The associations between type 2 diabetes and plasma biomarkers of Alzheimer's disease in the Health and Aging Brain Study: Health Disparities (HABS-HD).

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 (Aß42/42) ratio, total tau (t-tau), and neurofilament light (NfL) were measured via ultra-sensitive Simoa assays. The sample sizes were 1,552 for Aß42/40 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 Aß42/40 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 Aß42/40 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, ß = 0.26), associated with NfL among Mexican Americans. In contrast, blood glucose, HbA1c, and T2D diagnosis were negatively (b = -0.09, p < .01, ß = -0.26), not (b = 0.34, p = .71, ß = 0.04), and positively (b = 3.32, p < .01, ß = 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 Aß 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.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF, and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (Flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease.

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.

Perspectives of patients, care partners, and primary care physicians on management of mild cognitive impairment and mild Alzheimer's disease dementia.

OBJECTIVES: 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. METHODS: We conducted online surveys in the United States among patients/care partners and physicians in 2021. RESULTS: 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. CONCLUSIONS: 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.

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.[Figure: see text].

A public resource of baseline data from the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.

INTRODUCTION: The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aß) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. METHODS: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. RESULTS: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. DISCUSSION: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aß plaque deposition.

Feasibility and preliminary effects of exercise interventions on plasma biomarkers of Alzheimer's disease in the FIT-AD trial: a randomized pilot study in older adults with Alzheimer's dementia.

BACKGROUND: Alzheimer's disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-ß42 and Aß40 (Aß42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). METHODS: This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20-50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aß42, Aß40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen's d, and linear mixed models. RESULTSS: The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and -0.001 (0.010) for Aß42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and -0.020 (0.279) pg/mL and -0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [-0.33, 1.19]) and t-tau in cycling (-0.35 [-0.87, 0.17]). CONCLUSIONS: Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 2013.

Physical activity is associated with increased resting-state functional connectivity in networks predictive of cognitive decline in clinically unimpaired older adults.

Introduction: Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks. Methods: rs-fcMRI, amyloid beta (Aß) positron emission tomography (PET), PA (steps/day × 1 week), and longitudinal cognitive (Preclinical Alzheimer's Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used. We used linear and linear mixed-effects regression models to examine the associations between baseline PA and baseline network connectivity and between PA, network connectivity, and longitudinal cognitive performance. Results: Higher PA was associated selectively with greater connectivity in three networks previously associated with cognitive decline (default, salience, left control). This association with network connectivity accounted for a modest portion of PA's effects on Aß-related cognitive decline. Discussion: Although other mechanisms are likely present, PA may promote resilience with respect to Aß-related cognitive decline, partly by increasing connectivity in a subset of cognitive networks.

Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults.

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 (Aß), 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 Aß. We next examined associations between cytokine levels and neuroimaging biomarkers of Aß/tau/neurodegeneration. RESULTS: Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aß (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aß (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aß. 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.

Amyloid-beta burden predicts prospective decline in body mass index in clinically normal adults.

In the present study, we tested the hypothesis that higher amyloid-beta (Aß) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aß positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aß burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = -1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = -2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aß burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI <18.5 or >30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.

Longitudinal degradation of the default/salience network axis in symptomatic individuals with elevated amyloid burden.

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for ß-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.

Memory complaints, dementia, and neuropathology in older blacks and whites.

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.

Diabetes, Hemoglobin A1C, and Regional Alzheimer Disease and Infarct Pathology.

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.

Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk.

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.

Identification of risk loci for necrotizing meningoencephalitis in Pug dogs.

Due to their unique population structure, purebred dogs have emerged as a key model for the study of complex genetic disorders. To evaluate the utility of a newly available high-density canine whole-genome array with >170,000 single nucleotide polymorphisms (SNPs), genome-wide association was performed on a small number of case and control dogs to determine disease susceptibility loci in canine necrotizing meningoencephalitis (NME), a disorder with known non-Mendelian inheritance that shares clinical similarities with atypical variants of multiple sclerosis in humans. Genotyping of 30 NME-affected Pug dogs and 68 healthy control Pugs identified 2 loci associated with NME, including a region within dog leukocyte antigen class II on chromosome 12 that remained significant after Bonferroni correction. Our results support the utility of this high-density SNP array, confirm that dogs are a powerful model for mapping complex genetic disorders and provide important preliminary data to support in depth genetic analysis of NME in numerous affected breeds.

Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.

In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls.