APOE epsilon variants and composite risk of dementia, disability, and death in the health and retirement study.

BACKGROUND: Clinical trials in older adults are increasingly focused on functional outcomes, and the composite outcome of dementia, disability, and death is gaining pivotal importance. Genetic variation, particularly the APOE epsilon(ε) variants, may modify responses to new treatments. Although APOE ε4 is known to influence these outcomes separately, the magnitude of its effect on this composite outcome remains unknown. We tested the hypothesis that APOE ε4 increases, whereas APOE ε2 decreases, the risk of a composite outcome of dementia, disability, and death. METHODS: We evaluated clinical and genomic data from the Health and Retirement Study collected from 1992 to 2020. We used variants rs429358 and rs7412 to determine APOE genotypes, modeled dominantly (carriers/noncarriers). We conducted survival analysis, using multivariable Cox proportional hazards models with a composite endpoint of dementia, disability, and death. Our primary analysis evaluated participants with genetic data and no previous dementia or disability. In secondary analyses, we focused on persons aged > = 75 years without heart disease or stroke, a subpopulation increasingly important in clinical trials of older adults. RESULTS: We included 14,527 participants in the primary analysis. Over a median of 18 (Interquartile Range [IQR] 12-24) years, 6711 (46%) participants developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.15, 95%CI:1.09-1.22) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.92, 95%CI:0.86-0.99). In the secondary analysis, we included 3174 participants. Over a median of 7 (IQR 4-11) years, 1326 participants (42%) developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.25, 95%CI:1.10-1.41) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.84, 95%CI:0.71-0.98). CONCLUSIONS: APOE ε variants are linked to the risk of dementia, disability, and death in older adults. By examining these variants in clinical trials, we can better elucidate how they might alter the effectiveness of tested interventions. Importantly, this genetic information could help identify participants who may have greater absolute benefit from such interventions.

Bidirectional relationship between epigenetic age and brain health events.

Chronological age offers an imperfect estimate of the molecular changes that occur with aging. Epigenetic age, which is derived from DNA methylation data, provides a more nuanced representation of aging-related biological processes. This study examines the bidirectional relationship between epigenetic age and the occurrence of brain health events (stroke, dementia, and late-life depression). Using data from the Health and Retirement Study, we analyzed blood samples from over 4,000 participants to determine how epigenetic age relates to past and future brain health events. Study participants with a prior brain health event prior to blood collection were 4% epigenetically older (beta 0.04, SE 0.01), suggesting that these conditions are associated with faster aging than that captured by chronological age. Furthermore, a one standard deviation increase in epigenetic age was associated with 70% higher odds of experiencing a brain health event in the next four years after blood collection (OR 1.70, 95%CI 1.16-2.50), indicating that epigenetic age is not just a consequence but also a predictor of poor brain health. Both results were replicated through Mendelian Randomization analyses, supporting their causal nature. Our findings support the utilization of epigenetic age as a useful biomarker to evaluate the role of interventions aimed at preventing and promoting recovery after a brain health event.

Suboptimal Sleep Duration Is Associated With Poorer Neuroimaging Brain Health Profiles in Middle-Aged Individuals Without Stroke or Dementia.

BACKGROUND: The American Heart Association's Life's Simple 7, a public health construct capturing key determinants of cardiovascular health, became the Life's Essential 8 after the addition of sleep duration. The authors tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults. METHODS AND RESULTS: The authors conducted a prospective magnetic resonance neuroimaging study in middle-aged individuals without stroke or dementia enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (<7 hours), optimal (7-<9 hours), or long (≥9 hours). Evaluated neuroimaging markers included the presence of white matter hyperintensities (WMHs), volume of WMH, and fractional anisotropy, with the latter evaluated as the average of 48 white matter tracts. Multivariable logistic and linear regression models were used to test for an association between sleep duration and these neuroimaging markers. The authors evaluated 39 771 middle-aged individuals. Of these, 28 912 (72.7%) had optimal, 8468 (21.3%) had short, and 2391 (6%) had long sleep duration. Compared with optimal sleep, short sleep was associated with higher risk of WMH presence (odds ratio, 1.11 [95% CI, 1.05-1.18]; P<0.001), larger WMH volume (beta=0.06 [95% CI, 0.04-0.08]; P<0.001), and worse fractional anisotropy profiles (beta=-0.04 [95% CI, -0.06 to -0.02]; P=0.001). Compared with optimal sleep, long sleep duration was associated with larger WMH volume (beta=0.04 [95% CI, 0.01-0.08]; P=0.02) and worse fractional anisotropy profiles (beta=-0.06 [95% CI, -0.1 to -0.02]; P=0.002), but not with WMH presence (P=0.6). CONCLUSIONS: Among middle-aged adults without stroke or dementia, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because these neuroimaging markers precede stroke and dementia by several years, these findings are consistent with other findings evaluating early interventions to improve this modifiable risk factor.

APOE ε4 and Intracerebral Hemorrhage in Patients With Brain Arteriovenous Malformation.

Importance: Intracerebral hemorrhage (ICH) is a serious complication of brain arteriovenous malformation (AVM). Apolipoprotein E (APOE) ε4 is a well-known genetic risk factor for ICH among persons without AVM, and cerebral amyloid angiopathy is a vasculopathy frequently observed in APOE ε4 carriers that may increase the risk of ICH. Objective: To assess whether APOE ε4 is associated with a higher risk of ICH in patients with a known AVM. Design, Setting, and Participants: This cross-sectional study including 412 participants was conducted in 2 stages (discovery and replication) using individual-level data from the UK Biobank (released March 2012 and last updated October 2023) and the All of Us Research Program (commenced on May 6, 2018, with its latest update provided in October 2023). The occurrence of AVM and ICH was ascertained at the time of enrollment using validated International Classification of Diseases, Ninth Revision and Tenth Revision, codes. Genotypic data on the APOE variants rs429358 and rs7412 were used to ascertain the ε status. Main Outcomes and Measures: For each study, the association between APOE ε4 variants and ICH risk was assessed among patients with a known AVM by using multivariable logistic regression. Results: The discovery phase included 253 UK Biobank participants with known AVM (mean [SD] age, 56.6 [8.0] years, 119 [47.0%] female), of whom 63 (24.9%) sustained an ICH. In the multivariable analysis of 240 participants of European ancestry, APOE ε4 was associated with a higher risk of ICH (odds ratio, 4.58; 95% CI, 2.13-10.34; P < .001). The replication phase included 159 participants with known AVM enrolled in All of Us (mean [SD] age, 57.1 [15.9] years; 106 [66.7%] female), of whom 29 (18.2%) sustained an ICH. In multivariable analysis of 101 participants of European ancestry, APOE ε4 was associated with higher risk of ICH (odds ratio, 4.52; 95% CI, 1.18-19.38; P = .03). Conclusions and Relevance: The results of this cross-sectional study of patients from the UK Biobank and All of Us suggest that information on APOE ε4 status may help identify patients with brain AVM who are at particularly high risk of ICH and that cerebral amyloid angiopathy should be evaluated as a possible mediating mechanism of the observed association.

Brain Care Score and Neuroimaging Markers of Brain Health in Asymptomatic Middle-Age Persons.

OBJECTIVES: To investigate associations between health-related behaviors as measured using the Brain Care Score (BCS) and neuroimaging markers of white matter injury. METHODS: This prospective cohort study in the UK Biobank assessed the BCS, a novel tool designed to empower patients to address 12 dementia and stroke risk factors. The BCS ranges from 0 to 21, with higher scores suggesting better brain care. Outcomes included white matter hyperintensities (WMH) volume, fractional anisotropy (FA), and mean diffusivity (MD) obtained during 2 imaging assessments, as well as their progression between assessments, using multivariable linear regression adjusted for age and sex. RESULTS: We included 34,509 participants (average age 55 years, 53% female) with no stroke or dementia history. At first and repeat imaging assessments, every 5-point increase in baseline BCS was linked to significantly lower WMH volumes (25% 95% CI [23%-27%] first, 33% [27%-39%] repeat) and higher FA (18% [16%-20%] first, 22% [15%-28%] repeat), with a decrease in MD (9% [7%-11%] first, 10% [4%-16%] repeat). In addition, a higher baseline BCS was associated with a 10% [3%-17%] reduction in WMH progression and FA decline over time. DISCUSSION: This study extends the impact of the BCS to neuroimaging markers of clinically silent cerebrovascular disease. Our results suggest that improving one's BCS could be a valuable intervention to prevent early brain health decline.

Suboptimal Sleep Duration is Associated with Poorer Neuroimaging Brain Health Profiles.

Background: Cardiovascular health optimization during middle age benefits brain health. The American Heart Association's Life's Simple 7 recently added sleep duration as a key determinant of cardiovascular health becoming the Life's Essential 8. We tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults. Methods: We conducted a prospective MRI neuroimaging study in middle-aged persons without stroke, dementia, or multiple sclerosis enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (<7 hours), optimal (7-<9 hours), or long (≥9 hours). Evaluated neuroimaging markers of brain health included white matter hyperintensities (presence and volume) and diffusion tensor imaging metrics (fractional anisotropy and mean diffusivity) evaluated in 48 distinct neuroanatomical regions. We used multivariable logistic and linear regression models, as appropriate, to test for association between sleep duration and neuroimaging markers of brain health. Results: We evaluated 39,502 middle-aged persons (mean age 55, 53% female). Of these, 28,712 (72.7%) had optimal, 8,422 (21.3%) short, and 2,368 (6%) long sleep. Compared to optimal sleep, short sleep was associated with higher risk (OR 1.11; 95% CI 1.05-1.17; P<0.001) and larger volume (beta=0.06, SE=0.01; P<0.001) of white matter hyperintensities, while long sleep was associated with higher volume (beta=0.04, SE=0.02; P=0.01) but not higher risk (P>0.05) of white matter hyperintensities. Short (beta=0.03, SE=0.01; P=0.004) and long sleep (beta=0.07, SE=0.02; P<0.001) were associated with worse fractional anisotropy, while only long sleep associated with worse mean diffusivity (beta=0.05, SE=0.02; P=0.005). Conclusions: Among middle-aged adults without clinically observed neurological disease, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because the evaluated neuroimaging markers precede stroke and dementia by several years, our findings support early interventions aimed at correcting this modifiable risk factor.

Polygenic Risk of Epilepsy and Post-Stroke Epilepsy.

Background and Aims: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in post-acute brain injury epilepsy remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises post-stroke or Transient Ischemic Attack (TIA) survivor's risk of Post-Stroke Epilepsy (PSE). Methods: We conducted a three-stage genetic analysis. First, we identified independent epilepsy-associated ( p <5x10 -8 ) genetic variants from public data. Second, we estimated PSE-specific variant weights in stroke/TIA survivors from the UK Biobank. Third, we tested for an association between a polygenic risk score (PRS) and PSE risk in stroke/TIA survivors from the All of Us Research Program. Primary analysis included all ancestries, while a secondary analysis was restricted to European ancestry only. A sensitivity analysis excluded TIA survivors. Association testing was conducted via multivariable logistic regression, adjusting for age, sex, and genetic ancestry. Results: Among 19,708 UK Biobank participants with stroke/TIA, 805 (4.1%) developed PSE. Likewise, among 12,251 All of Us participants with stroke/TIA, 394 (3.2%) developed PSE. After establishing PSE-specific weights for 39 epilepsy-linked genetic variants in the UK Biobank, the resultant PRS was associated with elevated odds of PSE development in All of Us (OR:1.16[1.02-1.32]). A similar result was obtained when restricting to participants of European ancestry (OR:1.23[1.02-1.49]) and when excluding participants with a TIA history (OR:1.18[1.02-1.38]). Conclusions: Our findings suggest that akin to other forms of epilepsy, genetic predisposition plays an essential role in PSE. Because the PSE data were sparse, our results should be interpreted cautiously.

Current Advances in Immunotherapy for Glioblastoma Multiforme and Future Prospects.

Glioblastoma is the most frequent and malignant type of brain tumor. It has a reputation for being resistant to current treatments, and the prognosis is still bleak. Immunotherapies have transformed the treatment of a variety of cancers, and they provide great hope for glioblastoma, although they have yet to be successful. The justification for immune targeting of glioblastoma and the obstacles that come with treating these immunosuppressive tumors are reviewed in this paper. Cancer vaccines, oncolytic viruses (OVs), checkpoint blockade medications, adoptive cell transfer (ACT), chimeric antigen receptor (CAR) T-cells, and nanomedicine-based immunotherapies are among the novel immune-targeting therapies researched in glioblastoma. Key clinical trial outcomes and current trials for each method are presented from a clinical standpoint. Finally, constraints, whether biological or due to trial design, are discussed, along with solutions for overcoming them. In glioblastoma, proof of efficacy for immunotherapy approaches has yet to be demonstrated, but our rapidly growing understanding of the disease's biology and immune microenvironment, as well as the emergence of novel promising combinatorial approaches, may allow researchers to finally meet the medical need for patients with glioblastoma multiforme (GBM).