👤 James Leverenz

Alzheimer's disease pathology (ADP) and Lewy body pathology (LBP) are traditionally associated with distinct cognitive profiles. However, growing evidence highlights the role of behavioral and psychological symptoms of dementia (BPSD) in shaping clinical presentations. The combined influence of cognitive and behavioral symptoms across neuropathologically confirmed ADP, LBP, and mixed AD-LBP has not been systematically examined. This study aimed to identify clinically meaningful subtypes by jointly analyzing cognitive performance and BPSD profiles in individuals with autopsy-confirmed dementia pathology. This retrospective longitudinal cohort study used data from the National Alzheimer Coordinating Center (NACC), collected across multiple U.S. Alzheimer's Disease Research Centers. Participants had a Clinical Dementia Rating (CDR) Global score ≤1 at baseline and autopsy-confirmed ADP, LBP, or mixed AD-LBP. Cognitive outcomes included standardized tests of memory, executive function, and language. BPSD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), which captures ten symptom domains: agitation, apathy, depression, delusions, disinhibition, auditory and visual hallucinations, irritability, personality change, and REM sleep behavior disorder. Cluster analysis was applied to identify subtypes based on combined cognitive and BPSD data. The study included 1,028 participants (mean age at baseline 76.4 years; 47.6% female): 521 with ADP, 96 with LBP, and 411 with mixed AD-LBP. A three-cluster clinical subtype (CS) solution best fit the data. The most symptomatic group (CS-3) had the youngest age at first visit (mean 72.1 years), the highest BPSD burden, and the fastest cognitive and functional decline across ADP and AD-LBP groups. CS-1 and CS-2 exhibited milder early cognitive impairment and lower BPSD burden. Within ADP and AD-LBP, CS-2 showed slower progression than CS-1, fewer APOE ε4 carriers (41% vs. 58%), and better memory scores, despite reporting a higher frequency of agitation. These findings reveal distinct clinical subtypes that cut across traditional pathological boundaries, emphasizing the need to incorporate both cognitive and behavioral features into early dementia characterization. This multidimensional approach can improve guide personalized prognosis and care planning and enhance clinical trial design by considering disease heterogeneity. The study supports integrated clinical profiling as important factor in robust evaluation of dementia outcomes. Show less

BackgroundLogopenic primary progressive aphasia (LPA) is often associated with Alzheimer's disease (AD) pathology. However, few studies have compared cortical atrophy patterns in LPA and AD and their association with cognitive performance.ObjectiveTo identify atrophy patterns specific to LPA and determine whether those patterns relate to deficits in specific cognitive domains.MethodsElectronic health records from 2014-2024 were retrospectively reviewed to identify patients with LPA who had undergone MRI and neuropsychological (NP) examinations. Patients with LPA (n = 26) were matched in terms of age, sex, education, and symptom duration to patients with amnestic mild cognitive impairment (aMCI; n = 13). Logistic regression was used to assess group differences in MRI measures of cortical volume and thickness. Cluster analysis was used to identify patterns of atrophy that were associated with specific cognitive domains.ResultsThe LPA group performed significantly worse than the aMCI group on NP measures assessing verbal learning, attention/working memory, language, and executive functioning (p < 0.05). Compared to the aMCI group, the LPA group demonstrated both smaller and thinner cortex in the left lateral aspect of the superior temporal gyrus, superior temporal sulcus, and fusiform gyrus (p < 0.05), with the left superior temporal sulcus providing the most accurate measure of discrimination. Severity of language related cognitive deficits was not associated with a specific cluster in the LPA group.ConclusionsPatients with LPA demonstrate specific patterns of cortical atrophy that are distinguishable from atrophy due to aMCI and may be useful for diagnostic purposes. Show less

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. Show less

Although the human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from both cerebellum and frontal cortex of AD/ADRD patients and normal controls. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we pinpointed two likely causal genes, Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and three-dimensional (3D) genome data. Via CRISPRi experiments, we found that perturbation of rs4788201 and rs62056801 significantly inhibited the expression of their target genes, SEZ6L2 and KANSL1, in human iPSC-derived neurons. This cell subtype-specific regulatory landscape in the human cerebellum identified here offers novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less

Transposable element (TE) dysregulation is associated with neuroinflammation in Alzheimer's disease (AD) brains. Yet, TE quantitative trait loci (teQTL) have not been well characterized in human aged brains with AD. We leveraged large-scale bulk and single-cell RNA sequencing, whole-genome sequencing (WGS), and xQTL from three human AD brain biobanks to characterize TE expression dysregulation and experimentally validate AD-associated TEs using CRISPR interference (CRISPRi) assays in human induced pluripotent stem cell (iPSC)-derived neurons. We identified 26,188 genome-wide significant TE expression QTLs (teQTLs) in human aged brains. Subsequent colocalization analysis of teQTLs with AD genetic loci identified AD-associated teQTLs and linked locus TEs. Using CRISPRi assays, we pinpointed a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE; chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons. We identified widespread TE dysregulation in human AD brains and teQTLs offer a complementary analytic approach to identify likely AD risk genes. Widespread transposable element (TE) dysregulations are observed in human aging brains with degrees of neuropathology, apolipoprotein E (APOE) genotypes, and neuroinflammation in Alzheimer's disease (AD). A catalog of TE quantitative trait loci (teQTLs) in human aging brains was created using matched RNA sequencing and whole-genome sequencing data. CRISPR interference assays reveal that an upregulated intergenic TE from the MIR family (chr11: 47608036-47608220) suppresses expression of its nearest anti-inflammatory gene C1QTNF4 in human induced pluripotent stem cell-derived neurons. Show less

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less