👤 Rudolph E Tanzi

The choroid plexus (CP), known for producing cerebrospinal fluid, is increasingly implicated in the pathogenesis of Alzheimer's disease (AD). Neuroimaging studies document structural CP alterations in aging and AD. One such alteration, calcium deposition, increases with age and is typically considered benign, though the mechanism and clinical significance of CP calcification remain uncertain. Given established association between peripheral vascular calcification and cardiovascular risk, we hypothesized that the volume of calcium within CP would correlate with systemic cardiovascular health. Based on prior findings of APOEε4-specific associations between CP calcium and neurodegeneration, participants were stratified by APOEε4 status, a strong genetic risk factor for AD also implicated in cardiovascular disease. In this retrospective analysis of 105 adults (mean age 58.9 years; 39 APOEε4+), we examined whether CP calcium correlates with cardiovascular risk in cognitively normal adults. CP calcium was quantified using a previously validated MRI-CT method. Spearman correlations assessed the association of CP calcium and Framingham Cardiovascular Risk Score (FCRS), as well as individual cardiovascular risk factors. Overall, CP calcium was not associated with FCRS. Among APOEε4- subjects, CP calcium correlated positively with FCRS ( Show less

Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially reverted upon colony-stimulating factor 1 receptor (CSF1R) inhibition. Suppressing innate immunity reduced neuroinflammation and restored cognitive function in E4/E4 females, while exacerbating neuroinflammation and accelerating cognitive decline in E4/E4 males. Finally, in line with the E4/E4 humanized mouse model data, we show that APOE4 expression is linked to sexually dimorphic leukocyte activation profiles in the human brain. This study highlights the need for personalized therapies when targeting APOE, brain immunity, and meningeal lymphatics to promote cognitive resilience in both females and males. Show less

Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration. Show less

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry. We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry. For clinically diagnosed AD, we identified 14 new loci-five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing-based GWAS of diverse cohorts. We used whole-genome sequencing data from large and diverse cohorts. We found novel genome-wide association study findings based on whole-genome data. We performed a multiancestry meta-analysis and incorporated results from underrepresented groups. Show less

A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2C We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD. Show less

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2C We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD. Show less

Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild-type and AD-transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments. We examined the γ-secretase modulator GSM-15606 for potential AirPoll protection by its attenuating of amyloid beta (Aβ)42 peptide production. Male and female wild-type mice were fed GSM-15606 during an 8-week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP). GSM-15606 decreased Aβ42 during nPM and DEP exposure without changing beta- or gamma-secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%. These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aβ42 peptide. GSM-15606 attenuation of Aβ42 may benefit human exposure to AirPoll. Gamma-secretase modulator (GSM-15606) attenuates the amyloidogenic amyloid beta (Aβ)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aβ homeostasis among the chronic effects of GSM-15606 and other amyloid reduction treatments on secretase enzymes. Show less

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been previously identified, few studies have analyzed individuals of non-European ancestry. Here, we describe a multi-ancestry genome-wide association study of clinically-diagnosed AD and AD-by-proxy using whole genome sequencing data from NIAGADS, NIMH, UKB, and All of Us (AoU) consisting of 49,149 cases (12,074 clinically-diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants are of non-European ancestry. For clinically-diagnosed AD, we identified 14 new loci - five common (FBN2,/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/ AC008738.6) which were also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using WGS-based GWAS of diverse cohorts. Show less

Alzheimer's disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10 Show less