Sanjay Asthana’s research while affiliated with University of Wisconsin–Madison and other places

The gut microbiome modulates metabolic, immune, and neurological functions and has been implicated in Alzheimer’s disease (AD), though the specific mechanisms remain poorly defined. The bacterial metabolite imidazole propionate (ImP) has been previously associated with several AD comorbidities, such as type 2 diabetes and cardiovascular disease. Here, we show that elevated plasma ImP levels are associated with lower cognitive scores and AD biomarkers in a cohort of >1,100 cognitively unimpaired individuals. Metagenomic profiling identified gut bacteria encoding putative orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Chronic ImP administration to mice activated neurodegenerative pathways, worsened AD-like neuropathology, and increased blood-brain barrier (BBB) permeability. Complementary in vitro studies showed that ImP compromised the integrity of human brain endothelial cells. Collectively, these findings implicate ImP in AD progression via both neurodegenerative and cerebrovascular mechanisms, identifying it as a potential target for early intervention. One Sentence Summary Gut bacterial metabolite increases dementia risk.

INTRODUCTION Synapse loss is a key driver of cognitive decline in Alzheimer's disease (AD), yet its direct relationship with neurofibrillary tau tangle (NFT) burden remains unclear. This study leveraged positron emission tomography (PET) imaging to investigate the link between NFT accumulation and synaptic density in older adults with and without AD pathology. METHODS Older adults (N = 94) underwent PET imaging to quantify synaptic density ([¹¹C]UCB‐J distribution volume ratio [DVR]), Aβ plaque burden ([¹¹C]PiB DVR), and NFT burden ([¹⁸F]MK‐6240 standardized uptake value ratio). Analyses focused on NFT‐synaptic density correlations in the hippocampus (Hp) and entorhinal cortex (ERC), with additional subgroup analyses based on cognitive and Aβ status. RESULTS Hp NFT burden strongly correlated with synaptic density, while the ERC showed weaker effects. Subgroup analyses found robust Hp associations in unimpaired AD participants. CONCLUSION Hippocampal synaptic density is highly vulnerable to early NFT accumulation. SV2A PET imaging enables early detection of synaptic loss and may also identify resilience to AD pathology. Highlights Hippocampal synaptic density is similar in controls and unimpaired biologic AD. Hp synaptic density particularly vulnerable to Hp, ERC NFT burden. NFT–synaptic density relationship may vary between unimpaired and impaired biologic AD

Amyloid burden impacts cognitive decline in the pre-dementia stages of Alzheimer’s disease (AD), but there remains significant variability in cognitive trajectories that may be explainable by markers of synaptic function and neurodegeneration. Leveraging longitudinal data from two harmonized, at-risk but predominantly unimpaired cohorts, we examined how several proteins measured from cerebrospinal fluid (CSF) differ by amyloid status, cognitive status, and impact cognitive decline measured using a Preclinical Alzheimer’s Cognitive Composite. Four hundred and thirty-four individuals provided CSF biomarkers of amyloid-beta42 (ab42), phosphorylated tau (181), from which we identified Aβ + individuals using a cutoff based on a p-tau181/Aβ42 ratio. Other markers of neurodegeneration (N) included neurofilament light, neurogranin, SNAP-25, and NPTX2. Most biomarkers of N were higher in the Aβ + group and lower in cognitively unimpaired individuals, though NPTX2 exhibited the opposite pattern. Even in the face of Aβ+, NPTX2 was higher in individuals who showed slower rates of cognitive decline, suggesting NPTX2 may be associated with cognitive resilience. Moreover, a SNAP-25/NPTX2 ratio of synaptic dysfunction explained more variance in cognitive decline than other biomarkers alone. This work provides support for potentially useful biomarkers of synaptic function implicated in the clinical syndrome of AD, aiding in future diagnosis and staging efforts. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-025-04319-3.

INTRODUCTION Medical conditions prevalent in Black adults within the United States have been associated with plasma tau phosphorylated at threonine 217 (p‐tau217); however, insufficient p‐tau217 research has been conducted with Black adults. METHODS Participants included n = 233 predominantly cognitively unimpaired adults enrolled in the African Americans Fighting Alzheimer's in Midlife study. Subsamples had creatinine (n = 137) and positron emission tomography (PET; amyloid‐PET = 65 [amyloid‐PET‐positive = 16/65]; tau‐PET = 70). We tested whether p‐tau217 (ALZPath, Inc.) varied by medical condition and amyloid‐ and tau‐PET‐positivity status and assessed the diagnostic accuracy of p‐tau217. RESULTS Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², cardiovascular disease (CVD), and amyloid‐ and tau‐PET‐positive status demonstrated higher p‐tau217. Effect sizes (rpb): eGFR <60 group = 0.48, CVD = 0.25, amyloid‐PET‐positive status = 0.54; tau‐PET‐positive status = 0.56. Lower eGFR was related to higher p‐tau217 when adjusting for amyloid‐PET. For abnormal amyloid‐PET and tau‐PET, p‐tau217 exhibited areas under the curve of 0.90 and 0.89, respectively. DISCUSSION Plasma p‐tau217 showed promise as an Alzheimer's biomarker in Black adults; however, kidney function and CVD should be considered when interpreting levels. Highlights Plasma tau phosphorylated at threonine 217 (p‐tau217) was tested in a sample of Black middle‐aged and older adults. Level of p‐tau217 was higher in impaired kidney function and cardiovascular disease. Obesity and diabetes were not related to p‐tau217. Level of p‐tau217 was higher in amyloid‐ and tau‐PET‐positive status. Plasma p‐tau217 showed good receiver‐operating characteristic area under the curve for abnormal amyloid‐ and tau‐PET.

Sex differences in late-onset Alzheimers disease (AD) progression include accelerated decrements in cognitive status and greater amyloid and tau biomarker burdens in females. To identify sex-specific differentially methylated positions (DMPs) and genes in persons with mild cognitive impairment (MCI) and AD, we analyzed whole genome methylation sequencing on blood samples from participants with MCI (N=99, 52% female), AD (N=109, 43% female), and those cognitively unimpaired (CU; N=174, 52% female). Ninety-four percent of DMPs from MCI vs. CU, AD vs. CU, and AD vs. MCI pairwise comparisons were sex-specific. Female-specific DMPs were enriched in neurologic gene sets (e.g., synaptic membrane, ion channel complex), while male-specific DMPs showed limited enrichment. Sex-specific DMPs overlapped blood-specific enhancers, promoters, and transcription factor binding motifs, highlighting divergent epigenetic regulation by sex. These findings identify sex-specific genes and molecular pathways in MCI and AD and support that blood DNA methylation levels can distinguish cognitive status.

INTRODUCTION Multi‐etiology dementia necessitates in vivo markers of copathologies including misfolded α${{\alpha}}$‐synuclein (syn). We measured misfolded syn aggregates (syn‐seeds) via qualitative seed amplification assays (synSAA) and examined relationships with markers of Alzheimer's disease (AD). METHODS Cerebrospinal fluid (CSF) was obtained from 420 participants in two AD risk cohorts (35% male; 91% cognitively unimpaired; mean [standard deviation] age, 65.42 [7.78] years; education, 16.17 [2.23]) years). synSAA results were compared to phosphorylated tau (T), amyloid beta (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects. RESULTS Syn positivity (synSAA+) co‐occurred with T (in synSAA+ vs. synSAA−, 36% vs. 20% T+; Pp = 0.011) and with cognitive impairment (10% vs. 7% mild cognitive impairment; 10% vs. 0% dementia; p = 0.00050). synSAA+ participants’ cognitive performance declined ≈ 40% faster than synSAA– for Digit Symbol Substitution, but not other tests. DISCUSSION Findings support prevalent syn copathology in a mostly unimpaired AD risk cohort. Relationships with progression should be evaluated once more have declined. Highlights In a middle‐aged sample, misfolded α${{\alpha}}$‐synuclein (syn) co‐occurred with phosphorylated tau181 (T). syn+/T+ status was linked with higher levels of other cerebrospinal fluid biomarkers. syn+ individuals were more likely than syn– to be cognitively impaired. syn+ status was linked to faster decline on an executive function task.

This paper reports on a Conference organized by the Washington University School of Medicine's (WUSM) Knight Alzheimer Disease Research Center (Knight ADRC), entitled “Enhancing Participation by Minoritized Groups in Alzheimer Disease and Related Dementia (ADRD) Research.” It builds on recommendations from a 2018 Workshop. Representatives from all 37 federally funded ADRCs described strategies to enhance the recruitment and engagement of participants from historically minoritized groups. St. Louis community members attended and provided input. The Conference was guided by the 2015 National Institute on Aging (NIA) Health Disparities Research Framework, which delineates that “fundamental life‐course factors such as race, ethnicity, and socioeconomic status interact with behavioral and biological characteristics to determine health and disease.” The multiple ways of engaging participants described at the Conference provide guidance and strategies that can be adapted and utilized across the ADRC network and other research programs nationally to enhance inclusion of minoritized groups in ADRD research. Highlights Increasing representation in Alzheimer disease and related dementias (ADRD) research is a national priority. The National Conference described strategies to diversify participation in AD research. All Alzheimer's Disease Research Centers (ADRCs) were represented. Local community members attended and participated in breakout sessions. Many community‐engaged strategies are being used to enhance recruitment and retention. Approaches can be adapted for local needs and utilized by ADRCs.

INTRODUCTION Targeted proteomic assays may be useful for diagnosing and staging Alzheimer's disease and related dementias (ADRD). We evaluated the performance of a 120‐marker central nervous system (CNS) NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) panel in samples spanning the Alzheimer's disease (AD) spectrum. METHODS Cross‐sectional plasma samples (n = 252) were analyzed using NULISAseq CNS panel from Alamar Biosciences. Receiver‐operating characteristic (ROC) analyses demonstrated the accuracy from NULISAseq‐tau phosphorylated at threonine 217 (pTau217) in detecting amyloid (A) and tau (T) positron emission tomography (PET) positivity. Differentially expressed proteins were identified using volcano plots. RESULTS NULISAseq‐pTau217 accurately classified A/T PET status with ROC areas under the curve of 0.92/0.86; pTau217 was upregulated in A+, T+, and impaired groups with log2‐fold changes of 1.21, 0.57, and 4.63, respectively, compared to A−. Of interest, TAR DNA‐binding protein 43 (TDP‐43) phosphorylated at serine 409 (pTDP43‐409) was also upregulated in the impaired group and correlated with declining hippocampal volume and cognitive trajectories. DISCUSSION This study shows the potential of a targeted proteomics panel for characterizing brain changes pertinent to ADRD. The promising pTDP43‐409 findings require further replication. Highlights The NULISAseq pTau217 assay was comparable to the Simoa pTau217 assay, both utilizing the ALZpath antibody, in detecting amyloid positron emission tomography (PET) positivity, each with areas under the curve greater than 90%. Nineteen proteins were differentially expressed in participants with mild cognitive impairment (MCI) compared to those who were unimpaired. Markers of non‐AD proteinopathies such as pTDP43‐409, oligomeric alpha‐synuclein, and huntingtin (HTT), were among those upregulated in MCI. High levels of plasma pTDP43‐409 were associated with worsening hippocampal atrophy and cognitive decline, clinical indicators of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), compared to those with low pTDP43‐409.

Machine learning (ML) on structural MRI data shows high potential for classifying Alzheimer’s disease (AD) progression, but the specific contribution of brain regions, demographics, and proteinopathy remains unclear. Using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, we applied an extreme gradient-boosting algorithm and SHAP (SHapley Additive exPlanations) values to classify cognitively normal (CN) older adults, those with mild cognitive impairment (MCI) and AD dementia patients. Features included structural MRI, CSF status, demographics, and genetic data. Analyses comprised one cross-sectional multi-class classification (CN vs. MCI vs. AD dementia, n = 568) and two longitudinal binary-class classifications (CN-to-MCI converters vs. CN stable, n = 92; MCI-to-AD converters vs. MCI stable, n = 378). All classifications achieved 70–77% accuracy and 61–83% precision. Key features were CSF status, hippocampal volume, entorhinal thickness, and amygdala volume, with a clear dissociation: hippocampal properties contributed to the conversion to MCI, while the entorhinal cortex characterized the conversion to AD dementia. The findings highlight explainable, trajectory-specific insights into AD progression.

Objective Accelerated biological aging is a plausible and modifiable determinant of dementia burden facing minoritized communities but is not well-studied in these historically underrepresented populations. Our objective was to preliminarily characterize relationships between telomere length and cognitive health among American Indian/Alaska Native (AI/AN) and Black/African American (B/AA) middle-aged and older adults. Methods This study included data on telomere length and neuropsychological test performance from 187 participants, enrolled in one of two community-based cognitive aging cohorts and who identified their primary race as AI/AN or B/AA. Results Nested multivariable regression models revealed preliminary evidence for associations between telomere length and cognitive performance, and these associations were partially independent of chronological age. Discussion Small sample size limited estimate precision; however, findings suggest future work on telomere length and cognitive health in underrepresented populations at high risk for dementia is feasible and valuable as a foundation for social and behavioral intervention research.