👤 David Lukacsovich

Cognitive reserve (CR) refers to differences in the adaptability of cognitive processes that modify the impact of Alzheimer's disease (AD) pathology on cognitive performance. Currently there are no established blood-based biomarkers of CR in prodromal AD. In this study, we operationalize CR as memory reserve, defined as moderation (attenuation) of the CSF pTau181-memory association. DNA methylation (DNAm) integrates genetic and environmental influences and may capture biological processes that mitigate the impact of AD pathology on memory. We aimed to identify blood DNAm loci that moderate the association between cerebrospinal fluid (CSF) phosphorylated tau (pTau181) and memory in mild cognitive impairment (MCI). We also sought to determine if a DNAm-based signature of memory reserve predicts future memory decline. We analyzed 92 amyloid positive MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory scores (PHC_MEM) collected at the same visit. We first regressed memory scores on covariates (age, sex, number of After removing CpGs with low variability, we identified 6 CpGs with suggestive significance for DNAm×pTau181 interaction ( Blood DNAm patterns that moderate the pTau-memory relationship capture biology underlying memory reserve involving synaptic, vascular, immune, and metabolic pathways, and can be summarized into an MRS that predicts longitudinal memory trajectories in MCI. These findings support blood DNAm as a promising, non-invasive biomarker of cognitive resilience to AD pathology. Show less

As dementia cases continue to rise, effective prevention strategies are urgently needed. However, objective biomarkers that directly reflect lifestyle factors remain limited. Life's Essential 8 (LE8) is a composite of modifiable cardiovascular health metrics, and lower LE8 has been consistently associated with increased risk of dementia. In this study, we aimed to identify DNA methylation biomarkers associated with LE8 scores and investigate their relevance for dementia risk. We performed an epigenome-wide association study of 273 stroke-free, self-identified Hispanic adults aged 40 and older from the Northern Manhattan Study (NOMAS), a community-based urban cohort study. DNA methylation (DNAm) was assessed using Illumina MethylationEPIC arrays. Robust linear models identified CpGs associated with LE8 score, a composite score on eight health metrics including diet quality, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Differentially methylated regions were identified by combining P-values in sliding windows while accounting for spatial correlations across the genome. We also performed functional annotation, pathway analyses, and integrative analyses with gene expression, genetic variants, brain-blood correlations, and comparisons with previous dementia studies to identify the most biologically meaningful DNAm sites. After adjusting for age, sex, APOE ε4, immune cell composition, and ancestry, we found 11 CpGs with suggestive evidence of association with LE8 (P-value < 1 × 10 Our comparison with published results showed that a number of LE8-associated DNA methylation sites are associated with dementia, highlighting the possible connection between cardiovascular health and dementia risk and pointing to potential actionable targets for dementia prevention. Moreover, DNAm biomarkers have clinical potential as objective measures to identify individuals at elevated risk, stratify participants based on biologically informed risk profiles, and monitor epigenetic responses to lifestyle interventions in dementia prevention trials. Future studies in larger and more diverse cohorts are needed to validate and refine these methylation biomarkers for clinical applications. Show less

Ventral subiculum (vSUB) is integral to the regulation of stress and reward; however, the intrinsic connectivity and synaptic properties of the inhibitory local circuit are poorly understood. Neurexin-3 (Nrxn3) is highly expressed in hippocampal inhibitory neurons, but its function at inhibitory synapses has remained elusive. Using slice electrophysiology, imaging, and single-cell RNA sequencing, we identify multiple roles for Nrxn3 at GABAergic parvalbumin (PV) interneuron synapses made onto vSUB regular-spiking (RS) and burst-spiking (BS) principal neurons. Surprisingly, we find that intrinsic connectivity of vSUB and synaptic function of Nrxn3 in vSUB are sexually dimorphic. We reveal that PVs make preferential contact with RS neurons in male mice, but BS neurons in female mice. Furthermore, we determine that despite comparable Nrxn3 isoform expression in male and female PV neurons, Nrxn3 knockout impairs synapse density, postsynaptic strength, and inhibitory postsynaptic current (IPSC) amplitude at PV-RS synapses in males, but enhances presynaptic release and IPSC amplitude in females. Show less