Risk Factor For Alzheimer's Disease Research Articles

Sleep health disparities and its impact on Alzheimer’s disease risk: Examining race specific physiologic mechanisms

AbstractBlacks/African‐Americans (blacks) take longer to fall asleep, have lower sleep efficiency and spend a smaller proportion of time in deep stages of non‐rapid eye movement (NREM) slow wave sleep/activity [SWS]), relative to non‐Hispanic whites (whites). Notably, blacks have a higher burden of severe obstructive sleep apnea [OSA] with excessive daytime sleepiness (EDS). These sleep metrics have been linked to increased vascular risks, inflammation, brain injury, and cognitive impairment, all known risk factors for Alzheimer’s disease (AD). This presentation will provide an update on putative mechanisms that underlie the association between sleep and risk of developing AD, both from a mechanistic (primarily preclinical) as well as a clinical/epidemiological perspective, with a focus on how disturbed sleep might be a race‐dependent physiologic risk conferring increased AD‐risk in blacks. It is vital to examine how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks. Data presented will include cross‐sectional and longitudinal studies. Utilizing data from various cohorts including NYU cohort of older‐adults participating in studies of sleep, aging and memory, and the National Alzheimer’s Coordinating Center, we will describe novel evidence implicating sleep health disparities [SHD] (i.e., shorter sleep duration [SD], smaller proportion of time in deep stages of NREM SWS/SWA and disproportionate burden of symptomatic OSA, that are more prevalent among racial/ethnic minorities, as a risk factor for AD; as a physiologic marker associated with AD pathology/biomarkers (i.e. amyloid and tau), and as a modifier of AD‐risk. We will describe race and sex specific mechanisms underlying SHD‐AD risk, including independent and synergistic effects with Aβ and/or tau, as well as vascular risk. Race‐specific associations of micro and macro‐architectural sleep parameters with novel plasma AD biomarkers will also be presented. Findings will show that social determinants of health factors mediate heterogeneity in sleep and AD outcomes, with Black subjects having worse SHD metrics i.e., shorter SD, reduced NREM SWS/SWA and greater OSA severity, and exhibiting worse race‐specific AD pathology and CVD risk markers (i.e., worse office‐based Framingham Heart Study general CVD [FHS‐CVD] risk scores, & greater WML and abnormal DKI indices) potentially leading to AD disparities.

Synaptic tauopathy in a model of Alzheimer’s disease and traumatic brain injury

AbstractBackgroundSynapse loss is an early, pathogenic hallmark of Alzheimer’s disease (AD) and related neurodegenerative conditions. We recently demonstrated that traumatic brain injury (TBI) – the best‐established environmental risk factor for AD – also causes synapse loss, thus establishing a potential pathomechanistic connection between these conditions. One likely contributor is the microtubule associated protein tau. Phosphorylated isoforms of tau can be identified in the brain after TBI and are classically associated with AD‐related pathology. The extent to which these pathoisoforms reach synapses and contribute to their loss, however, is minimally explored.MethodWe combined the PS19 mouse model, which exhibits age‐dependent tau aggregation and synapse loss, with early TBI and subsequent aging to investigate tauopathic synaptic alterations in relation to traumatic and AD‐related processes. TBI was induced with a diffuse, closed‐head injury model called modCHIMERA (Sauerbeck et al, 2018) that causes delayed synapse loss. Synaptic analysis was performed with SEQUIN (Sauerbeck et al, 2020, Reitz et al, 2021), a super‐resolution imaging and analysis platform for quantifying synaptic density as well as nanostructure and molecular features in mammalian neuropil.ResultBoth TBI and expression of the P301S mutation resulted in accumulation of pathoisoforms of tau at synapses and regional synapse loss that evolved over time. Temporal and spatial patterns of tau accumulation varied by phosphoisoform. TBI resulted in an additional burden of synapse loss in PS19 animals, suggesting that TBI may increase the risk of AD through a potentiation of synaptic injury. We are exploring the functional consequences of this connection in ongoing experiments.ConclusionThese studies demonstrate novel subcellular targets of pathological tau isoforms and suggest that tau is a key factor in synapse loss in TBI and AD. This shared mechanism may help explain the elevated risk of AD following TBI. Further characterization of these processes may suggest ways to sever this link, as well as prevent synapse loss in primary AD.

Effect of the combination of tetrahydrocannabinol and melatonin (IGC‐AD1) on blood pressure variability in patients with mild to moderate Alzheimer’s Disease

AbstractBackgroundBlood pressure (BP) variability (BPV) is a risk factor for Alzheimer’s disease (AD). Medications, such as atypical antipsychotics used to treat neuropsychiatric symptoms (NPS) common in AD, contribute to altering BP. Here we present preliminary data on the use of IGC‐AD1, a combination intervention of tetrahydrocannabinol (THC) and melatonin, on BP and BPV.MethodParticipants with hypertension (n = 12) and mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) were enrolled in a three‐Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, Cohort‐2 and Cohort‐3, one ml QD, BID, and TID of IGC‐AD1 were administered respectively for 14‐days with a minimum of 4‐days washout between Cohorts. For all Cohorts, BP was recorded daily. Coefficients of variation (CV), ∆DBP and ∆SBP (diastolic and systolic blood pressure) were calculated to assess SBP‐variability for each Cohort. A chi‐square was performed to verify whether the difference between controlled and uncontrolled SBP (>140mmHg in more than 20% of values per participant) was related to IGC‐AD1. SBP‐CV difference among Cohorts was determined with a one‐way ANOVA. The difference between active and placebo for each Cohort was assessed with independent t‐tests (dplr R‐Studio). BP‐associated adverse events (AEs) were evaluated daily.ResultVariability measures fell within the normal range (∆DVP = 45.0±13.5 mmHg, ∆SBP = 66.44±22.9 mmHg, CV = 7.6±5.3 mmHg) for all three Cohorts. Cohort‐1 (mmHg): ∆SBP = 42.3±15.56, ∆DVP = 25.6±8.86, CV = 10.14±3.84; Cohort‐2 (mmHg): ∆SBP = 41.9±11.73, ∆DVP = 23±9.7, CV = 8.95±1.96; Cohort‐3 (mmHg): ∆SBP = 39.6±11.76, ∆DVP = 23.6±7.82, CV = 8.84±7.83. IGC‐AD1 had no statistically significant effect between controlled and uncontrolled SBP (X2(2) = 1.15, p = 0.562). There was no SBP‐CV mean‐difference among Cohorts (F (2,27) = 0.589, p = 0.562). No differences were detected between placebo and active (Cohort‐1: t(1.64) = 0.315, p = 0.788, Cohort‐2: t(1.31) = ‐0.225, p = 0.85, Cohort‐3: t(3.53) = 1.63, p = 0.188). While BP related AEs were reported, none were deemed, by the PI, to be associated with IGC‐AD1.ConclusionPreliminary data indicate that IGC‐AD1, a cannabis‐based formulation, in trials to treat NPS did not statistically affect BP or BPV in a MAD study indicating that it may not contribute as a risk factor for AD; warranting a larger placebo‐controlled trial.

Evaluation of HIVEP3 polymorphic variants and gene expression in Alzheimer’s disease

AbstractBackgroundIt has been increasingly recognized that neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease (AD). The HIVEP3 gene encodes a transcription factor that regulates inflammatory response, and variants in this gene have been associated with increased risk for Parkinson’s disease. HIVEP3 gene expression is transiently decreased following nerve damage, consistent with a role during neuronal remodeling . In the present work, we investigate genetic variants in the HIVEP3 gene as risk factors for AD, and study HIVEP3 gene expression in human cerebral cortex.MethodWe have used three different cohorts to assess the association of HIVEP3 polymorphisms with the risk of developing AD: the International Genomics of Alzheimer’s Project (IGAP), the Quebec Founder Population Cohort (QFP) and Kunkle et al. stage 1 GWAS dataset. In the QFP cohort, we measured HIVEP3 protein levels (using ELISA) and mRNA levels (using RT‐PCR) in the frontal cortex of autopsied‐confirmed AD and control subjects.ResultWe have found that the rs10493098 C variant is associated with increased risk of AD in IGAP 2009 (p = 0.018, OR = 1.04), QFP (p< 5 × 10−8, OR = 1.37) and Kunkle et al. 2019 stage 1 IGAP GWAS (p = 0.006). In the IGAP cohort, this variant is associated with increased risk of AD only in APOE4 negative participants (p = 0.0009). Cortical HIVEP3 protein levels are increased in subjects with AD compared to controls (p = 0.029) and in subjects with at least one copy of the rs10493098 C variant compared to non‐carriers (p = 0.03). There are no changes in mRNA levels as a function of disease status or presence of the rs10493098 C variant. There is no correlation between HIVEP3 protein or mRNA levels and senile plaques or neurofibrillary tangles densities.ConclusionWe have identified a new genetic variant associated with increased risk for AD. The HIVEP3 rs10493098 C variant is associated with increased risk of AD, particularly in APOE4 negative participants. HIVEP3 proteins levels are increased in the frontal cortex of AD subjects compared to controls and in rs10493098 C carriers.

Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms

AbstractBackgroundSubclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.MethodCognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p<0.05.ResultHigher blood epinephrine level (p<0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p<0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p<0.007) and Subiculum (p<0.013) subfields (Fig.2). Lower GM volume in the CA1 (p<0.008) and DG/CA2‐3‐4 (p<0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.ConclusionSubclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.

Nutrition in Alzheimer’s Disease: A Review of an Underappreciated Pathophysiological Mechanism

AbstractBackgroundPharmacy therapy of Alzheimer’s disease (AD) is one of the areas that are well funded, but where little progress has been made due to the complex pathogenesis. The gut‐microbiota‐brain axis has gained tremendous traction in the pathogenesis of AD through bidirectional communication with multiple neural, immune, and metabolic pathways, providing new insights into novel therapeutic strategies. Dietary nutrition is an important and profound environmental factor that influences the composition and function of the microbiota. The Nutrition for Dementia Prevention Working group recently found that dietary nutrition can affect the cognition of AD‐related dementia directly or indirectly through complex interactions of behavioral, genetic, systemic, and brain factors. This review aimed to emphasize the knowledge gaps to provide direction for future research and to establish optimal nutrition‐based intervention strategies for AD.MethodThis review discusses the associated evidence between malnutrition and the onset and development of AD for modifying the potentially reversible nutrition‐related risk factors of AD, describe the potential pathogenesis underlying the role of nutrition in the progression of AD and emphasize the current knowledge gaps for further research.ResultThe role and effects that nutrition and diet have on AD are more pervasive than previously believed. We identified and highlighted a novel vicious cycle comprising malnutrition, development of AD, and heavy caregiver burden (Figure 1). As pharmacological approaches demonstrate limited benefits for improving the symptoms of AD, early nutritional intervention for preventing or delaying the progression of AD are worth attempting. The mechanisms underlying the effect of nutrition on the development of AD remain uncertain, including genetics and epigenetics, AD‐specific biomarkers, metabolic pathways, the gut‐microbiota‐inflammation‐brain axis, and their complex interactions (Figure 2).ConclusionThese potential nutrition‐related pathogenic pathways can be exploited as an important environmental factor and could be the focus of targeted AD interventions. Future research is needed to fill in the discussed gaps in knowledge, including prospective studies to identify nutritional biomarkers that can predict AD, multi‐omics studies to elucidate the exact mechanisms by which nutrition influences AD, and clinical trials to identify the best nutritional intervention strategies to prevent and improve cognitive and behavioral disturbances in the AD population.

Maya Angelou Center for Health Equity Caregiver College: a culturally‐relevant training for African American Alzheimer’s disease caregivers

AbstractBackgroundAfrican American (AA) caregivers of patients with Alzheimer’s disease (AD) and related disorders can play a critical role in maintaining patient health. The Maya Angelou Center for Health Equity at Wake Forest University School of Medicine Caregiver College (MC2) aims to (1) improve informal caregivers’ knowledge of AD and related disorders, (2) enhance the quality of life for AD patients and caregiver’s by providing awareness of and access to resources that can help reduce caregiver burden, (3) provide strategies to effectively manage patient symptoms associated with AD, and (4) fill gaps in culturally relevant health education and awareness on AD, brain health, and dementia caregiving skills for AAs.MethodThe 40‐hour inaugural session of MC2 was conducted in‐person in October 2022. Educational sessions were facilitated by experts in various fields including AD, social work, nursing, aging, nutrition, and pharmacy. Topics covered over the course of the educational week included: Alzheimer’s Disease Overview, Health Disparities in AAs, Risk Factors for AD, End of Life Planning, and Caregiver Health. The 21‐item Dementia Knowledge Assessment Tool (DKAT), version 2 (Toye, et al. 2013) was used to track changes in AD knowledge and awareness. A DKAT pre‐test was administered before the educational sessions began on Day 1, and a post‐test assessment was administered at the end of the last educational session on Day 5.ResultAttendees (N = 21) are African American (100%), primarily female (90.48%), with an average age of 66.8 years (range 42‐82 years, 1 missing value). DKAT assessments from the week‐long educational training, showed an 8% increase in knowledge about AD in this sample of dementia caregivers based on a 5.7 percentage point increase on the DKAT from an average of 71.4% correct pre‐training to an average of 77.1% correct post‐training.ConclusionFindings suggest that community‐based educational training is a useful strategy for improving AD knowledge and resource awareness for AA informal caregivers. Results will be used to expand this training to include community members who will be engaged through presentations by attendees of the MC2.

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology

AbstractBackgroundThe association between hearing impairment and Alzheimer’s disease (AD) and the mechanisms involved remain unclear.MethodsSurvival analyses were performed in 66,577 participants from the UK Biobank to investigate whether hearing impairment is associated with an increased risk of AD. The association of hearing status with cognitive function, brain structure and CSF proteins were explored in cross‐sectional, longitudinal, and mediation analyses across the UK Biobank (n = 165,550), Chinese Alzheimer’s Biomarker and Lifestyle (CABLE, n = 867), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 802).ResultsHearing impairment was associated with an increased risk of AD over 11 years of follow‐up (HR 1.80, 95%CI 1.50‐2.15). Poor hearing status was associated with worse cognitive function in cross‐sectional and longitudinal studies. Moreover, hearing impairment was significantly related to lower volume of the temporal cortex, hippocampus, amygdala, inferior parietal lobe, precuneus and orbitofrontal cortex, to lower integrity of white matter tracts, and to a higher level of CSF tau protein. Mediation analyses showed that brain structure and CSF tau partly mediated the association between hearing impairment and cognitive decline.ConclusionHearing impairment is a risk factor for AD, and is associated with brain structure, tau pathology, and cognitive decline.

Asian Cohort for Alzheimer’s Disease Pilot Study on Genetic and Non‐Genetic Risk Factors for Alzheimer’s Disease among Asian Americans and Canadians

AbstractBackgroundAsian Americans and Canadians (ASACs) are the fastest growing minority group in the U.S. and Canada. However, ASACs are under‐sampled in Alzheimer’s disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer’s Disease (ACAD), the first large dementia genetics cohort currently focuses on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research.MethodThe ACAD pilot study has 7 recruiting sites (5 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and a centralized data management system in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure the protocol consistency, ACAD implemented a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment in collaboration with community partners, clinics, and nursing homes that serve Asian communities.ResultAs of December 2022, ACAD’s pilot study has consented 606 participants, 527 participants have complete DCP data submitted to REDCap (448 Chinese, 54 Korean, and 25 Vietnamese), and more than 1,500 people have expressed interests in ACAD. The majority 66.2%)women. The age range of the sample is 60‐93 years. 47.3% have college or graduate level education. 451 participants provided a saliva (274) or a blood (177) sample. Feedback in pilot indicates a need to adapt the Early Life Enrichment inventory further to apply to wartime deprivation conditions for this population, as well as more cultural tailored neuropsychological tests.ConclusionACAD has learned valuable experience in interactions with ASACs and shown the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on minority, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD.

Age‐related relative comorbidity burden of mild cognitive impairment: A US database study

AbstractBackgroundAs novel therapies emerge, timely detection and diagnosis of early Alzheimer’s disease (AD) become increasingly relevant. While primary care would be the most suitable setting for early detection, diagnosis rates of mild cognitive impairment (MCI) are low and systematic screening of asymptomatic individuals is currently not recommended. We investigated whether a predictive algorithm based on established AD risk factors can help to identify individuals at elevated risk of having undiagnosed MCI, in particular in younger age cohorts.MethodOur retrospective study used MarketScan insurance claims data to identify individuals aged ≥50 years with MCI (but without dementia) and assemble controls without MCI/dementia diagnoses matched on age, sex, and geographic region. Medical conditions previously identified as AD risk factors in the literature were considered MCI risk factors if their prevalence in MCI individuals was statistically significantly higher than in controls. Logistic regression and extreme gradient boosting (XGBoost; a machine learning method) were applied to discriminate MCI from control individuals based on area under the curve (AUC). Analyses were conducted for the overall cohort and by age group (50‐64, 65‐79, and ≥80 years).ResultTwenty‐five medical conditions had statistically higher frequency in the MCI cohort (n = 5,185) compared to controls (n = 15,555). The top MCI risk factors (with odds ratio for the 50‐64, 65‐79, and ≥80 years subgroups, respectively) were: depression (4.4, 3.1, 1.9); stroke/transient ischemic attack, TIA (6.4, 3.0, 2.1); obstructive sleep apnea, OSA (3.6, 2.5, 1.7); hyperlipidemia (1.7, 1.5, 1.4); and hypertension (1.6, 1.5, 1.5) (all p‐values <0.0001). The logistic regression models for identifying MCI individuals reached AUCs of 0.75, 0.69, and 0.66, for the 3 age groups, respectively. The XGBoost approach reached AUC = 0.94 (training set) and AUC = 0.78 (test set). Each approach was most accurate when discriminating MCI for the youngest age group.ConclusionOur two modeling approaches were able to predict MCI with acceptable accuracy. The predictions were more accurate in the 50‐64 age group than in the older groups, suggesting that the use of prediction models for triage in primary care will play a greater role in younger age groups.

Depression and Hippocampal Subfield Volume in Older Adults

AbstractBackgroundMajor Depressive Disorder (MDD) is associated with higher risk for developing Alzheimer’s Disease (AD), (Bennett & Thomas, 2014). Both conditions are associated with smaller hippocampal subfield volumes, and both preferentially affect females (Shi et al., 2021). We examined the relationship between depression diagnosis and hippocampal subfield volume, by carrier status for AD genetic risk variant APOE4 and sex. We hypothesized that the association between depression and subfield volume would be stronger in females due to the higher rate of depression.MethodWe examined 1726 cognitively intact older adults from the Health and Aging Brain Study ‐ Health Disparities (HABS‐HD) cohort (Table1) who had available hippocampal high resolution MRI scans (Siemens Skyra or Vida‐3T). Scans were segmented into CA1, CA23DG, and subiculum using Automatic Segmentation of Hippocampal Subfields (ASHS) software and subfield volume was averaged bilaterally. We used separate multiple linear regressions to assess the association between depression and each hippocampal subfield volume, covarying for age, sex, years of education, number of MRI slices segmented, intracranial volume, and scanner. We corrected for multiple comparisons across regions using FDR correction. We also evaluated CA1 and CA23DG volume to depression diagnosis, stratifying by APOE4 positivity and sex and testing for formal interactions.ResultSee Table 2 for results. Depression was associated with smaller CA1 and CA23DG volume across all participants. Depression was associated with smaller CA1 and CA23DG in the APOE4 negative group, but not the APOE4 positive group. The depression by APOE4 interaction was significant for CA23DG volume (𝛽 = 0.25, p = 0.049). Depression was associated with smaller CA1 and CA23DG volumes in males, but not in females, with trend level interaction effects in the CA1 (𝛽 = 0.13, p = 0.095) and CA23DG (𝛽 = 0.17, p = 0.067).ConclusionDepression was associated with smaller CA1 and CA23DG volumes in older adults consistent with past literature. In contrast to our hypotheses, depression was associated with lower hippocampal subregional volumes more in those with lower risk for Alzheimer’s disease (male and APOE4‐ adults).Variability induced by other AD risk factors may mask the relationship between depression and hippocampal subregion volume when AD risk is higher.

Telomeres are associated with markers and regions sensitive to aging and not Alzheimer’s disease in cognitively unimpaired older adults

AbstractBackgroundTelomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to date has assessed the links between the percentage of short telomeres (ST) and blood, neuroimaging markers of aging, neurodegeneration, amyloid and tau pathologies in healthy elderly.MethodBaseline data from 125 cognitively unimpaired older adults (65 to 83 years old; mean ± SD: 68.9 ± 2.8) from the Age‐Well trial (NCT02977819), who completed multimodal neuroimaging and blood sampling, were analyzed. Neuroimaging data included structural T1‐weighted MRI, T2‐weighted high‐resolution scan of the hippocampus, DKI, FDG‐PET and AV45‐PET (perfusion and amyloid load). ST, as well as neurodegeneration, amyloid, and tau biomarkers (NFL, GFAP, Aß42/40 ratio and pTau181) were measured in blood samples. Multiple linear regressions between ST and each marker were conducted corrected for age, sex, education and body mass index. Additional adjustments for APOE and amyloid status were made. Statistical significance was set to p<0.05, except for voxelwise analyses (puncorrected<0.005, kuncorrected = 500 voxels).ResultST was associated with lower white matter integrity (measured by kurtosis fractional anisotropy (kFA)) in prefrontal and temporal regions (Fig.1), and with the hippocampal subiculum volume, but not with total gray matter volume, mean kurtosis, glucose metabolism, brain perfusion or amyloid load; nor with blood markers of neurodegeneration, amyloid, or tau. Additional adjustments for APOE/amyloid status gave similar results.ConclusionTelomere dysfunctions were associated with lower white matter integrity in regions vulnerable to aging, but not to AD, nor with neurodegeneration, amyloid or tau biomarkers, and neither with AD risk factors (APOE or amyloid status). When we focused on the hippocampus, a specific link was found with the subiculum volume, an hippocampal subfield known to be the most sensitive to aging, which is not the case in AD. These results give further evidence for the tight connection between cellular and cerebral aging, but not with AD in cognitively unimpaired older adults.

Relationships between excessive daytime sleepiness and arterial stiffness with cognitive function in a racially diverse high‐risk cohort

AbstractBackgroundAs pathologic processes leading to Alzheimer’s disease (AD) begin many years before clinical diagnosis, assessment of pre‐clinical AD risk factors in high‐risk individuals is needed. Excessive daytime sleepiness (EDS) is associated with increased cardiovascular dysfunction, neuroinflammation, and neurodegeneration, leading to cognitive impairment. We tested the hypothesis that EDS and increased arterial stiffness are related to worse cognitive function in a cohort of Black or African American (B/AA) and non‐Hispanic White (NHW) participants.MethodA community‐based racially diverse sample of cognitively unimpaired adults (47‐83 years), most (87%) with a family history of AD, were enrolled. Cognitive testing took one hour and included domains of executive function, working memory, and verbal and visuospatial ability and language. Daytime sleepiness was measured with Epworth Sleepiness Scale (ESS); EDS was defined as ESS≥10. Arterial stiffness was measured using pulse wave velocity (PWV).ResultParticipants (N = 85) were 64±8 years of age, 75% female, 48% B/AA, and highly educated (81% ≥college). Mean central blood pressures were 126±18 mmHg (systolic) and 80±10 mmHg (diastolic), with no differences by race or sex. Scores were lower among B/AA versus NHW participants for Judgement of Line of Orientation (17.71±6.0 versus 23.53±6.0, p<.001, Cohen’s d = .083) and Multilingual Naming Test (28.25±2.7 versus 30.57±2.0, p = .005, d = .950). EDS was present among 15% of participants and associated with lower scores on Digit Symbol (p = .004, d = .917), and Multilingual Naming Test (p = .006, d = 1.455). Total time on Trails A was higher among those with EDS (36s versus 30s, p = .040, d = .575). Higher PWV values were associated with lower scores on Digit Symbol Substitution (r = ‐.259, p = .029), Buschke Selective Reminding Test (‐.298, p = .012), CERAD Word List (‐.306, p = .009), F‐A‐S (r = ‐.253, p = .033), and Animal Fluency (r = ‐.326, p = .006).ConclusionIn a racially diverse cohort at risk for AD, we found that excessive self‐reported daytime sleepiness and increased arterial stiffness were associated with worse scores across multiple cognitive domains. Poor sleep and vascular dysfunction are known contributors to AD pathology, providing potential modifiable targets of intervention to reduce or delay the development of AD in cognitively normal, but high‐risk individuals. Further work is needed for a better understanding of modifiable AD risk factors in diverse populations

Telomeres are associated with markers and regions sensitive to aging and not Alzheimer’s disease in cognitively unimpaired older adults

AbstractBackgroundTelomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to date has assessed the links between the percentage of short telomeres (ST) and blood, neuroimaging markers of aging, neurodegeneration, amyloid and tau pathologies in healthy elderly.MethodBaseline data from 125 cognitively unimpaired older adults (65 to 83 years old; mean ± SD: 68.9 ± 2.8) from the Age‐Well trial (NCT02977819), who completed multimodal neuroimaging and blood sampling, were analyzed. Neuroimaging data included structural T1‐weighted MRI, T2‐weighted high‐resolution scan of the hippocampus, DKI, FDG‐PET and AV45‐PET (perfusion and amyloid load). ST, as well as neurodegeneration, amyloid, and tau biomarkers (NFL, GFAP, Aβ42/40 ratio and pTau181) were measured in blood samples. Multiple linear regressions between ST and each marker were conducted corrected for age, sex, education and body mass index. Additional adjustments for APOE and amyloid status were made. Statistical significance was set to p<0.05, except for voxelwise analyses (puncorrected<0.005, kuncorrected = 500 voxels).ResultST was associated with lower white matter integrity (measured by kurtosis fractional anisotropy (kFA)) in prefrontal and temporal regions (Fig.1), and with the hippocampal subiculum volume, but not with total gray matter volume, mean kurtosis, glucose metabolism, brain perfusion or amyloid load; nor with blood markers of neurodegeneration, amyloid, or tau. Additional adjustments for APOE/amyloid status gave similar results.ConclusionTelomere dysfunctions were associated with lower white matter integrity in regions vulnerable to aging, but not to AD, nor with neurodegeneration, amyloid or tau biomarkers, and neither with AD risk factors (APOE or amyloid status). When we focused on the hippocampus, a specific link was found with the subiculum volume, an hippocampal subfield known to be the most sensitive to aging, which is not the case in AD. These results give further evidence for the tight connection between cellular and cerebral aging, but not with AD in cognitively unimpaired older adults.

Altered patterns of brain activity during a fMRI memory task in cognitively normal adults carrying the APOE ε4 allele

AbstractBackgroundThe ε4 allele of the Apolipoprotein E gene (APOE) is a well‐established risk factor for Alzheimer’s disease (AD), ε4 carriers showing earlier onset and more severe memory impairment than non‐carriers. Neuroimaging evidence suggests that APOEε4 may modulate neural activity in AD since early stages. The purpose of this study was to determine whether APOEε4 influences brain activity in the memory circuit in older cognitively unimpaired individuals.MethodThirty cognitively unimpaired participants (n = 10 APOEε4 heterozygous carriers, age = 65± 5 years, 50% females, MMSE score = 29±1; n = 20 APOEε4 non‐carriers, age = 68±5 years, 35% females, MMSE score = 30±1) were recruited and underwent multidomain (i.e., memory, visuospatial abilities, language, attention) neuropsychological exams and functional MRI scan during an associative memory task, which consisted of two phases: (i) encoding of face‐name associations; (ii) recognition of the name associated to each face. Image preprocessing and voxel‐wise comparisons were conducted using the Statistical Parametric Mapping (SPM, v12). Clusters were considered significant at an uncorrected threshold of p<0.001.ResultParticipants were comparable for demographic and cognitive features (p>0.10) and performed similarly on the in‐scanner face‐name association memory task (p>0.10). Compared to ε4 non‐carriers, carriers showed (i) greater activation during the encoding task in the left temporo‐occipital cortex/fusiform gyrus, (ii) greater activation during the recognition task in the middle temporal gyrus/temporo‐occipital cortex bilaterally and in the right cerebellum, and (iii) lower activation during the recognition task in the medial supplementary motor area.ConclusionThese preliminary results confirm that the APOE ε4 allele is associated with a different pattern of brain functional activity during an associative memory task in cognitively unimpaired older. Given the similar cognitive performance between groups, higher activation in temporo‐occipital regions might reflect a compensatory process in regions vulnerable to AD pathology.

Uncovering the Role of an ABCA7 Frameshift Deletion in African American Alzheimer’s Disease Cellular Pathology

AbstractBackgroundThe ATP Binding Cassette Subfamily A Member 7 (ABCA7) gene is a risk factor for Alzheimer’s disease (AD). While ABCA7 has been implicated as a genetic determinant of AD across populations, the risk effect is the strongest in African Americans (AAs). We previously identified a common 44 base pair deletion in ABCA7 (p.Arg578Alafs) that is predicted to truncate the protein and is significantly associated with AD in AAs (frequency in cases = 15.2%, cognitively unimpaired (CU) = 9.74%, p = 1.41×10−5). Clinically, deletion homozygotes are similar to deletion heterozygotes, supporting dominant gain‐of‐function as a putative disease‐causing mechanism. We sought to determine if the deletion transcript is stable and if the truncated protein is expressed as steps to understanding the mechanism leading to AD risk.MethodRT‐PCR analysis of heterozygotes was conducted to assess the stability of the deletion transcript. FLAG‐tagged Arg578Alafs and wildtype ABCA7 vectors were constructed then overexpressed in HEK293APPsw cells. Western blot analysis of FLAG‐Arg578Alafs was performed to determine if the deletion produces a truncated protein. Induced pluripotent stem cell (iPSC) lines from six AA individuals with AD bearing the Arg578Alafs mutation (three heterozygous; three homozygous) were created in pair with isogenic CRISPR‐corrected control lines. These iPSC lines were validated for pluripotency, genomic stability, and lack of off‐target editing. The isogenic ABCA7 deletion and CRISPR‐corrected control iPSC lines will be differentiated into microglia and neurons and functionally assessed for cell type‐specific AD phenotypes.ResultInitial results comparing AD patients to CU individuals show that patient‐derived microglia have normal rates of phagocytosis but are impaired in the uptake and clearance of fibrillar Aβ. RT‐PCR analysis of the deletion in heterozygotes demonstrates that a stable RNA transcript is expressed from the ABCA7 deletion allele. Western blot analysis of overexpressed FLAG‐Arg578Alafs shows that the truncated protein is expressed, albeit at low levels compared to the wildtype protein.ConclusionThis ABCA7 deletion produces a stable transcript which appears to be translated into low levels of protein. This supports a potential gain of function as the disease risk mechanism. Studies in isogenic lines will further elucidate the functional effects of this ABCA7 deletion on AD pathology in AAs.

Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal

AbstractStrong 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.

Multi‐ethnic genome‐wide, gene‐based study identifies genes that interact with vascular risk factors in Alzheimer’s Disease (AD)

AbstractBackgroundCardiovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and AD, and over 30% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with CVRFs (p = 6.6e‐07) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. The goal here was to identify additional genes that contribute to the interaction between CVRFs and AD.MethodA collection of eight multi‐ethnic cohorts was explored to study genome‐wide gene‐CVRF score interaction analysis for AD, in 7,441 AD patients and 10,453 controls. The cardiovascular risk factors score (CVRF score) was created from a first principal component of the four vascular risk factors; self‐reported history of hypertension, diabetes, and heart disease, and measured body mass index. Gene‐based interaction test was performed using the adaptive gene‐environment interaction (aGE) test. Results were summarized using a meta‐analysis. We investigated the association of gene expression with pathological AD and AD phenotype (amyloid‐β, tau, or brain infarcts) in 1,092 samples from the frontal cortex in ROSMAP. The pathway enrichment analysis was performed on the differentially expressed genes. Age and sex were adjusted in the models.ResultThe previous interaction of CVRF score with FMNL2 (p = 3.64e‐07) was strengthened and additional genes were identified including BRINP1 (p = 2.45e‐06), CFAP99 (p = 3.3e‐06), and PRG3 (p = 3.71e‐06). FMNL2 encodes a formin‐related protein important in regulating actin and microtubules. FMNL2 and BRINP1 expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006, respectively). The expression level of BRINP1 interacted with brain infarcts on pathological AD (p = 0.02) and with amyloid‐β or tau on brain infarcts (p = 0.02 and p = 0.01, respectively). The pathways were relevant to cellular interactions between astrocytes and endothelia as well as the immune system reaction in the glio‐vascular niche.ConclusionThe four novel genes are likely to be involved in the complex interaction between Alzheimer’s disease pathologies (amyloid and phosphorylated tau deposition) and cerebrovascular pathology, for example, at the glia‐vascular interface during AD progression. Understanding how these genes interfere with the mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain will be essential.

Sex‐specific effects of genetically predicted BMI and education on risk of AD

AbstractBackgroundExamining sex differences on the impact of modifiable risk factors in Alzheimer’s disease (AD) risk can help us better understand the mechanisms underlying sex differences in the prevalence and incidence of AD. Here, we used polygenic risk scores (PRS) and Mendelian randomization (MR) to investigate sex‐specific effects of sleep duration, insomnia, blood pressure, diabetes, alcohol intake, smoking, body mass index, high cholesterol, and education on AD risk.MethodWe obtained combined and sex‐stratified genome‐wide association study (GWAS) summary statistics for each risk factor from the UK Biobank and used them as the base dataset for constructing PRS and exposure datasets in the MR analysis. Linkage disequilibrium clumping was performed to identify independent genome‐wide significant single nucleotide polymorphisms (SNPs) across the sex‐combined, male‐specific, and female‐specific GWAS. The combined lead SNPs were then weighted by their strata‐specific effect sizes in the stratified PRS and MR analyses. PRS were constructed for each risk factor in participants from the Alzheimer’s Disease Genetics Consortium. Linear regression was used to investigate the association of each PRS with AD risk, adjusting for age, principal components, and cohort. MR was used to estimate sex‐stratified causal effects of each risk factor on AD. Sex differences in PRS associations and MR causal estimates were determined using Fisher’s Z score method.ResultsAssociation testing of the PRS with AD risk in sex stratified cohorts revealed that the BMI PRS was associated with differential effects in men and women (OR [95%CI]: males: 1.05 [1.00, 1.10] vs females: 0.96 [0.93, 0.99], p = 0.003). Furthermore, the university completion PRS was non‐significant in men but was associated with reduced risk in women (OR [95%CI]: males: 0.96 [0.92, 1.01] vs females: 0.92 [0.89, 0.96], p = 0.12). In the follow‐up MR analysis, university completion was also causally associated with reduced risk in women only (OR [95%CI]: males: 1.09 [0.77, 1.53] vs females: 0.55 [0.42, 0.72], p = 0.002) (Figure 1). No other risk factors showed evidence of sex‐differences.ConclusionOur study found sex‐specific effects of genetically predicted BMI and educational attainment on AD risk. These findings suggest the need for sex‐specific approaches to AD prevention and management.

Investigating the role of ketogenic conditions on cholesterol metabolism and neuroinflammation in APOE4 carriers

AbstractBackgroundThe study of genetic risk factors in Alzheimer’s Disease (AD) in conjunction with lifestyle factors is critical in order to fully understand manifestations of disease phenotypes. APOE4, the primary genetic risk factor for AD, is a mutant implicated in dysfunctional lipid and cholesterol transport. We have demonstrated that APOE4‐expressing oligodendrocytes produce a multitude of dysfunctional cholesterol synthesis conditions including decreased cholesterol transport, increased cholesterol accumulation, and reduced levels of myelination (Blanchard et al. 2022). One avenue to study the intersection of genetic and lifestyle factors is to explore APOE mutants with particular dietary conditions that may implicate neuro‐inflammatory phenotypes. The role of cholesterol metabolic dysfunctionality in APOE4 carriers, taking into account the diverse diets that humans consume, has yet to be studied.MethodIn order to investigate this, we developed a 3D multi‐cellular integrated brain tissue (miBrain) technology that contains iPSC‐derived neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes. This model has the ability to recapitulate physiological conditions of disease with great accuracy. To study different dietary conditions with our miBrain technology, we employed ketogenic vs. glucose media conditions on APOE4‐carrying cell types within the miBrain model.ResultWe have found that ketogenic conditions promote a neuro‐inflammatory phenotype in APOE4 carriers. This is shown by our observed differences in cholesterol accumulation, levels of myelination, and transcriptomics, between APOE3 and APOE4 miBrain models treated with ketogenic energy sources. We are confirming these findings using in vivo models.ConclusionKetogenic conditions may exacerbate the cholesterol abnormalities in APOE4 carriers, through promoting neuro‐inflammatory conditions that give rise to AD pathogenesis. Findings from these studies highlight therapeutic and diagnostic strategies to reduce the risk of developing AD in APOE4 carriers.