Late-onset Alzheimer's Disease Research Articles

An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains

The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450μg (n=42) or placebo (n=23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months. CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P<0.001), and three amyloid-related imaging abnormality cases (one symptomatic). Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

SOURCES OF BURDEN IN CAREGIVERS OF PERSONS WITH EARLY- AND LATE-ONSET ALZHEIMER’S DISEASE

Abstract Functional impairment and neuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD) and contribute to caregiver burden. Persons with early-onset AD (EOAD) on average experience greater functional impairment and NPS compared to late-onset AD (LOAD), yet their contribution to caregiver burden have not been explored. Objectives were to: 1) compare functional impairment, NPS, and caregiving burden in EOAD and LOAD; 2) identify sources of caregiver burden including functional impairment and NPS in EOAD and LOAD. Caregivers of 85 persons with EOAD (n=63) and LOAD (n=22) completed questionnaires [Functional Activities Questionnaire, Neuropsychiatric Inventory, Zarit Burden Inventory]. T-tests compared group differences in function, NPS, and caregiver burden. Persons with EOAD had greater NPS frequency than LOAD (t= 2.275, p=0.026). There were no significant differences between groups in function or caregiver burden. Multivariate regression analyses were performed in AD groups, with function and NPS frequency as predictors of caregiver burden covarying for age, caregiver sex, and global cognitive function (MMSE). In the total AD sample, the model explained 12.6% of the variance in caregiver burden [F(5,52)=2.64, adjusted R2=0.126; p=0.033] and poor function was a significant predictor (standardized B=0.42, p=0.003) of caregiver burden. In EOAD, the model explained 17% of the variance in caregiver burden [F(5,35)=2.64, adjusted R2=0.17; p=0.04], and poor function was a significant (standardized B=0.42, p=0.015) predictor of caregiver burden; however this was not the case in LOAD. Results suggest poor function predicts caregiver burden in EOAD. Although NPS in EOAD are more frequent, this was not a predictor of caregiver burden.

Elevated Ghrelin Promotes Hippocampal Ghrelin Receptor Defects in Humanized Amyloid-β Knockin Mice During Aging.

Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer's disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin (hAβ KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAβ KI mice as well as primary neuron cultures. We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings.

Modeling Late-Onset Alzheimer's Disease in Mice

As part of our participation in the Model-AD consortium, the UCI group has developed at least 12 novel mouse models that are relevant to studying the mechanisms underlying late-onset Alzheimer's disease (LOAD). These new models include variants in Abca7, Clu, Picalm, and Trem2. Modeling LOAD is hampered by the subtle effects imparted by the GWAS variants versus the much stronger phenotypic effects imparted by autosomal dominant AD mutations. We have successfully built a platform mouse in which the Aβ sequence has been humanized, and we found that wildtype-hAβ is sufficient to induce synaptic deficits and loss and accelerate the formation of astrocyte-associated Periodic Acid Schiff granules, normally associated with aging. We are actively introducing human tau alleles into these platform mice. Our strategy is to couple the humanizing of critical AD genes (APP, tau) with GWAS variants (Abca7, Clu, Picalm,) to better assess the impact that these alleles have on the phenotype. Modeling late-onset Alzheimer's disease represents a significant challenge, but success will likely yield substantial insights into disease mechanisms and advance drug discovery and evaluation efforts.

Novel Pathogenic Mechanism of Late-onset Alzheimer's Disease by Deficiency of NMDA Receptor Subunit GluN3A

Late-onset Alzheimer’s disease (AD) and related dementia (ADRD) are serious neurodegenerative disorders among aging populations. The progress of AD/ADRD cultivates over years to decades in humans and several months in animal models. Ca&lt;sup&gt;2+&lt;/sup&gt; homeostasis is a core function of neurons where the N-methyl-D-aspartate (NMDA) receptor plays a major role in excitatory neuronal activities. The Ca&lt;sup&gt;2+&lt;/sup&gt; hypothesis of AD proposes that even slight but sustained Ca&lt;sup&gt;2+&lt;/sup&gt; dyshomeostasis in the brain is a critical pathophysiology or pathogenesis of AD. However, instigating factors like the trigger and time/duration of the Ca&lt;sup&gt;2+&lt;/sup&gt; dysregulation in AD progression have been largely obscure, while β-amyloid (Aβ) peptides are often indicated as the trigger. Hyperactivities of excitatory neurons and NMDARs have been implicated in AD as a main mediating mechanism caused by AD pathologies such as Aβ deposition. NMDAR overactivation is restrained by the unique regulatory GluN3 subunits (GluN3A and GluN3B; previously known as NR3A and NR3B). Expression of GluN3A in the receptor complex reduces NMDAR currents and Ca&lt;sup&gt;2+&lt;/sup&gt; influx, while deletion of GluN3A causes larger NMDA currents and elevated intracellular Ca&lt;sup&gt;2+&lt;/sup&gt;. Significant GluN3A levels are detected in both rodent and human adult/aging brains. We hypothesized that the “gatekeeper” role of GluN3A is constantly required for Ca&lt;sup&gt;2+&lt;/sup&gt; homeostasis and normal aging; its deficiency can lead to slowly evolved “degenerative excitotoxicity”. Our in vitro, ex vivo, and in vivo studies using GluN3A knockout (KO) mice of young and older ages revealed neuronal hyperactivity, moderate but sustained elevation of cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt;, chronic inflammation, neuronal loss/apoptosis, synaptic impairments and progressive cognitive deficits. The AD hallmarks of Aβ and tau pathology were identified after, but not before, cognition decline. In the “gain of function” experiment, expression of GluN3A in the GluN3A KO brain prevented AD progression. Specific regional knockdown of GluN3A in the cortex and hippocampus of wild-type mice at the adult age (3 months old) resulted in similar AD/ADRD phenotypic alterations in the following 3-6 months. The NMDAR antagonist memantine (MEM) is approved by FDA as a symptomatic treatment for moderate-severe AD patients. According to the chronic neurohyperactivity in AD progression and the modified Ca&lt;sup&gt;2+&lt;/sup&gt; hypothesis that Ca&lt;sup&gt;2+&lt;/sup&gt; dysregulation is an early and “life-long” pathogenesis, the maintenance of NMDAR normal activity by MEM or other safe NMDAR antagonists could be a disease-modifying early treatment in preclinical/prodromal stages. This prediction is endorsed by clinical trials using MEM and other NMDAR antagonists in mild cognitive impairment (MCI) and early AD patients, showing beneficial effects of maintaining cognitive functions. Consistently, we showed that, in GluN3A KO mice and 5xFAD mice, early and chronic MEM treatment (started at 3-month of age and lasted for 3-6 months) prevented or attenuated AD phenotypes. Meanwhile, the chronic MEM therapy in mice showed preconditioning effect of neuroprotection against ischemic stroke that strikes over 50% AD patients. Large clinical trials of long-term and more systematic examinations on AD/ADRD progression and the comorbidity of stroke are warranted for this innovative therapy. Our results support the modification of Ca&lt;sup&gt;2+&lt;/sup&gt; hypothesis of AD with the novel amyloid-independent mechanism. Specifically, the deficiency of GluN3A alone causes lifelong Ca&lt;sup&gt;2+&lt;/sup&gt;-related progression of AD pathophysiology and amyloid pathology. The long-term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for late-onset AD/ ADRD.

APOE Independent Associations of TOMM40 rs2075650 Genotype on Hippocampal Volume

Apolipoprotein E ε4 (APOE ε4) confers the greatest genetic risk for late-onset Alzheimer's disease (AD). The adjacent Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene may increase risk through APOE ε4 independent associations with AD- sensitive brain regions like the hippocampus. ANOVA and multiple linear regression tested TOMM40 rs2075650 ('650) G vs. A genotype on total hippocampal volume using UK Biobank data (n=10,130), across all participants and by APOE haplotype groups. Age and sex interactions with TOMM40 '650 were also tested. Across participants, having both APOE ε4 and TOMM40 '650 G carriage was related to hippocampal atrophy. Among non-APOE ε4 adults, age and sex jointly modulated '650 G carriage effects. Compared to younger middle- aged adults, older women and men respectively showed modest protective and markedly detrimental associations. TOMM40 '650 G carriage may have APOE ε4-independent associations with hippocampal volume based on age and sex.

The rat brain transcriptome: from infancy to aging and sporadic Alzheimer’s disease-like pathology

Functional traits of the adult brain, which are established early in life, may impact susceptibility to Alzheimer’s disease (AD). Results from prior research conducted on senescence-accelerated OXYS rats, a prominent model for sporadic AD, provide evidence in favor of this hypothesis. The present study examined the transcriptomes of the prefrontal cortex (PFC) and hippocampus in OXYS and Wistar rats (control) during the early postnatal period (at age P3 and P10; P: postnatal day of life) to identify the signaling pathways and processes that contribute to delayed brain maturation in OXYS rats and assess their potential role in the development of AD traits later in life. Next, we compared the differentially expressed genes (DEGs) in the rat PFC and hippocampus throughout the five stages of AD-like pathology, from infancy to the progressive stage. Additionally, we noted conspicuous variations between the strains in the number of DEGs throughout all five ages. Significant differences were found in the number of DEGs between OXYS rats and Wistar rats in both brain structures at both P3 and P10. Notably, changes in gene expression patterns in the PFC and hippocampus of OXYS rats at 3 and 10 days of age are broadly associated with all basic mechanisms involved in Alzheimer’s pathogenesis, which are modified in OXYS rats at different stages of AD. Gene expression changes at P3 and P10 are associated with molecular processes including neuronal plasticity, immune responses, cerebrovascular function, and mitochondrial function. Remarkably, changes in the expression of genes associated with Aβ function were detected. The expression profile of genes linked to APP processing in the brain of OXYS rats is reduced during the early postnatal period. An intriguing finding, with potential significance for the development of AD pathology, is the decreased expression of the Abca7 gene, an important genetic factor of late-onset AD, in both brain regions of OXYS rats during the early postnatal period. The data demonstrated a decrease in Abca7 expression in the brains of OXYS rats at P20 and at 5 and 18 months (p 0.05). Additionally, three genes (Thoc3, Exosc8, and Smpd4) demonstrated overexpression in both brain regions of OXYS rats throughout their lifetimes. In conclusion, we have conducted a comparative analysis of changes in the rat brain transcriptomes from infancy to the advanced stage of AD-like pathology for the first time. The significant and comparable distinctions in gene expression and related processes were noteworthy during the early postnatal timeframe and in the severe stage of the pathology. Our findings indicate that a reduction in the effectiveness of neural network formation in the brain of OXYS rats at an early age is a clear contributor to AD symptomatology. The cause of this phenomenon remains unclear. However, we can identify shortened gestational age, low birth weight, and delayed brain development in infancy as major risk factors for the emergence of a disease-like pathology later in life, as these conditions are typically found in affected rats. Further investigation is needed to determine the causal relation between delayed brain development in infancy and neurodegeneration.

Epigallocatechin Gallate Modulates Microglia Phenotype to Suppress Pro-inflammatory Signalling Cues and Inhibit Phagocytosis

Microglia are crucial players in the pathogenesis of late-onset Alzheimer’s disease (AD), with evidence for both deleterious and beneficial effects. Identifying interventions to modulate microglial responsiveness, promote amyloid β (Aβ) clearance, disrupt plaque formation, or dampen excessive inflammation has therapeutic potential. Bioavailable flavonoids, such as the flavan 3-ols, are of interest due to their antioxidant, metal chelating, signalling, and anti-inflammatory potential. Primary microglia were treated with a series of structurally related flavanol 3-ols to assess effects on phagocytosis, cytokine release, and transcriptional responses by RNA sequencing. Data indicated that the extent of hydroxylation and the presence of the galloyl moiety were strong determinants of flavan 3-ol activity. Epigallocatechin gallate (EGCG) was the most effective flavan-3-ol tested and strongly inhibited phagocytosis of Aβ independent of any metal chelating properties, suggesting a more direct modulation of microglia responsiveness. EGCG was broadly anti-inflammatory, reducing cytokine release and downregulating transcription, particularly of components of the microglia extracellular matrix such as MMP3 and SerpinB2. Collectively, this brings new insight into the actions of flavonoids on microglial responsiveness with potential implications for the therapeutic use of EGCG and structurally related flavanol-3-ols in AD.

Gene therapy: an alternative to treat Alzheimer's disease.

Alzheimer's disease (AD), a neuro-degenerative disease that primarily affects the elderly, is a worldwide phenomenon. Loss of memory, cognitive decline, behavioural changes, and many other signs are used to classify it. Various hypotheses that may contribute to Alzheimer's disease have been found during decades of survey, including tau theory, the amyloid theory, the cholinergic hypothesis, and the oxidative stress hypothesis. According to some theories, the two leading causes of AD are the accumulation of amyloid beta plaque and development of NFTs in the brain. The hippocampus and cerebral cortex are the primary sites where amyloid beta plaques gather in the body. NFT formation in the brain impairs the brain's neurons' potential of signalling. According to the age at which it manifests in a person, there are two subtypes of AD: 'LOAD (Late Onset Alzheimer's Disease)' and 'EOAD (Early Onset Alzheimer's Disease)'. Long-term research into AD treatment has resulted in the introduction of some medications that provided symptomatic relief to patients but did not alter the disease's pathophysiology, like cholinesterase inhibitors, inhibitors of tau aggregation, and monoclonal antibodies to Aβ aggregation. Even though the medications did not halt the progression of AD, researchers did not discontinue their work, which lead to the introduction of gene therapy - a recently created cutting-edge method of delivering genes to target sites where they can express the intended functionalities. Viral or non-viral vectors could be used to deliver the gene, each with advantages and limitations of their own. Gene therapy is proven to be a potential disease-modifying treatment for AD. This article discusses about gene therapy, its merits and demerits and the various ways of gene delivery. Additionally, it focuses on AD as the target for treatment through gene therapy, the pathophysiology of AD, and the multiple targets for gene therapy in the treatment of AD.

Generation of the Human iPSC Line from Spontaneous Late-Onset Alzheimer’s Disease Patient with ApoE3/3 Genotype and Sex-, Age-, and ApoE-Matched Healthy Control

Human induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) isolated from a patient diagnosed with spontaneous late-onset Alzheimer’s disease (AD) carrying ApoE3/3 gene and one age-, sex-, and ApoE-matched healthy control. Reprogramming was done using a commercially available Epi5 Reprogramming Kit containing OCT4, SOX2, KLF4, LIN28, and L-MYC as reprogramming factors. The pluripotency of the iPSC lines was verified by the expression of pluripotency markers and by their capacity to differentiate into all three embryonic germ layers in vitro. These newly established iPSC lines offer a valuable platform for in vitro modeling of AD.

PICALM Variation Moderates the Relationships of APOE ɛ4 with Alzheimer's Disease Cerebrospinal Biomarkers and Memory Function Among Non-Demented Population.

APOE ɛ4 and PICALM are established genes associated with risk of late-onset Alzheimer's disease (AD). Previous study indicated interaction of PICALM with APOE ɛ4 in AD patients. To explore whether PICALM variation could moderate the influences of APOE ɛ4 on AD pathology biomarkers and cognition in pre-dementia stage. A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ɛ4 carriers) were genotyped for PICALM rs3851179 and APOE ɛ4 at baseline and were followed for influences on changes of cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis. The interaction term of rs3851179×APOE ɛ4 accounted for a significant amount of variance in baseline general cognition (p = 0.039) and memory function (p = 0.002). The relationships of APOE ɛ4 with trajectory of CSF Aβ42 (p = 0.007), CSF P-tau181 (p = 0.003), CSF T-tau (p = 0.001), and memory function (p = 0.017) were also moderated by rs3851179 variation. APOE ɛ4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ɛ4 in pre-dementia stage.

Associations Between TREML2 Gene Variants and Alzheimer's Disease: Biomarkers, Neuroimage, and Cognition.

Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

Examination of Genetic Risk Factors for Alzheimer’s Disease in a Cohort of Familial Longevity: the Long Life Family Study

AbstractBackgroundGenetic risk factors have been explored extensively for late onset Alzheimer’s Disease (LOAD). The largest meta‐analysis GWAS studies to date (Bellenguez et al., 2022) identified 83 single nucleotide polymorphisms (SNPs) associated with LOAD in the general population. The Long Life Family Study (LLFS) is aimed to identify factors associated with familial longevity and healthy aging by examining US and Danish families. Our earlier studies have shown that LLFS families are at lower risk of several age‐related diseases, including LOAD. Here, we will: (1) compare allele frequencies and effect sizes of the identified meta‐GWAS variants against those in LLFS; and (2) assess whether a polygenic risk score (PRS) based on meta‐GWAS variants differs between LOAD vs. cognitively healthy in LLFS.MethodWe examined LLFS participants who were Non‐Hispanic Whites, had available cognitive and whole genome sequencing (WGS) (n = 4,220). Allele frequencies were estimated based on founders only. Association analyses were performed via logistic regression using Wald test and adjusting for sex, age, site, education, first principal components, and the genetic relationship matrix. PRS was calculated using a weighted formula, and to account for family structure, means for each status per family were obtained.ResultIndependent of LOAD status, 13 SNPs had significantly different allele frequencies between the two studies. Minor allele frequencies of 10 of the SNPs were lower in LLFS when compared with Bellenguez et al. When examining the relations between LOAD and the 77 available SNPs, only five variants appeared to be associated in LLFS. The direction of association differed for two of the SNPs. Lastly, estimated PRS scores did not differ by LOAD status (affected vs unaffected: ‐0.059 vs. ‐0.054, respectively).ConclusionHere we show that variants associated with LOAD in the general population were not necessarily associated with LOAD in in the LLFS cohort, a cohort ascertained for familial healthy aging. When estimating disease risk using genetic markers, as expected, ascertainment needs to be taken into consideration.

Multi‐Omics Insights Into The Heterogeneity Of Depression In Alzheimer’s Disease

AbstractBackgroundDepression is a common, though heterogenous, comorbidity in late‐onset Alzheimer’s Disease (LOAD) patients. Moreover, individuals with depression are at greater risk to develop LOAD. In prior work, we performed pleiotropy analysis and found shared genetic etiology between LOAD and Major Depressive Disorder (MDD), suggesting inter‐relationship between LOAD and depression symptoms. However, the underpinning genetic, epigenetic, and transcriptomic etiologies predisposing the comorbidity of depression in LOAD, are largely unknown.MethodThis work applied various bioinformatics methods including analyses of polygenic risk scores (PRS), differential gene expression and DNA‐methylation. The discovery analyses were performed using ROSMAP datasets including, genotypes, transcriptomic, DNA‐methylomic and depression diagnosis. When available the NACC dataset was used for validation. In addition, MDD‐GWAS summary statistics from the Psychiatric Genomics Consortium were used to create the PRS.ResultWe constructed PRS based on MDD‐GWAS data and assessed its performance in predicting depression onset in LOAD patients. The PRS showed marginal results in standalone models for predicting depression onset in both ROSMAP (AUC = 0.540) and NACC (AUC = 0.527). Full models, with baseline age, sex, education, and APOEε4 allele count, showed improved prediction of depression onset (ROSMAP AUC: 0.606, NACC AUC: 0.581). In time‐to‐event analysis, standalone PRS models showed significant effects in ROSMAP (P = 0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in LOAD for both datasets (P&lt;0.001). Next, we investigated differential gene expression in LOAD patients with and without comorbid depression and didn’t reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex‐stratification, we identified 25 differential expressed genes (DEGs) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Finally, we tested differences in DNA‐methylation and found significant hypomethylation with only one CpG probe.ConclusionOur study is the first multi‐omics genome‐wide exploration of the genomic landscapes underlying the heterogeneity of depression in LOAD. Our developed PRS accurately predicted LOAD patients with depressive symptoms. Furthermore, we discovered sex‐dependent differences in gene expression associated with the risk of depression symptoms in LOAD. Collectively, our results have clinical implications for the diagnosis and treatment of depression in LOAD patients.

Integrative single‐nucleus multi‐omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer’s disease brains

AbstractBackgroundThe genetic underpinnings of late‐onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD‐associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.MethodsIn this study we performed a parallel single‐nucleus (sn) multi‐omics analysis to simultaneously profile gene expression (snRNA‐seq) and chromatin accessibility (snATAC‐seq) using nuclei from 12 normal and 12 LOAD brains. We developed a pipeline based on integrative analysis of multimodal datasets that utilizes several bioinformatics packages to catalogue cis‐ and trans‐ regulatory network and their target genes.ResultsWe identified cell subtype specific LOAD‐associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co‐accessibility networks (CCANs). Integrative analysis defined disease‐relevant CCANs in multiple cell subtypes and discovered LOAD‐associated cell subtype specific candidate cis regulatory elements (cCRE), their candidate target genes, and trans‐interacting transcription factors (TF), some of which were LOAD‐DEG, for example, ELK1 in a specific sub type of excitatory neurons and ATF7 and JUN, found in multiple cell subtypes. Overall, our analysis discovered 53 new candidate LOAD genes and validated 16 gene previously implicated in LOAD. Finally, we focused on a subset of cell subtype‐specific CCANs that overlap known LOAD‐GWAS regions and catalogued putative functional SNPs disrupting TF motifs within LOAD‐cCREs linked to LOAD‐DEGs including, APOE and MYO1E in a specific subtype of microglia.ConclusionsIn this study we identified candidate cis‐ and trans‐ regulatory factors and their target genes that contribute to the pathogenesis of LOAD. To our knowledge, this study represents the most comprehensive systematic interrogation of regulatory networks underlying gene dysregulation in LOAD at an unprecedented cell‐subtype resolution. Collectively, our findings provide a rich dataset for future mechanistic experiments, confirm known LOAD‐GWAS loci while also identifying novel loci, and suggest the disease‐relevant cell types and subtypes for follow‐up validation studies using in vitro and in vivo disease model systems. This information is important for the development of new therapeutic targets and interventions for LOAD.

Association of APOE with Alzheimer’s disease in Mexico, Caribbean‐Hispanics, Peruvian and Mexican Americans

AbstractBackgroundThe Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Late Onset Alzheimer’s disease (LOAD). However, its genetic effect is heterogeneous across different ethnicities. We investigated the association of APOE with LOAD in five different Hispanic studies: Mexicans in the Mexican Health and Aging Study (MHAS), Caribbean Hispanics in the Washington Heights Inwood Aging project (WHICAP), Peruvians in the Genetics of Alzheimer’s disease In Peruvian Populations (GAPP) and Mexican Americans from The Health &amp; Aging Brain among Latino Elders (HABLE) and the Texas Alzheimer’s Research and Care Consortium (TARCC).MethodA total of 7,832 participants were included in the analysis. APOE genotypes were generated by direct genotyping or imputation. SNPs associations with LOAD were assessed using multivariate logistic regression models in PLINK. Analyses were adjusted for age (≥60 years old), sex, and education. Global ancestry proportions, Native Americans, European, African were estimated with ADMIXTURE software using the Human Genome Diversity Project as the reference panel. Genetic ancestry specific secondary analyses were conducted using the same models.ResultThe genetic ancestral composition was significantly different across cohorts. Peruvians and Mexicans showed a predominant native ancestry, Caribbean‐Hispanics appeared to have a major contribution of European ancestry, and Mexican Americans exhibited similar proportions of both European and Native ancestries. We observed a significant association with e4 allele dosage in all the cohorts, except for MHAS. The genetic effect of at least one copy of the e4 allele on LOAD risk was very similar in GAPP and HABLE (OR = 3.42, SE = 0.39 and OR = 3.33, SE = 0.33, respectively), while attenuated in TARCC (OR = 2.81, SE = 0.28) and WHICAP (OR = 1.82, SE = 0.16). Among MHAS participants with a predominant European ancestry, APOE association achieved statistical significance with an increased disease risk (OR = 3.42, SE = 0.55) for homozygous carriers. Within the native‐prevalent ancestry subsample, the increased LOAD risk among APOE_ e4 heterozygous carriers were similar in both GAPP and HABLE cohorts (OR = 3.61, SE = 0.44 and OR = 3.64, SE = 0.43, respectively).ConclusionOur results showed a differential risk for LOAD from the APOE_ e4 allele across populations with admixed genetic ancestry.

Neuropathological characterization of PiB binding in postmortem striatum in Down syndrome

AbstractBackgroundAmyloid‐beta plaques form in the brain throughout life in people with Down syndrome (DS) and are one of the hallmarks of Alzheimer disease (AD) neuropathology. The regional progression of amyloid buildup in DS is similar to that of late onset AD (LOAD) in the neurotypical population. The development of positron emission tomography (PET) ligands like Pittsburgh Compound B (PiB) has allowed researchers and clinicians to visualize and track amyloid accumulation in the brain throughout life. Using this technology, a unique pattern emerges in people with DS, where the earliest and strongest PiB PET retention is in the striatum, unlike LOAD but similar to autosomal dominant AD. Frontal cortex PiB PET retention is similar in all groups. We used a fluorescent derivative of PiB, cyano‐PiB (CN‐PiB), to investigate PiB labeling postmortem in DS striatum. We hypothesized that striatal CN‐PiB load increases with age and is greater than in the frontal cortex, similar to observations from PiB PET studies of adults with DS.MethodWe conducted CN‐PiB labeling in postmortem striatum and frontal cortex from 44 cases with DS ages ranging from 42 to 70 years (25F/19M, mean PMI 7.4 hours). Whole slide imaging and automated image analysis were used to derive individual plaque‐level information regarding load, size, and distribution of CN‐PiB+ plaques in DS with age.ResultCN‐PiB labeled plaques in both the striatum and frontal cortex were also positive for amyloid‐beta antibodies targeting epitopes 1‐16, 17‐24, and x‐42. Preliminary data suggest that striatal CN‐PiB load (median = 2.3%) is not higher compared to the frontal cortex in DS (median = 10%). Striatal CN‐PiB load did not change with age from 42 to 70 years, suggesting an early saturation (IQR = 3.5%).ConclusionCN‐PiB labeled amyloid‐beta plaque load in the striatum in DS is comparable to conventional neuropathologic analysis and does not differ from frontal cortical load. Other aspects of PiB‐binding or pathologies may contribute to the early and prominent striatal PiB PET retention reported in DS. It will be important in future studies to include younger cases with DS.

Both clinically informed and brain region agnostic approaches identify neuroimaging derived phenotypes associated with genetically regulated gene expression of late‐onset Alzheimer’s disease genes

AbstractBackgroundGenetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regions associated with late‐onset AD (LOAD) via gene expression.MethodThis study contained brain region‐agnostic and region‐informed approaches. Both approaches utilized a set of 25 genes causally associated with LOAD in our previous cross‐tissue transcriptome‐wide association studies (TWAS) (Chen et al., 2021) to identify LOAD‐associated GReX‐mediated NIDPs. We leveraged the UK Biobank (UKBB) neuroimaging TWAS resource to provide GReX‐mediated NIDP information. Region‐agnostic: We assessed associations between GReX of LOAD genes and T1‐derived cortical and subcortical grey matter NIDPs from the UKBB neuroimaging TWAS. Region‐informed: We identified a set of AD‐associated cortical grey matter NIDPs from diagnosed AD patients (Westman et al., 2013). Next, we subset the UKBB neuroimaging TWAS data to those describing associations between GReX of LOAD genes and the selected AD NIDPs.A Benjamini‐Hochberg FDR p‐value threshold of 0.05 was used to establish statistical significance, and causal inference testing on associations between GReX of LOAD genes and NIDPs was conducted by implementing MR‐JTI in both approaches.Result Region‐agnostic: This approach found associations between GReX of 8 LOAD‐associated genes and 14 NIDPs (Figure 1). The most significant association is the GreX of ZNF296 and the right pars opercularis of the inferior frontal cortex, which replicated across 16 different tissues. Region‐informed: A single highly significant causal association between the GReX of PSMC3 and the ventral diencephalon was identified and replicated in gene expression models of 3 different bansal ganglia‐derived tissue models.ConclusionOur study shows the highly significant causal association between the GReX of ZNF296 and the right pars opercularis on LOAD through the region‐agnostic approach and the strong causal association between the GReX of PSMC3 and the ventral diencephalon on LOAD in AD‐associated region‐informed analyses. Our methodologies provide opportunities to explore brain regions associated with LOAD that are mediated by GReX of AD‐associated genes illuminating the impact of LOAD‐associated genes on gene expression and brain physiology.

Novel mouse models of late‐onset Alzheimer’s disease

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Consortium was established to generate and characterize more translatable animal models for late‐onset Alzheimer’s disease (LOAD) based on human genetic risk variants. While numerous genetic risk loci for LOAD have been identified, few have been experimentally verified in vivo and in many cases the risk variants have not been validated. The development of new models incorporating LOAD genetic risk should improve our understanding of disease mechanisms and improve preclinical testing of potential therapeutics.MethodCoding and non‐coding LOAD risk variants were prioritized based on human data sets, with the goal of targeting diverse pathways (e.g., neuroinflammation, vascular risk, metabolic function, lipid homeostasis). Risk variants in Abca7, Adamts4, Bin1, Erc2, Mthfr, Mtmr4, Plcg2, Ptk2b, Slc6a17, Snx1, Sorl1 and other loci were engineered into mouse models expressing humanized APOE4 and the Trem2*R47H risk variant; in more recent models, a humanized Abeta allele was also included. A novel transcriptomic panel, based on clinical LOAD samples (Preuss et al, 2020) was used to evaluate how well each model replicated clinical transcriptomic changes with disease. Models were aligned to ROSMAP clinical subtypes.ResultWe have identified specific human AD‐related pathways disrupted in an age‐dependent manner in these novel mouse models. Specifically, mouse models carrying human AD risk variants Abca7*A1527G, Mthfr*C677T, and Plcg2*M28L exhibited transcriptomics changes similar to those seen in LOAD patients. Most models could be readily matched to either the inflammatory or non‐inflammatory subtype.ConclusionWe have prioritized mouse models expressing LOAD risk variants in Abca7, Mthfr, and Plcg2 for comprehensive phenotyping using clinically relevant measures including transcriptomics and proteomics, biomarkers, neuropathology and in vivo imaging at advanced ages (24 months). Ongoing projects will use human data to guide how to combine alleles to create models that match multi‐omic signatures of AD subtypes and test the effects of environmental risk factors such as high‐fat diet. Through this effort we aim to develop improved models for testing targeted therapeutics.