Faculty Bibliography

Reliable structural brain measurements are essential for studying neurodegeneration and for designing adequately powered aging and Alzheimer's disease (AD) research. We evaluated the test-retest reliability of FreeSurfer 7.1 morphometric measures in 100 older adults (mean age 73.5 years) ranging from cognitively unimpaired to dementia. Each participant underwent two T1-weighted 3T MRI scans on the same scanner within a short interval (mean 5.5 weeks), minimizing biological change. Segmentation was performed in both standard cross-sectional and longitudinal FreeSurfer modes, focusing on AD-relevant volumes of entorhinal cortex, hippocampus, lateral ventricles, choroid plexus, and the AD cortical thickness signature. Reliability was quantified using absolute and root-mean-square test-retest differences, standard deviation of differences, and intraclass correlation coefficients. Longitudinal processing improved precision by 15-50% across most measures compared with cross-sectional processing, with the largest gain observed for entorhinal thickness. Larger, anatomically well-defined regions (e.g., hippocampus, AD signature) demonstrated higher reliability than small structures or those with complex geometry (e.g., entorhinal cortex, choroid plexus). Image quality, indexed by the Euler characteristic, was the only factor significantly associated with measurement variability; reliability was unrelated to age, sex, cognitive status, inter-scan interval, or amyloid/tau PET burden. Power analyses indicated that detecting a 1% within-individual change requires sample sizes ranging from 36 (AD signature) to >300 (entorhinal cortex). We observed low reliability of choroid plexus volumetry by FreeSurfer 7. These results provide practical benchmarks for expected FreeSurfer measurement variability in older adults. They highlight the advantages of longitudinal processing and rigorous quality control for research on brain aging and AD.

INTRODUCTION/BACKGROUND:Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been linked to dementia risk, but prior studies were limited by small sample sizes. METHODS:We assessed the association between baseline NLR and incident Alzheimer's disease (AD) and Alzeimer's disease and related dementias (AD/ADRD) using electronic health records from New York University (NYU) (n = 284,530) and the Veterans Health Administration [VA] (n = 85,836) Hospitals from 2011 to 2023. AD/ADRD diagnoses were identified via International Classification of Diseases (ICD) codes ≥6 months post-baseline. Cox models and cumulative incidence functions (CIFs) adjusted for demographic and clinical variables, with death as a competing risk. RESULTS:Higher NLR was associated significantly with increased AD/ADRD risk in both cohorts (NYU hazard ratio [HR] = 1.07, 95% confidence interval [CI] 1.02-1.15; VA HR = 1.21, 95% CI 1.10-1.34). Spline analysis further confirmed a continuous dose-response relationship, and subgroup analyses showed higher risk among female and Hispanic patients. DISCUSSION/CONCLUSIONS:Elevated NLR is independently associated with higher AD/ADRD risk across diverse populations, highlighting the role of systemic inflammation and neutrophil-mediated pathways in neurodegeneration.

INTRODUCTION/BACKGROUND:Though brain fog is common in Long-coronavirus disease 2019 (Long-COVID), the incidence of mild cognitive impairment (MCI) is unknown. METHODS:In an observational cohort study, recovered COVID-positive, Long-COVID, and COVID-negative subjects underwent blinded evaluation using National Alzheimer's Coordinating Center (NACC) and National Institute on Aging (NIA) -Alzheimer's Association diagnostic criteria for dementia and MCI. The cumulative incidence of MCI was calculated for each group, and the hazard of MCI was compared between groups. RESULTS:Among 260 subjects, the cumulative incidence of MCI over 4.4 years was higher with Long-COVID (27%) versus recovered-COVID (5%) or COVID-negative status (1%). There was a higher hazard of MCI for patients with Long-COVID compared to those without (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.86-8.31, p < 0.001), and specifically for the Alzheimer's disease (AD) -related MCI subtype (HR 3.20, 95% confidence interval [CI] 1.14-9.00, p = 0.027). DISCUSSION/CONCLUSIONS:The cumulative incidence and adjusted hazard of MCI (and specifically AD-related MCI) at 4.4 years was significantly higher among Long-COVID patients compared to recovered-COVID and COVID-negative controls.

Worldwide, over half of all individuals with dementia are undiagnosed. In the United States, racial, ethnic, and economic inequities mirror global findings, with higher rates of missed and delayed diagnosis and poorer diagnostic quality among minoritized and disadvantaged groups. For example, delayed diagnosis is more prevalent among people identifying as non-Hispanic Black or Latino than non-Hispanic White. Systematic efforts to improve detection can increase diagnosis rates; there is broad consensus that earlier detection and initiation of focused care and support services benefit both affected individuals and their loved ones. Systemic under-detection and its contributions to persistent population-level suffering underscore the importance of early detection of dementia as a key public health issue. Improving early detection calls for comprehensive, coordinated responses from local, regional, and national public health systems in partnership with health care delivery systems and community-based organizations. The Public Health Center of Excellence on Early Detection of Dementia (PHCOE on EDD), funded by the Centers for Disease Control and Prevention (CDC), is a national resource to promote understanding and implementation of evidence-based and evidence-informed public health strategy for early detection of dementia. We, together with the PHCOEs on Dementia Risk Reduction and Dementia Caregiving, and nearly four dozen state and local initiatives, seek to operationalize the priorities of the Building Our Largest Dementia Infrastructure for Alzheimer's Act and National Healthy Brain Initiative, established by federal legislation in 2018 and 2024. Our efforts support the CDC's mandate to build a national public health infrastructure for brain health and dementia.

INTRODUCTION/BACKGROUND:The Neighborhoods Study (TNS) is a novel investigation of adverse social exposome and brain health leveraging 22 Alzheimer's Disease Research Centers (ADRCs). TNS aims to understand if the adverse social exposures increase Alzheimer's disease and related dementias (ADRD) risk. METHODS:TNS uses innovative methods to determine lifetime addresses of living (n = ≈ 3116) and brain bank cohorts (n = ≈ 8637). Addresses are linked to time-concordant adverse social exposome using the Area Deprivation Index (ADI) and summarized over time. Brain health measures are provided by the National Alzheimer's Coordinating Center. RESULTS:We highlight a general overview and methodology of TNS. Data collection is ongoing; however, preliminary findings indicate that the adverse social exposome is related to ADRD biomarkers, neuropathology, and cognitive function. DISCUSSION/CONCLUSIONS:TNS is the largest study of adverse social exposome and ADRD, using the ADRC network to build robust scientific consortia. Its findings will inform ADRD interventions, precision medicine, and policy. HIGHLIGHTS/CONCLUSIONS:The Neighborhoods Study (TNS) investigates adverse social exposome and brain health. TNS is a collaboration among 22 Alzheimer's Disease Research Centers. TNS will give insight on environmental and exposomal factors which may be modifiable. Participant lifetime addresses are linked to temporal adverse social exposome metrics. This study's findings will inform precision approaches to mitigate dementia risk.

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β₄₂ ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

PURPOSE/OBJECTIVE:The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS:We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS:There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS:Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

BACKGROUND:Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). METHODS:Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. RESULTS:Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.

BACKGROUND:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS:We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.