We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, ...variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR 95% CI = 1.54 1.310-1.820). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.
Alzheimer's disease (AD) affects Latinos disproportionately. One of the reasons underlying this disparity may be type 2 diabetes (T2D) that is a risk factor for AD. The purpose of this study was to ...examine the associations of T2D and AD blood biomarkers and the differences in these associations between Mexican Americans and non-Hispanic Whites. This study was a secondary analysis of baseline data from the observational Health and Aging Brain Study: Health Disparities (HABS-HD) that investigated factors underlying health disparities in AD in Mexican Americans in comparison to non-Hispanic Whites. HABS-HD participants were excluded if they had missing data or were large outliers (z-scores >|4|) on a given AD biomarker. Fasting blood glucose and glycosylated hemoglobin (HbA1c) levels were measured from clinical labs. T2D was diagnosed by licensed clinicians. Plasma amyloid-beta 42 and 40 (Aβ42/42) ratio, total tau (t-tau), and neurofilament light (NfL) were measured via ultra-sensitive Simoa assays. The sample sizes were 1,552 for Aβ42/40 ratio, 1,570 for t-tau, and 1,553 for NfL. Mexican Americans were younger (66.6±8.7 vs. 69.5±8.6) and had more female (64.9% female vs. 55.1%) and fewer years of schooling (9.5±4.6 vs. 15.6±2.5) than non-Hispanic Whites. Mexican Americans differed significantly from non-Hispanic Whites in blood glucose (113.5±36.6 vs. 99.2±17.0) and HbA1c (6.33±1.4 vs. 5.51±0.6) levels, T2D diagnosis (35.3% vs. 11.1%), as well as blood Aβ42/40 ratio (.051±.012 vs. .047±.011), t-tau (2.56±.95 vs. 2.33±.90), and NfL levels (16.3±9.5 vs. 20.3±10.3). Blood glucose, blood HbA1c, and T2D diagnosis were not related to Aβ42/40 ratio and t-tau but explained 3.7% of the variation in NfL (p < .001). Blood glucose and T2D diagnosis were not, while HbA1c was positively (b = 2.31, p < .001, β = 0.26), associated with NfL among Mexican Americans. In contrast, blood glucose, HbA1c, and T2D diagnosis were negatively (b = -0.09, p < .01, β = -0.26), not (b = 0.34, p = .71, β = 0.04), and positively (b = 3.32, p < .01, β = 0.33) associated with NfL, respectively in non-Hispanic Whites. To conclude, blood glucose and HbA1c levels and T2D diagnosis are associated with plasma NfL levels, but not plasma Aβ and t-tau levels. These associations differ in an ethnicity-specific manner and need to be further studied as a potential mechanism underlying AD disparities.
Objective
To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the ...population‐attributable risk for dementia in older black and white persons.
Methods
A total of 4,015 community‐based persons (28% black; 74% women; mean baseline age = 78 years) were enrolled in 1 of 4 longitudinal cohort studies, and another 2,937 in a population‐based cohort. Memory scores, assessed using 2 questions (5‐point Likert scales) were categorized as complaints present or absent. Global cognition and 5 cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1,350 deceased subjects with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology.
Results
Baseline memory complaints (n = 1,310; 33% of 4,015) were associated with lower cognition and faster decline in all domains (global score estimate = −0.032, standard error = 0.004, p < 0.0001), during a mean follow‐up of 6 (standard deviation = 2) years. Persons with memory complaints had higher dementia risk (hazard ratio = 1.64, 95% confidence interval CI = 1.42–1.89) and odds of pathologic Alzheimer disease (odds ratio OR = 1.96, 95% CI = 1.51–2.54), neocortical Lewy bodies (OR = 2.47, 95% CI = 1.54–3.96), and other neurodegenerative pathologies. Results for dementia risk were similar among blacks and whites. Among 2,937 older persons in a population‐based cohort with similar data, the population‐attributable risk for incident dementia due to memory complaints was 14.0% (95% CI = 2.6–23.0), and did not vary between the black and white groups.
Interpretation
Memory complaints are common in older black and white persons, and relate to cognitive decline, dementia risk, and neurodegenerative pathologies. Ann Neurol 2018;83:718–729
Strong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in ...life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP≥135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.
Strong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in ...life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP = 135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.
Alzheimer's disease (AD) is not a normal part of aging, but many people develop AD as they age, and it is the seventh leading cause of death in the US. AD is a neurological condition that begins as ...mild cognitive impairment (MCI) or mild AD dementia. To understand the medical journey of patients with MCI or mild AD dementia, we surveyed 103 patients with MCI or mild AD dementia, 150 care partners, and 301 doctors. Patients had several symptoms before talking to a doctor, including forgetfulness and short-term memory loss; most patients (64%) first discussed these symptoms with a primary care physician (PCP) on average 15 months later. However, most patients were not diagnosed or treated by a PCP for MCI or mild AD dementia. We asked patients/care partners who they believe is the coordinator of their care for MCI and mild AD dementia. Thirty-seven percent felt the PCP was the coordinator of care. Most surveyed PCPs (74%) considered themselves to be the coordinator of care for their patients with MCI or mild AD dementia. In conclusion, PCPs play a key role in the care of patients with MCI and mild AD dementia. It is important for patients and care partners to understand the symptoms of MCI and mild AD dementia, and the need to get a diagnosis and treatment soon after symptoms appear. PCPs can play an important role in early diagnosis and treatment and serve as coordinators of care for their patients with MCI and mild AD dementia.
Early diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia is crucial for effective disease management and optimizing patient outcomes. We sought to better understand the MCI and mild AD dementia medical journey from the perspective of patients, care partners, and physicians.
We conducted online surveys in the United States among patients/care partners and physicians in 2021.
103 patients with all-cause MCI or mild AD dementia aged 46-90 years, 150 care partners for someone with all-cause MCI or mild AD dementia, and 301 physicians (101 of which were primary care physicians, PCPs) completed surveys. Most patient/care partners reported that experiencing forgetfulness (71%) and short-term memory loss (68%) occurred before talking to a healthcare professional. Most patients (73%) followed a common medical journey, in which the initial discussion with a PCP took place 15 months after symptom onset. However, only 33% and 39% were diagnosed and treated by a PCP, respectively. Most (74%) PCPs viewed themselves as coordinators of care for their patients with MCI and mild AD dementia. Over one-third (37%) of patients/care partners viewed PCPs as the care coordinator.
PCPs play a vital role in the timely diagnosis and treatment of MCI and mild AD dementia but often are not considered the care coordinator. For the majority of patients, the initial discussion with a PCP took place 15 months after symptom onset; therefore, it is important to educate patients/care partners and PCPs on MCI and AD risk factors, early symptom recognition, and the need for early diagnosis and treatment. PCPs could improve patient care and outcomes by building their understanding of the need for early AD diagnosis and treatment and improving the efficiency of the patient medical journey by serving as coordinators of care.
Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although ...apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
We examined the relationship of diabetes and hemoglobin A1C (A1C) to 2 common causes of dementia. The study included 1228 subjects who underwent annual clinical evaluations and a brain autopsy at ...death, as part of a Rush longitudinal cohort study of aging. A total of 433 subjects had A1C data available. Neuropathologic evaluations documented the size and location of infarcts. Modified silver stain-based Alzheimer disease (AD) measures included global and regional scores. We used regression analyses to examine associations of diabetes and A1C with overall and regional neuropathology. Diabetes odds ratio (OR)=0.94; 95% confidence interval (CI), 0.73-1.20) and A1C (OR=0.83; 95% CI, 0.62-1.10) were not associated with global AD pathology across the brain, nor with overall or individual measures of neuropathology in mesial temporal or neocortical regions separately (all P>0.05). Diabetes was associated with a higher odds of any infarct (OR=1.43; 95% CI, 1.07-1.90), and particularly with gross (OR=1.53; 95% CI, 1.14-2.06) but not microinfarcts (P=0.06), and subcortical (OR=1.79; 95% CI, 1.34-2.39) but not cortical infarcts (P=0.83). In summary, we found no relationship of diabetes or A1C with global or regional AD pathology, including in the mesial temporal lobe. Diabetes is associated with gross subcortical infarcts. Our results suggest that the diabetes-dementia link is based on subcortical vascular pathology and not on regional AD pathology.
Background
While physical activity (PA) may promote resilience to cognitive decline and AD dementia, the mechanisms underlying this effect are poorly understood. Our group previously demonstrated ...lower levels of functional connectivity (rs‐fcMRI) in the default, salience, and control networks were associated with greater prospective cognitive decline, both alone and synergistically with β‐amyloid (Buckley and Schultz et al., 2017). In this context, we assessed whether higher PA may be associated with greater connectivity, and whether PA effects on connectivity may mediate the relationship of PA to prospective cognitive decline.
Method
A waist mounted pedometer was used to record PA (steps/day during one week) in 167 cognitively unimpaired adults aged 63‐90 (mean 74.0; SD 6.1) participating in the Harvard Aging Brain Study. Participants underwent baseline rs‐fcMRI and β‐amyloid imaging with Pittsburgh Compound B PET. We analyzed rs‐fcMRI in the 3 networks previously associated with cognitive decline (default, salience, and control) as well as in 4 motor or sensory networks in which connectivity strength is not associated with cognitive change. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC). We used linear regression to examine associations between PA and connectivity in these networks, controlling for age, sex, and APOE e4 status. We conducted exploratory analyses using linear mixed effects models to examine if associations between PA and connectivity strength may partially explain PA associations with cognitive decline in the context of elevated β‐amyloid.
Result
Higher baseline PA was significantly associated with increased connectivity in the default, salience, and control networks (all p<0.017) after adjusting for covariates and controlling for multiple comparisons. PA was not associated with connectivity in any of the other networks examined. Greater connectivity in these networks was a weak partial mediator of PA's association with longitudinal PACC decline in participants with elevated β‐amyloid (figure 1).
Conclusion
Greater PA is associated with increased connectivity in three networks (default, salience, and control) in which greater connectivity is associated with less cognitive decline. One potential mechanism by which PA may promote resilience to cognitive decline is through increased functional connectivity in a core set of AD‐relevant cognitive networks.
Introduction
Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline ...in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aβ), remains unclear.
Methods
We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aβ. We next examined associations between cytokine levels and neuroimaging biomarkers of Aβ/tau/neurodegeneration.
Results
Higher IL‐12p70 was associated with slower cognitive decline in the setting of higher Aβ (false discovery rate FDR = 0.0023), whereas higher IFN‐γ was associated with slower cognitive decline independent of Aβ (FDR = 0.013). Higher IL‐12p70 was associated with less tau and neurodegeneration in participants with higher Aβ.
Discussion
Immune dysregulation is implicated in early‐stage cognitive decline, and greater IL‐12/IFN‐γ axis activation may be protective against cognitive decline and early‐stage AD progression.
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