Citations

Abstract Background Some cases of Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) feature the mislocalization of the normally nuclear TAR DNA binding protein (TDP‐43) to the cytoplasm where it is incorporated into inclusions in affected brain regions. TDP‐43 plays a crucial role in the suppression of cryptic exons in the mature RNA of many targets in both AD and FTD. One such target, Stathmin‐2 (STMN2), is misspliced in the absence of TDP‐43 leading to a reduction of STMN2 RNA and protein while the levels of the cryptic splice variant is increased. Cryptic exons are not conserved across species, meaning previous Tdp‐43 models did not capture Stmn2 processing defects and Stmn2 loss of function (LOF). We hypothesize that STMN2 LOF contributes to cognitive phenotypes observed in AD and FTD. Method We have generated a novel mouse that more accurately models human disease mechanisms by expressing short‐hairpin (shRNA) via adeno associated virus in the central nervous system of a recently described humanized Stmn2 mouse model in which Stmn2 splicing is dependent on Tdp‐43. In this mouse we will simultaneously model Tdp‐43 loss of function and aberrant Stmn2 splicing. Result Our preliminary experiments demonstrate that humanized Stmn2 mice expressing shRNA against Tardbp have a reduction of Tardbp RNA and TDP‐43 protein compared to mice expressing a non‐targeting shRNA. Tdp‐43 knock‐down is accompanied by cryptic splicing of endogenous mouse targets, Sortilin 1 and Translin . As anticipated, we also detected cryptic Stmn2 splicing, suggesting that correct Stmn2 splicing is dependent on Tdp‐43 in this model. We will further characterize motor and cognitive functions in addition to neurodegeneration and gliosis in these animals. Conclusion We anticipate this novel model, and our subsequent studies will identify relevant disease mechanisms and provide an invaluable tool with which to investigate therapies for AD and FTD.

Abstract Background The interplay between vascular dysfunction and brain amyloidosis in driving Alzheimer's disease (AD) pathogenesis and cognitive decline is increasingly recognized. The retina, sharing an embryonic origin with the brain, offers an accessible CNS organ for high‐resolution, noninvasive imaging of AD‐related vascular pathology. However, the exact nature of retinal vascular damage in AD—especially in early disease stages—and its relationship with cerebral amyloid angiopathy (CAA) and cognitive impairment remain understudied. Method We examined vascular abnormalities in retinas of MCI and AD via histopathology and in‐vivo imaging studies. Postmortem retinas from 53–62 individuals (CN: 22; MCI/AD: 31–40) underwent immunohistochemistry for pericyte integrity, vascular Aβ42/40, and endothelial TJ proteins, with dysregulated proteins quantified by mass spectrometry in 12 additional AD/CN cases. Retinal curcumin‐amyloid imaging by scanning‐laser ophthalmoscope in 28–34 live participants (CN[MOCA>26]: 8–15; MCI/AD[MOCA≤26]: 13–19) assessed peri‐arteriolar/venular amyloid plaques (APs). Perivascular AP burden was correlated with MRI measures (hippocampal volume, WMH lesions) and cognitive/neuropsychiatric parameters. Result Retinal pericyte loss, reflected by PDGFRβ deficiency and apoptosis, was evident in MCI and AD patients and correlated with vascular Aβ42/40 accumulation and CAA severity (r=0.68–0.84; p <0.01–0.0001). Retinal endothelial ZO‐1 and claudin‐5 levels were significantly reduced, correlating with arteriolar Aβ40 deposition, suggesting impaired retinal Aβ clearance. Retinal capillary claudin‐5 and arteriolar Aβ40 strongly associated with CAA (r=0.75–0.77, p <0.0001), while ZO‐1 moderately correlated with brain amyloidosis/tauopathy, CAA, and cognitive decline (r=0.43–0.57, p <0.01–0.001). Both histological and in‐vivo imaging studies revealed greater Aβ deposition in retinal arterioles, particularly in secondary and tertiary branches, compared to venules or capillaries ( p <0.01–0.0001). Retinal perivascular APs in secondary/tertiary branches imaged in living patients correlated with cognitive impairment (global CDR, MOCA), hippocampal atrophy, and WMH lesions (r=0.51–0.66, p <0.05–0.001). Perivascular APs in the secondary (β=0.397, p = 0.033) and tertiary (β=0.756, p = 0.017) arteriolar branches showed significant interactions with hippocampal volumetry for visual memory. Conclusion Retinal arteriolar Aβ accumulation, pericyte loss, and TJ dysfunction contribute to early AD vascular pathology. If validated in larger cohorts, these findings support retinal vascular biomarkers as tools for predicting cognitive decline, monitoring AD progression, and assessing CAA severity.

Abstract Background Our group recently performed the largest‐to‐date X‐chromosome wide association study (XWAS) of Alzheimer's disease (AD). Here, we expand on this with additional samples, novel sex‐ and APOE *4‐stratified analyses, and evaluate escape from random X chromosome inactivation (eXCI) to better capture female‐biased risk genes. We then integrate these results with XWASs of various AD‐relevant traits to elucidate shared genetic signals and ultimately uncover novel AD risk genes and mechanisms. Method The AD XWAS design is shown in Figure 1A and includes random X chromosome inactivation (rXCI) and eXCI models. We further assessed suggestive AD signals ( p <1x10 ‐3 ) for pleiotropy using genetic colocalization with 2852 AD‐relevant traits (Figure 2A). Loci exhibiting X chromosome‐wide significance ( p <1x10 ‐5 ) or apparent trait colocalization underwent quantitative trait locus (QTL) colocalization analyses across 62 tissues and cell types to functionally prioritize AD risk genes. Result Full sample analyses reproduced Belloy et al. 2024 findings and identified 3 additional loci, including a male‐specific signal near GLUD2 that impacts glutamate/glutamine metabolism (Figure 1B). APOE *4‐stratified analyses revealed 9 additional loci, including 3 eXCI hits in APOE *4 carriers (Figure 1C‐D). Pleiotropy colocalization identified 38 loci, most being novel and many driven by eXCI and/or female‐specific AD XWAS, including MOSPD2, PNMA3 and GABRE loci that showed extensive colocalization with brain imaging traits (Figure 2B). The most significant XWAS locus, SLC9A7 , colocalized with total testosterone, HDL‐C, and various brain imaging traits. Only the NLGN4X locus colocalized with amyloid positivity, linking its proposed role in synaptic dysfunction to amyloid pathology. The locus at KDM6A , previously implicated as an AD resilience gene, colocalized with a functional MRI (fMRI) phenotype. QTL colocalization analyses confirmed gene prioritizations in Belloy et al. 2024, and additionally provided support for PNMA3 , an antigen highly expressed in the brain, and 3 APOE ‐stratified loci, including ACLS4 , which impacts lipid metabolism. Conclusion This study provides novel insights into biological mechanisms that contribute to X‐linked genetic risk for AD in an APOE *4 and sex‐specific manner, identifying various novel risk loci. Notably, 29 female‐biased risk loci were uncovered, which may shed light on sex disparities in AD. Overall, our findings will aid in elucidating AD pathways and drug targets relevant to personalized medicine.

Abstract Background Alzheimer's disease (AD) affects all brain cells and has complex genomic and immunological alterations. Previous research discovered missense AD risk or protective variants in microglial genes ABI3 and PLCG2, respectively. Expression levels of these genes are altered in AD and can influence microglial function. This study aims to uncover protective, and risk microglial molecular signatures associated with these variants to determine their role in microglial subtypes and states in AD by single cell expression and functional studies. Method We generated microglia‐enriched snRNAseq data from donors harboring either AD protective PLCG2 or AD risk ABI3 missense mutations, or neither mutation. After standard snRNAseq QC, we performed differential expressed gene (DEG) analysis of all microglial cells between variant carriers and non‐carriers using MAST. We defined protective signature as genes that are both down in ABI3 and up in PLCG2 mutation‐carriers. In contrast, risk signature genes are up in ABI3 and down in PLCG2 mutation‐carriers. We investigated the conservation of protective and risk signatures across multiple datasets, including scRNAseq data from iPSC‐derived microglia cells carrying PLCG2 protective variant, snRNAseq data from AD‐resilient donors, and data from AD and other diagnostic groups across multiple brain regions sourced from external datasets. Result We obtained snRNAseq profiles of 35,000 microglia from AD variant carriers. Our DEG analysis among all microglia cells provided 227 microglial protective and 293 risk signature genes defined by these variants. Using integrated analysis of multiple internal and external datasets, we further narrowed down these signatures. We determined that these high‐confidence protective signature genes are downregulated in early AD, upregulated in late AD brains and positively‐correlated with protective variant load in in vitro models. In contrast, risk signature genes are upregulated in early AD, downregulated in late AD and resilient donors. Risk signature expression is decreased with protective PLCG2 variant load, and altered with Aβ treatment in in vitro models. Conclusion Our study uncovers microglia specific protective and risk signatures associated with AD using sn/scRNAseq datasets from multiple sources and models. These findings nominate novel immune targets and pathways with implications for microglial function in health and disease, and ultimately therapeutic potential.

Abstract Background Disparities in structural and social determinants of health in Latino and Black communities may increase the burden of Alzheimer disease and related dementias (ADRD). Identifying dementia risk factors, which may account for up to 45% of ADRD risk, is crucial to implement effective risk‐reduction strategies. This study aimed to assess ADRD risk factors in community‐dwelling, cognitively normal, Latino and Black Americans by measuring the frequency of modifiable dementia risk factors through subjective and objective measures. Method Community‐dwelling, cognitively normal, Latino and Black adults (≥45‐years‐old) were enrolled in a longitudinal study of memory and aging at Mayo Clinic in Jacksonville, Florida. Baseline assessments conducted between Mach 2022 and November 2024 included demographics, self‐reported race/ethnicity, and history of dementia risk factors. Socioeconomic deprivation [Area Deprivation Index (ADI) State scores] and modifiable dementia risk factors were reported by participants and directly measured, including hypertension (BP >130/80 mmHg), obesity (BMI≥30), hyperlipidemia (LDL>100 mg/dL), hyperglycemia (HbA1C >5.6%), low vitamin B12 (B12<350 pg/mL), hearing loss (bedside assessment), vision loss (bedside assessment), and depression (Geriatric Depression Scale ≥5). Result 105 participants (47 Latino, 55 Black), 64.7 (±8.8) years‐old, female 66 (63%), with 16 (±2.3) years of education were assessed. Black participants experienced higher socioeconomic deprivation than Latino participants (median ADI 7 vs 3; p <0.001). Dementia risk factors were common in Latino and Black participants. These included, hypertension (55.3%, 70.3%; p = 0.291), hyperlipidemia (58.7%, 55.8%; p = 0.908), obesity (29.8%, 45.5%; p = 0.263), hyperglycemia (51.1%, 49.1%; p = 0.834), low vitamin B12 (23.9%, 28.0%; p = 0.270), hearing loss (19.1%, 7.3%; p = 0.111), vision loss (85.1%, 85.2%; p = 0.771), and depression (6.4%, 5.5%; p = 0.168). Objective measures revealed a higher frequency of risk factors compared with participant‐provided history, highlighting a substantial proportion of unrecognized or inadequately treated risk factors: hypertension (62.3%, 45.1%; p = 0.067), hyperlipidemia (57.6%, 47.5%; p = 0.004), hyperglycemia (49%, 20%; p = <0.001), vitamin B12 deficiency (27.8%, 9.3%; p = 0.170), and depression (6.9%, 11.9%; p = 0.009). Conclusion Modifiable dementia risk factors were detected in most cognitively normal Latino and Black adults engaged in a longitudinal study of memory and aging. Objective measures highlighted unrecognized and undertreated risk factors. Active surveillance programs are needed to detect and treat modifiable ADRD risk factors in underrepresented populations.

Abstract Background The National Institute on Aging Alzheimer's Disease Family Based Study (NIA‐ AD FBS) is a multi‐site, longitudinal study aimed to be a data and bio sample resource for investigators worldwide. Since its inception in 2002 the FBS goal has been to promote greater cooperation and sharing of clinical and biological resources among researchers. Methods The focus of the Family Based Study (FBS) has been the recruitment of families with at least two affected individuals and a third first degree relative with or without dementia and willing to participate. Participants are from different ethnic backgrounds including Caucasian, African American and Hispanics. The FBS study is actively recruiting both late onset (LOAD) and early onset Alzheimer's Disease (EOAD) families as well as conducting follow up evaluations every two years, approximately. Uniform assessments are completed across all sites and include DNA, Plasma, PaXgene and PBMC samples collection and brain autopsies whenever possible. We conduct both in person and remote evaluations and use the services of a mobile phlebotomy company to collect bio samples. In addition, we’ve created a protocol for genetic testing on the proband for EOAD families where an additional sample is sent to a CLIA approved lab and after genetic counseling, the presence or not of AD related mutations is disclosed to the families. Results To date, this cohort has recruited 1,756 families and acquired data from 9,682 family members. Families are from Caucasian, African Americans and Hispanics ethnic groups. The cohort has longitudinal clinical data, cognitive assessment, family history and bio samples available for sharing. Genotype data includes APOE, GWAS, WES, WGS, brain methylation, RNA sequencing and biomarkers data. Conclusion The NIA‐LOAD FBS study is the largest collection of familial Alzheimer's Disease worldwide and many genetic studies of Alzheimer's disease (AD) have included cases and controls from this dataset. Over 140 publications have used data and/or samples from FBS to address the genetics of Alzheimer's Disease. The enriched resources provided by this cohort are invaluable to the scientific community.

Abstract Background The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial ( n = 977;ClinicalTrials.gov:NCT03243422) demonstrated that hearing intervention slowed 3‐year cognitive decline by 48% among a subgroup of participants. To further investigate differences by treatment with respect to cognitive benefit, we tested the hypothesis that hearing intervention is associated with improved neurodegeneration blood biomarkers 3‐years post‐randomization and assessed whether combining biomarkers and cognitive results improved power in the trial design. Method The ACHIEVE study is a multicenter, parallel‐arm, randomized trial (hearing intervention vs health education control) on 3‐year cognitive decline among adults 70–84years with untreated hearing loss and without substantial cognitive impairment. Participants were recruited from two populations: (1) a long‐standing cardiovascular health observational study (Atherosclerosis Risk in Communities [ARIC]), and (2) de novo community volunteers. Plasma was collected in year 3 in a subsample ( n = 540) while ARIC participants ( n = 164) also had baseline plasma. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) neurodegenerative biomarkers were derived using the Alamar CNS protein panel. Regression models estimated the association of treatment with 3‐year biomarkers and global cognitive differences in the combined sample and by recruitment source and annualized change from baseline in the ARIC sample. We included a simple composite score of the standardized outcomes (Table 2). Result Among the subsample, baseline characteristics were balanced by treatment. There were no significant differences on 3‐year neurodegeneration biomarker levels by treatment in the combined (Table 1) or de novo groups (Table 2). Among ARIC participants, intervention resulted in lower 3‐year GFAP (mean:‐0.415;95%CI:‐0.712,‐0.118) and NfL (mean:‐0.349;95%CI:‐0.652,‐0.046) (Table 2). Annualized change from baseline analyses among ARIC participants (Table 3) revealed intervention was associated with a slower rate of cognitive decline (difference‐in‐means:0.059;95%CI:0.018,0.100) and a slower rate of increase in GFAP (difference‐in‐means: ‐0.060;95%CI:‐0.112,‐0.009). Differences in estimates suggest combined score, relative to cognition alone, may increase power in clinical trials that show a positive effect (ARIC subgroup: p = 0.02vs. 0.08[Table 2] and p = 0.0009vs.0.048[Table 3]). Conclusion Hearing intervention was associated with positive 3‐year effects on neurodegeneration blood biomarkers in ARIC participants which parallels cognitive decline results. Results provides objective evidence of brain changes following hearing intervention and potential signal of a more powerful combined outcome approach for future brain health clinical trials.

Abstract Background Individuals living in socioeconomically disadvantaged areas are disproportionately affected by dementia. However, the pathway leading from neighbourhood deprivation to cognitive symptoms is not well understood. To test our hypothesis that this relationship is associated with cerebral small vessel disease (SVD), we examined (1) whether neighbourhood deprivation related to midlife SVD burden and cognition, and (2) whether these links can be explained by modifiable lifestyle risk factors. Method In this multi‐centre cross‐sectional study, 514 cognitively healthy midlife participants aged 40‐59 years (median 52 years, 64.6% female) underwent clinical assessment and 3T MRI. Postcode data were used to obtain national indices of neighbourhood deprivation. To quantify SVD, we assessed white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, and lacunes. Cognition was assessed using the Computerized Assessment of Information Processing (COGNITO) battery. Lifestyle risk factors were evaluated based on clinical data. Using multivariate statistics like structural equation modelling (SEM) and canonical correlation analysis (CCA), we examined associations between these constructs both globally and at the item‐level (i.e., distinction between domains of cognition/deprivation), to shed light on specific domains that could inform targeted prevention strategies. Result Neighbourhood deprivation related to greater prevalence of lifestyle risk factors ( r = 0.36, p < .001), greater SVD burden (b=0.18, p = .01; Figure 1), and greater cognitive impairment ( r = 0.36, p < .001), independent of educational attainment, sex, and age. These links with neighbourhood deprivation were largely driven by lifestyle factors relating to vascular health (sleep, physical activity, obesity, hypertension) (Figure 2), and cognitive deficits consistent with SVD (processing speed, visuospatial) (Figure 3). Residents of deprived neighbourhoods displayed greater prevalence of lifestyle risk factors, except alcohol consumption. Lower cognitive scores were most closely associated with deprivation domains of Crime and Living Environment (Figure 3). The DEPRIVATION→SVD path was mediated by lifestyle risk factors (z=2.57, p = .010), and the DEPRIVATION→COGNITION path was mediated by SVD (z=‐2.14, p = .032) (global SVD & hypertensive subtype, but not CAA‐SVD). Conclusion The pathway linking neighbourhood disadvantage to cognitive impairment at midlife is influenced by vascular risk factors and cerebrovascular burden. Tailored strategies could promote resilience against dementia by promoting health behaviours aligned with the community's unique needs.

Abstract Background Neighborhood socio‐economic conditions may increase Alzheimer's disease (AD) risk through amyloid, tau, atrophy or vascular pathways, potentially varying by genetic risk, race or ethnicity and sex. We examined associations between Area Deprivation Index (ADI) and cognition, AD pathology, gray matter (GM) and white matter hyperintensities (WMH) volume in cognitively unimpaired older adults by race or ethnicity, sex and APOE4 status. Method We included 1896 non‐demented older adults from US POINTER study with available cognitive evaluations, ADI level – a census–based neighborhood disadvantage metric (categorized as low, moderate and high) and a subsample with neuroimaging data ( N = 806). Linear/logistic regressions were used to assess interactions of ADI with sex, race or ethnicity, and APOE4 on (1) the Preclinical Alzheimer's Cognitive Composite, (PACC‐5), (2) MRI‐derived GM volume meta‐ROI (entorhinal, fusiform, parahippocampal, mid‐temporal, inferior temporal), (3) WMH and (4) AD pathology (amyloid and tau PET), adjusted by age, sex and intracranial volume when appropriate. Result African American participants ( p <0.001) and females ( p <0.001) were more likely to live in deprived areas. African American participants had significantly lower PACC‐5 ( p <0.001) and GM volume ( p <0.001), “Other or multiple races” participants showed significantly higher amyloid burden ( p = 0.001), and White participants higher WMH ( p = 0.013). Females showed higher PACC‐5 scores ( p <0.001), while APOE4 carriers showed lower PACC‐5 ( p = 0.042) and higher amyloid burden ( p <0.001) (Table 1). Race and ADI interacted on PACC‐5 ( p = 0.043) and showed a borderline interaction on Tau ( p = 0.079), with higher ADI linked to lower PACC‐5 in White, Hispanic, and “Other or Multiple Races” and higher Tau in Hispanic. Further, there was a borderline ADI*APOE4 status interaction on WMH ( p = 0.059) and a significant ADI*APOE4 interaction on amyloid ( p = 0.001), where APOE4 carriers in deprived areas showed higher WMH and lower amyloid burden (Figure 1). No significant ADI*sex interactions were observed. Conclusion Neighborhood disadvantage was more commonly observed in African American participants, but interaction with cognition was primarily seen in other racial/ethnic groups. APOE4 carriers showed increased amyloid burden, but those from more disadvantaged neighborhoods exhibited a higher vascular component alongside lower amyloid‐driven pathology. These results may indicate varying effects of social disadvantages across groups or sample bias.