45 Senolytic Therapy Transiently Reduces Inflammatory Markers in Primary Blood Mononuclear Cells of Individuals with Early Alzheimer’s Disease: Exploring the Conserved Transcriptional Response to Adversity as a Biomarker for Disease State

OBJECTIVES/GOALS: Determine if the Conserved Transcriptional Response to Adversity transcriptomic profile established in primary blood mononuclear cells (PBMC) of chronically stress caregivers, is present in individuals with early Alzheimer’s disease. Chronic stress is a risk factor for Alzheimer’s, and may be an untapped biomarker for disease risk and pathology. METHODS/STUDY POPULATION: To collect preliminary data on the Conserved Transcriptional Response to Adversity profile in individuals with Alzheimer’s disease, we were able to utilize primary blood mononuclear cell samples from a small open label pilot study called Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease, designed to clear stressed senescent cells. We hypothesized senolytics may beneficially reverse this stress profile. We developed a NanoString assay (measuring 19 inflammatory, 31 type-1 interferon, and 3 antibody synthesis genes) to compare these transcriptomic changes within 4 individuals measured at baseline, post-treatment with an intermittent 12-week senolytic therapy, and at an optional extended post-treatment follow-up time point \u3e 3 months after their post treatment visit. RESULTS/ANTICIPATED RESULTS: There was relative downregulation of expression in transcription in 7 of 19 measured inflammatory genes (FOS, PTGS2, IL8, FOS, Il1b, JUNB, and JUN) in Alzheimer’s disease participants after receiving senolytic treatment (baseline vs. post-treatment). This is consistent with a decrease in the inflammatory arm of the Conserved Transcriptional Response to Adversity profile. These differences were not significant between baseline and the extended follow-up, indicative of a transient effect of senolytic. There were no changes in type 1 interferon or antibody synthesis genes. This data provides preliminary evidence for larger controlled studies to further establish this profile in Alzheimer’s disease, providing exciting evidence for transcript changes that may be reproducible with senolytic therapy. DISCUSSION/SIGNIFICANCE: Literature relevant to Alzheimer’s disease indicates global increases in inflammation paired with deficits in immune response, capturing some genes associated with the Conserved Transcriptional Response to Adversity. This profile may be a useful biomarker for prediction of disease severity or risk of dementia due to chronic stress

Elevated Serum C-Reactive Protein Relates to Increased Cerebral Myoinositol Levels in Middle-Aged Adults

C-reactive protein (CRP), a systemic marker of inflammation, is a risk factor for late life cognitive impairment and dementia, yet the mechanisms that link elevated CRP to cognitive decline are not fully understood. In this study we examined the relationship between CRP and markers of neuronal integrity and cerebral metabolism in middle-aged adults with intact cognitive function, using proton magnetic resonance spectrocospy. We hypothesized that increased levels of circulating CRP would correlate with changes in brain metabolites indicative of early brain vulnerability. Thirty-six individuals, aged 40 to 60, underwent neuropsychological assessment, a blood draw for CRP quantification, and 1H MRS examining N-acetyl-aspartate, myo-inositol, creatine, choline, and glutamate concentrations in occipito-parietal grey matter. Independent of age, sex and education, serum CRP was significantly related to higher cerebral myo-inositol/creatine ratio (F(4,31) = 4.74, P = 0.004), a relationship which remained unchanged after adjustment for cardiovascular risk (F(5,30) = 4.356, CRP β = 0.322, P = 0.045). Because these biomarkers are detectable in midlife they may serve as useful indicators of brain vulnerability during the preclinical period when mitigating intervention is still possible

Depressive Symptoms in Older Adult Couples: Associations with dyadic physical health, social engagement, and close friends

Objective: The objective of this study was to examine associations between level of depressive symptoms in older adult spouse/partner couples and their physical health and social factors (social activity and number of close friends). Methods: Using data from 116 community-dwelling couples (age 76.2 ± 8.5), we simultaneously analyzed associations between depressive symptoms (Geriatric Depression Scale, range 0–11) and dyadic physical health, engagement in social activities, and connectedness with close friends. Results: Greater engagement in social activities was associated with fewer depressive symptoms in men, whereas more close friendships were associated with fewer depressive symptoms in women, controlling for partner eects, age, education, and cognitive function, with good model fit. Additionally, more disparate physical health within the couple (latent incongruence score) was associated with greater depressive symptoms in men. Discussion: Less social activity and fewer close friends were associated with depressive symptoms in older adult couples, but may be distinctly influential depending on gender and in the context of the older adult couple’s physical health

Blood biomarkers for cognitive decline and clinical progression in a Mexican American cohort

Introduction: The clinical translation of biofluid markers for dementia requires validation in diverse cohorts. The study goal was to evaluate if blood biomarkers reflecting diverse pathophysiological processes predict disease progression in Mexican American adults. Methods: Mexican American adults (n = 745), 50 years of age and older, completed annual assessments over a mean of 4 years. Serum collected at baseline was assayed for total tau, neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI, glial fibrillary acidic protein (GFAP), soluble cluster of differentiation 14 (sCD14), and chitinase‐3‐like protein 1 (YKL‐40). Results: Higher GFAP and NFL were associated with global cognitive decline. Only GFAP was associated with increased incident dementia risk (hazard ratio: 1.611 (95% confidence interval: 1.204‐2.155)) and inclusion of additional biomarkers did not improve model fit. Discussion: Among a panel of six blood biomarkers previously associated with neurodegenerative disease, only GFAP predicted incident dementia in our cohort. The findings suggest that blood GFAP levels may aid dementia‐risk prediction among Mexican American adults

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the Second Latinos and Alzheimer's Symposium

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD

A population-based meta-analysis of circulating GFAP for cognition and dementia risk

Funding Information: The authors thank the study participants, the study teams, and the investigators and staff of the cohort studies. Dr. Pase is supported by a Heart Foundation Future Leader Fellowship (GNT102052). Dr DeCarli is supported by the UCD ADRC P30 AG 010129. Dr Aparicio is supported by an American Academy of Neurology Career Development Award, Alzheimer's Association (AARGD‐20‐685362), and National Institutes of Health (L30 NS093634). Funding was provided by the CHARGE infrastructure grant (HL105756). Funding Information: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, 75N92021D00006, and grants R01AG15928, R01AG20098, U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG053325, K24AG065525, and R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. Funding Information: This work was made possible by grants from the Alzheimer's Drug Discovery Foundation (GDAPB‐202010‐2020940), National Institutes of Health (N01‐HC‐25195, HHSN268201500001I, 75N92019D00031) and the National Institute on Aging (AG059421, AG054076, AG049607, AG033090, AG066524, NS017950, P30AG066546, UF1NS125513). Funding Information: The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contract Nos. HHSN26820180003I, HHSN26820180004I, HHSN26820180005I, HHSN26820180006I, and HHSN26820180007I from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra‐agency agreement between NIA and NHLBI (No. AG0005) . Funding Information: The Age, Gene/Environment Susceptibility‐Reykjavik Study was supported by NIH contracts N01‐AG‐1‐2100 and HHSN27120120022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Funding Information: Dr. Pase is supported by a Heart Foundation Future Leader Fellowship (GNT102052). Dr DeCarli is supported by the UCD ADRC P30 AG 010129. Dr Aparicio is supported by an American Academy of Neurology Career Development Award, Alzheimer's Association (AARGD‐20‐685362), and National Institutes of Health (L30 NS093634). Funding was provided by the CHARGE infrastructure grant (HL105756). Funding Information Publisher Copyright: © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Objective: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings. Methods: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models. Results: Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15-years of follow-up. Interpretation: Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.Peer reviewe

Advancements in dementia research, diagnostics and care in Latin America : highlights from the 2023 Alzheimer's association international conference satellite symposium in Mexico City

While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics and care. In 2023, the Alzheimer’s Association hosted its eighth Satellite Symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm. A wide range of topics were covered, including epidemiology, social determinants, dementia national plans, risk reduction, genetics, biomarkers, biobanks, and advancements in treatments. Large initiatives in the region including intra-country support showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care and implement affordable biomarkers in the region was highlighted