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Inflammation plays a major role in cognitive aging. Most studies on peripheral inflammation and cognitive aging focused on selected major inflammatory biomarkers. However, inflammatory markers are regulated and influenced by each other, and it is therefore important to consider a more comprehensive panel of markers to better capture diverse immune pathways and characterize the overall inflammatory profile of individuals. We explored 23 circulating inflammatory biomarkers using data from 1,743 participants without dementia (≥ 65 years-old) from the community-based, multiethnic Washington Heights Inwood Columbia Aging Project. Using principal component analysis (PCA), we developed six inflammatory profiles (PC-1 to PC-6) based on these 23 biomarkers and tested the association of resulting inflammatory profile with cognitive decline, over up to 12 years of follow-up. PC-1 described a pro-inflammatory profile characterized by high positive loadings for pro-inflammatory biomarkers. A higher PC-1 score was associated with lower baseline cognitive performances. No association of this profile with cognitive decline was observed in longitudinal analysis. However, PC-5 characterized by high PDGF-AA and RANTES was associated with a faster cognitive decline. Among older adults, a circulating pro-inflammatory immune profile is associated with lower baseline cognitive performance, and some specific pro-inflammatory cytokines might be associated with faster cognitive decline.

Background Over 900 travel-associated Zika virus cases have been identified in New York City (NYC), New York. A survey was administered in NYC adapted from the Knowledge, Attitudes, and Practices (KAP) survey on Zika virus developed by the World Health Organization (WHO). Methods A standardized, self-administered, anonymous questionnaire was administered to a convenience sample in Manhattan and the Bronx from June 30th, 2016 to October 21st, 2016. Responses were grouped into six domains based on the content and structure of the questions and were summarized using descriptive statistics or converted into a continuous knowledge score and assessed for associations with pregnancy status and travel history using linear regression. Results There were 224 respondents with a mean age of 33 (SD ± 11.6) with 77% (170/224) female and 24% (51/224) pregnant. The majority (98% (213/217)) were unable to identify all of the symptoms associated with acute Zika virus infection and all modes of transmission (97% (213/219)). Most participants (85% (187/219)) identified mosquitoes as a mode of transmission. 95% (116/122) reported an association between Zika virus and microcephaly. The most concerning aspect of Zika virus in 46% (91/200) was the risk of disabilities to babies, and risk of sexual transmission (25% (49/200)). When asked what precautions pregnant persons should to reduce the risk of transmission when traveling to a Zika endemic region, only 27% (50/185) identified using condoms during intercourse or refraining from intercourse while pregnant. Knowledge of Zika transmission is significantly positively associated with pregnancy status, but not with travel history. Conclusion Our results indicate an overall poor understanding of Zika virus symptoms and possible complications, transmission modes, and current recommended prevention guidelines. Pregnancy is positively associated with Knowledge of Zika Transmission , but not other knowledge scores. Reported travel history to Zika endemic regions is not significantly associated with Zika knowledge. There is a need for implementing future public health interventions that particularly focus on protection against Zika transmission, that Zika is sexually transmitted, and risks that the Guillain-Barré Syndrome poses a risk to adults.

Blood‐based phosphorylated tau (Ptau) 181 and 217 biomarkers are sensitive and specific for Alzheimer's disease. In this racial/ethnically diverse cohort study, participants were classified as biomarker positive (Ptau+) or negative (Ptau‐) based on Ptau 181 and 217 concentrations and as cognitively impaired (Sym) or unimpaired (Asym). The four groups, Ptau‐/Asym, Ptau+/Asym, Ptau‐/Sym, and Ptau+/Sym, differed by age, APOE‐4 allele frequency, total tau, neurofilament light chain, and cortical thickness measured by MRI. Our results add to increasing evidence that plasma Ptau 181 and 217 concentrations are valid Alzheimer's disease biomarkers in diverse populations.

INTRODUCTION The Información de la Enfermedad de Alzheimer para Latinos (IDEAL) Study is a randomized clinical trial investigating the psychosocial, behavioral, and cognitive impacts of apolipoprotein E (APOE) genotype disclosure for late‐onset Alzheimer's disease (AD) among Latinos. METHODS We used address‐based sampling to recruit English‐ and Spanish‐speaking Latinos aged 40–64 living in northern Manhattan for a community‐based Baseline Survey about their knowledge and opinions about AD. Participants eligible for the clinical trial were invited to complete an Introductory Session, including AD and genetics education and informed consent, before undergoing genotyping for APOE. Participants were then randomized to learn their risk of AD by age 85 (range: 21%–55%) based on either Latino ethnicity and family history alone, or the same factors and their APOE genotype. Risk information is provided in a semi‐structured genetic counseling session. Psychological impacts, health‐related behavioral changes, and cognitive performance are evaluated 6 weeks, 9 months, and 15 months later via surveys and qualitative interviews. To promote cultural competence, study materials were developed by a multidisciplinary team including bilingual and bicultural staff, Latinx content experts, and genetic counselors. RESULTS We sent invitations to 91,433 households; 5542 (6.1%) responded, 2120 completed the Baseline Survey (78.5% online; 21.5% via computer‐assisted telephone interview), and 2087 were deemed eligible, yielding a response rate of 2.3%. Many participants expressed appreciation for the opportunity to contribute to AD research. We randomized 374 participants for the clinical trial. DISCUSSION We describe the study design, recruitment and retention strategies, and interventions employed in the IDEAL Study. Our design provides a framework for future studies using rigorous mixed methods. Our findings may facilitate the development of culturally‐sensitive educational materials about AD and genetic testing, as well as genetic counseling protocols, to improve coping and adjustment in response to receiving risk information. Highlights The Información de la Enfermedad de Alzheimer para Latinos (IDEAL) Study investigates apolipoprotein E (APOE) genotype disclosure among Latinos using mixed methods. We recruited adults 40–64 years of age without Alzheimer's disease (AD) for a community‐based survey and randomized trial. Trial participants receives AD risk estimates with or without APOE genotypes. Psychosocial, behavioral, and cognitive impacts are assessed over 15 months. Findings may inform AD educational materials and genetic counseling protocols.

BACKGROUND Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination. METHODS In 628 CU individuals from a multi‐ethnic cohort, amyloid beta (Aβ)42, Aβ40, phosphorylated tau‐181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured in plasma. RESULTS Higher baseline levels of p‐tau181/Aβ42 ratio were associated with an increased risk of incident dementia. A biomarker pattern (with elevated Aβ42/Aβ40 but low p‐tau181/Aβ42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in this protective biomarker pattern reflecting AD‐specific pathological change. DISCUSSION Elevated levels of AD biomarker p‐tau181/Aβ42, by itself or combined with a low Aβ42/Aβ40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition. Highlights We discuss a multi‐ethnic, urban community study of elderly individuals. The study consisted of a longitudinal assessment over 6 years with repeated clinical assessments. The study used blood‐based biomarkers as predictors of mild cognitive impairment and Alzheimer's disease.

Background Hispanics, one of the fastest‐growing populations in the United States, are disproportionately affected by Alzheimer’s disease (AD). Understanding the variations in AD risk associated with sex and the impact of relocation from their home country is crucial in designing interventions to address health disparities. This study explores the differential impact of sex and geographic relocation on dementia risk and its associated factors among Hispanics. Method We utilized data from two observational samples, encompassing 4,960 individuals from the Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), primarily based in the Dominican Republic, and 2,614 individuals enrolled in the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP), based in the US. In both, we evaluated AD‐related risk factors and biomarker concentrations by sex and disease status, using two‐sample t‐tests and chi‐squared tests. We assessed AD risk across the full sample and conducted sex‐stratified logistic regression analyses, along with linear regression to compare biomarker concentrations and disease onset age among sexes. Results In the EFIGA study, the risk of AD was found to be lower among women (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI]: 0.75‐0.98), whereas in WHICAP, no significant sex‐based differences were observed. Concerning the age of onset, women in EFIGA exhibited an earlier onset (β = ‐1.42, p < 0.001), contrasting with a later onset in WHICAP (β = 1.02, p = 0.007). In the sex‐stratified analyses, both men (OR = 1.66, 95% CI: 1.32‐2.09) and women (OR = 1.64, 95% CI: 1.40‐1.91) in EFIGA showed distinct associations of AD with APOE ε4, a pattern only seen among women in WHICAP (OR = 1.34, 95% CI: 1.06‐1.68). With respect to biomarker concentrations, sex‐related differences were noted in Ab42/40 ratio, total tau, phosphorylated tau, glial fibrillary acidic protein, and neurofilament light, although the specific patterns varied between WHICAP and EFIGA. Conclusion Sex‐related differences in AD risk and associated factors among Hispanics, were evident in both EFIGA and WHICAP studies, and are potentially further influenced by geographic relocation and migration patterns.

Background Plasma biomarkers may be utilized to assist in diagnosis of Alzheimer's disease. However, in a cohort of Caribbean Hispanic individuals we have shown that there are both individuals who are biomarker positive but without dementia, and biomarker negative but diagnosed with dementia. Here we examine education and neuropsychological testing performance in these subgroups with biomarker‐inconsistent dementia diagnosis. Method Adults of Caribbean Hispanic ethnicity were recruited in both New York City and the Dominican Republic. The group reported here includes 1173 individuals. Plasma biomarkers including AB40, AB42, total tau, phosphorylated‐tau181, Neurofilament light chain (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured in samples processed, stored at ‐80°C, and thawed for analysis. Measurements were made using the Simoa Quanterix HD‐X platform. Result In this group of 1172 individuals, 885 (75.5%) were assessed as clinically without dementia, and 288 (24.5%) as clinically with dementia. Of those without dementia, 627 (70.8%) were biomarker negative, and 258 (29.2%) were biomarker positive for p‐tau181. Of those with dementia, 173 (60.1%) were biomarker positive, and 115 (39.9%) were biomarker negative for p‐tau181. For those without dementia, there was no significant difference in education level or performance on most neuropsychological measures between those biomarker positive or negative, except that delayed recall on the SRT word‐list‐learning test was lower in those with higher p‐tau181 (mean 4.25 ± 2.27 vs. 4.65 ± 1.98; p=0.009). For those with dementia, education was significantly lower in those that were p‐tau181 negative (2.87 ± 3.36 vs. 4.18 ± 4.73 yr;p=0.011), but these individuals also performed significantly better in neuropsychological tests including SRT immediate (p=0.003) and delayed recall (p<0.001), orientation (p=0.002), and Benton‐matching (p=0.012). Conclusion Plasma biomarkers may perform well in diagnosis of dementia in clinic populations, but less well in underserved populations, with more persons without dementia but with positive biomarkers, and with dementia but with negative biomarkers. For those without dementia but with positive biomarkers, likely many have pre‐symptomatic Alzheimer's; lower performance on memory tests supports this explanation. For those with dementia, but without positive biomarkers, explanations may include lower cognitive reserve/educational attainment level, increased comorbidities affecting functional status, and the presence of non‐Alzheimer's brain disorders.

Background Despite concerns about the transferability of polygenic risk scores (PRS) derived from European ancestry data to Hispanics, recent research suggests that many genetic loci identified through European ancestry genome‐wide association studies (GWAS) for complex traits are also relevant in Hispanics. Furthermore, studies on dementia have shown improved PRS performance in this group, even with PRS developed from European GWAS. Recent research also indicates that APOE ε4‐independent PRS associations vary depending on APOE ε4 status. This study evaluates the relationship between multiple recent European GWAS‐derived APOE‐independent PRS in Hispanics and the interaction between APOE ε4 and PRS in relation to Alzheimer’s Disease (AD). Methods We constructed a range of PRS based on three recently published GWAS (Kunkle et al., 2019, Bellenguez et al., 2022, FinnGen) of European ancestry among 1,429 Hispanics from the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP) using clumping and thresholding methods. For each GWAS, we first evaluated the associations of several P‐value thresholds with AD to determine the threshold for further analysis. Empirical P‐values were used to avoid overfitting for the optimized PRS. We then tested whether and how APOE ε4 can modify the association between PRS and AD. All associations were fitted by logistic regression with sex, age, education, and the first 5 principal components as covariates. Results Across all European GWAS, the optimal P‐threshold for the most predictive PRS is at a conservative P‐threshold (Kunkle: 2.87e‐6, Bellenguez: 1.11e‐6, FinnGen: 1.80e‐5). PRS constructed based on the Bellenguez GWAS are most strongly associated with AD (OR = 1.29, 95% CI: 1.17‐1.42), and the FinnGen‐derived PRS show the least association (OR = 1.06, 95% CI: 0.98‐1.14). The association of all three PRSs is stronger among APOΕ ε4 carriers (ORKunkle: 1.51, 95% CI: 1.26‐1.81; ORBellenguez: 1.60, 95% CI: 1.35‐1.91; ORFinnGen: 1.12, 95% CI: 0.97‐1.26) compared to non‐carriers (ORKunkle: 1.09, 95% CI: 0.96‐1.23; ORBellenguez: 1.16, 95% CI: 1.03‐1.31; ORFinnGen: 1.03, 95% CI: 0.93‐1.14). Similar findings were observed concerning cognition and progression to dementia. Conclusion PRS derived from a European GWAS identified individuals at high risk for AD dementia among Hispanics, and the association is strongest among APOE ε4 carriers.

Background We investigated the relationship between the cerebrospinal fluid (CSF) proteome in Alzheimer's disease (AD) and the clinical and biomarker‐assisted diagnoses, and with CSF biomarker levels of AD. Methods CSF was collected in 500 individuals of non‐Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City. CSF biomarkers of AD were measured including p‐tau181, Aβ40, Aβ42, total‐tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co‐abundant modules of proteins were tested with the clinical diagnosis of AD, as well as biologically defined AD pathological process based on CSF p‐tau181 and other biomarker levels. Results from replicated in 397 participants from the Accelerated Medicine Partnership‐Alzheimer's Disease CSF cohort and significantly associated proteins were functionally validated in postmortem human brains and zebrafish models. Results CSF levels of 41 proteins were significantly associated with p‐tau181 levels after multiple testing correction. Notably phospholipase D3 (PLD3, p = 2.41E‐09), APOE (p = 4.25e‐08) and osteopontin (OSTP, p = 1.4E‐16) were increased and autotaxin (ENPP2, p = 8.39E‐09) and ceruloplasmin (CERU, p = 2.72E‐07) were decreased among individuals with high p‐tau181 levels. These proteins were also associated with CSF Aβ42/Aβ40 ratio and total Tau levels but not with NfL. OSTP was also associated with CSF levels of GFAP (p = 1.32e‐05). We did not identify any protein association with clinical AD. Among proteins associated with p‐tau181 levels, pathways related to axon development (p = 2.4E‐12), axonogenesis (p = 1.45E‐11) and regulation of axonogenesis (p = 5.1E‐09) were enriched. Immunostaining on postmortem human and zebrafish brains found that ENPP2 expression reduces significantly with AD and amyloidosis, respectively. LPA administration into the zebrafish CSF mitigated Aβ42‐induced vascular, neural, and glial changes. Conclusion Unbiased profiling of circulating CSF proteins identified key proteins associated with β‐amyloid and phosphorylated tau pathology. Biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.

We investigated the relationship between the cerebrospinal fluid (CSF) proteome in Alzheimer's disease (AD) and the clinical and biomarker-assisted diagnoses, and with CSF biomarker levels of AD. CSF was collected in 500 individuals of non-Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City. CSF biomarkers of AD were measured including p-tau181, Aβ40, Aβ42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co-abundant modules of proteins were tested with the clinical diagnosis of AD, as well as biologically defined AD pathological process based on CSF p-tau181 and other biomarker levels. Results from replicated in 397 participants from the Accelerated Medicine Partnership-Alzheimer's Disease CSF cohort and significantly associated proteins were functionally validated in postmortem human brains and zebrafish models. CSF levels of 41 proteins were significantly associated with p-tau181 levels after multiple testing correction. Notably phospholipase D3 (PLD3, p = 2.41E-09), APOE (p = 4.25e-08) and osteopontin (OSTP, p = 1.4E-16) were increased and autotaxin (ENPP2, p =  8.39E-09) and ceruloplasmin (CERU, p = 2.72E-07) were decreased among individuals with high p-tau181 levels. These proteins were also associated with CSF Aβ42/Aβ40 ratio and total Tau levels but not with NfL. OSTP was also associated with CSF levels of GFAP (p = 1.32e-05). We did not identify any protein association with clinical AD. Among proteins associated with p-tau181 levels, pathways related to axon development (p = 2.4E-12), axonogenesis (p = 1.45E-11) and regulation of axonogenesis (p = 5.1E-09) were enriched. Immunostaining on postmortem human and zebrafish brains found that ENPP2 expression reduces significantly with AD and amyloidosis, respectively. LPA administration into the zebrafish CSF mitigated Aβ42-induced vascular, neural, and glial changes. Unbiased profiling of circulating CSF proteins identified key proteins associated with β-amyloid and phosphorylated tau pathology. Biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.