range of neuropsychiatric symptoms in the undiagnosed population using logistic regression. RESULTS: Findings suggest that people living with dementia who have better cognition, have more years of education, or live in more deprived areas are less likely to have a diagnosis. In terms of neuropsychiatric symptoms, depression and sleep problems were associated with being undiagnosed. Apathy was common across all people living with dementia, but those with a diagnosis were more likely to have severe apathy. CONCLUSIONS: This study has clinical practice implications as the findings may help clinicians be more aware of characteristics and symptoms of people who are undiagnosed or who are at greater risk of remaining undiagnosed, enabling them to be more vigilant in picking up signs of dementia at an earlier stage.

Predictors of Awareness of Functional Ability in People with Dementia: The Contribution of Personality, Cognition, and Neuropsychiatric Symptoms - Findings from the IDEAL Program.

INTRODUCTION: Discrepancy scores reflecting the difference between parallel ratings made by people living with dementia (PwD) in the mild-to-moderate stages and by their informants provide a way to investigate awareness of functional ability in relation to activities of daily living (ADL). METHODS: Two measures of ADL (Functional Activities Questionnaire; Dependence Scale) were completed by 1,227 PwD and their informants in the IDEAL cohort study baseline assessment. Self-rated and informant-rated scores were used to calculate discrepancies, which were used as an indicator of awareness of functional ability. Smaller discrepancy scores were considered to reflect greater awareness on the part of PwD. PwD completed questionnaires on depression, personality, comorbidities, neuropsychiatric symptoms, and completed a measure of cognition. Informants provided ratings of stress. Univariable and multiple regressions were used to investigate factors related to ADL discrepancy. RESULTS: A similar pattern of associations were found for both ADL discrepancy scores. Smaller discrepancy scores were associated with higher levels of depression, higher neuroticism, fewer neuropsychiatric symptoms, higher comorbidity, lower carer stress, and receipt of less than 1 hour of care per day from the informant. DISCUSSION/CONCLUSION: There was a clear pattern of factors that were associated with greater awareness for both measures of functional ability. These factors associated with smaller discrepancy scores could be used to identify PwD who might benefit from targeted interventions to support their independence.

A cohort study of the impact of COVID-19 on the quality of life of people newly diagnosed with dementia and their family carers.

Introduction: COVID-19 has impacted people with dementia and their family carers, yet little is known about effects on overall quality of life. Methods: In a UK cohort study, pre- and post-pandemic data were collected from 114 carers and 93 recently diagnosed people with dementia. Latent growth curve modeling examined change in quality of life. Results: Carers reported significant decline in quality of life, although no change was demonstrated by people with dementia. In multivariable analyses, higher levels of cognitive impairment, deprivation, study site, and lower number of memory clinic contacts were associated with greater decline in carer quality of life. Discussion: Maintaining life quality for people with dementia during the pandemic appears to have come at the expense of their family carers. This inequity has fallen hardest on those caring for people with more severe dementia, in deprived areas, and with least support from memory services. These effects may be prevented or reversed by post-diagnostic care.

A multi-hit hypothesis for an APOE4-dependent pathophysiological state.

The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease-related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi-hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi-hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE-centric literature.

Longitudinal Trajectories of Quality of Life Among People With Mild-to-Moderate Dementia: A Latent Growth Model Approach With IDEAL Cohort Study Data.

OBJECTIVES: We aimed to examine change over time in self-rated quality of life (QoL) in people with mild-to-moderate dementia and identify subgroups with distinct QoL trajectories. METHODS: We used data from people with mild-to-moderate dementia followed up at 12 and 24 months in the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort study (baseline n = 1,537). A latent growth model approach examined mean change over time in QoL, assessed with the QoL-AD scale, and investigated associations of baseline demographic, cognitive, and psychological covariates with the intercept and slope of QoL. We employed growth mixture modeling to identify multiple growth trajectories. RESULTS: Overall mean QoL scores were stable and no associations with change over time were observed. Four classes of QoL trajectories were identified: 2 with higher baseline QoL scores, labeled Stable (74.9%) and Declining (7.6%), and 2 with lower baseline QoL scores, labeled Stable Lower (13.7%) and Improving (3.8%). The Declining class had higher baseline levels of depression and loneliness, and lower levels of self-esteem and optimism, than the Stable class. The Stable Lower class was characterized by disadvantage related to social structure, poor physical health, functional disability, and low psychological well-being. The Improving class was similar to the Stable Lower class but had lower cognitive test scores. DISCUSSION: Understanding individual trajectories can contribute to personalized care planning. Efforts to prevent decline in perceived QoL should primarily target psychological well-being. Efforts to improve QoL for those with poorer QoL should additionally address functional impairment, isolation, and disadvantage related to social structure.