Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease.

APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased interleukin (IL)-17 and IL-1 coexpressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFß and immune checkpoints, including LAG3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration, limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of the neurodegenerative phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE ε4 female carriers with cognitive impairment.

Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration.

BACKGROUND: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. METHODS: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aß, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). RESULTS: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. CONCLUSION: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Parental History of Memory Impairment and ß-Amyloid in Cognitively Unimpaired Older Adults.

Importance: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain ß-amyloid (Aß) burden, reduced brain metabolism, and lower gray matter volumes. Objective: To characterize maternal vs paternal history of memory impairment in terms of brain Aß-positron emission tomography (Aß-PET) and baseline cognition among a large sample of cognitively unimpaired older adults. Design, Setting, and Participants: This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aß levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded. Main Outcomes and Measures: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aß-PET and the Preclinical Alzheimer Cognitive Composite. Results: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aß-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aß-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aß in both early-onset and late-onset groups. There was no association with cognition. Conclusions and Relevance: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aß burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aß burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy.

OBJECTIVE: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. METHODS: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. RESULTS: Using a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. CONCLUSION: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study.

OBJECTIVES: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults. DESIGN: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. SETTING: Community-dwelling participants assessed at research visits in an academic medical center. PARTICIPANTS: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). MEASUREMENTS: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. RESULTS: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aß, we observed an association between AES-I and inferior temporal tau. CONCLUSIONS: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard aging brain study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults.

BACKGROUND AND OBJECTIVES: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with ß-amyloid (Aß) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aß, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aß and tau. METHODS: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aß imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aß, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. RESULTS: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aß burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aß and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. DISCUSSION: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aß or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-ß), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-ß, and microglial ADPRS was associated with amyloid-ß and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

Using community-based geographical information system (GIS) to recruit older Asian Americans in an Alzheimer's disease study.

OBJECTIVE: This study aims to show the usefulness of incorporating a community-based geographical information system (GIS) in recruiting research participants for the Asian Cohort for Alzheimer's Disease (ACAD) study for using the subgroup of Korean American (KA) older adults. The ACAD study is the first large study in the USA and Canada focusing on the recruitment of Chinese, Korean and Vietnamese older adults to address the issues of under-representation of Asian Americans in clinical research. METHODS: To promote clinical research participation of racial/ethnic minority older adults with and without dementia, we used GIS by collaborating with community members to delineate boundaries for geographical clusters and enclaves of church and senior networks, and KA serving ethnic clinics. In addition, we used socioeconomic data identified as recruitment factors unique to KA older adults which was analysed for developing recruitment strategies. RESULTS: GIS maps show a visualisation of the heterogeneity of the sociodemographic characteristics and the resources of faith-based organisations and KA serving local clinics. We addressed these factors that disproportionately affect participation in clinical research and successfully recruited the intended participants (N=60) in the proposed period. DISCUSSION: Using GIS maps to locate KA provided innovative inroads to successful research outreach efforts for a pilot study that may be expanded to other underserved populations across the USA in the future. We will use this tool subsequently on a large-scale clinical genetic epidemiology study. POLICY IMPLICATION: This approach responds to the call from the National Institute on Aging to develop strategies to improve the health status of older adults in diverse populations. Our study will offer a practical guidance to health researchers and policymakers in identifying understudied and hard-to-reach specific Asian American populations for clinical studies or initiatives. This would further contribute in reducing the health and research disparity gaps among older minority populations.

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.

Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was associated with both diffuse and neuritic Aß plaques, while microglial (Mic) ADPRS was associated with neuritic Aß plaques, microglial activation, tau, and cognitive decline. Causal modeling analyses further clarified these relationships. In an independent neuroimaging dataset of cognitively unimpaired elderly (n=2,921), Ast-ADPRS were associated with Aß, and Mic-ADPRS was associated with Aß and tau, showing a consistent pattern with the autopsy dataset. Oligodendrocytic and excitatory neuronal ADPRSs were associated with tau, but only in the autopsy dataset including symptomatic AD cases. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

Multicellular communities are perturbed in the aging human brain and Alzheimer's disease.

The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.

Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau.

Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau231, correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma Aß42/40 ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau231, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau231 concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aß) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; ß = 0.35, SE = 0.01, P = 6.2 × 10-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; ß = 0.07, SE = 0.01, P = 9.2 × 10-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; ß = 0.1, SE = 0.02, P = 2.4 × 10-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; ß = 0.16, SE = 0.03, P = 1.1 × 10-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, ß = 0.79, SE = 0.14, P = 1.4 × 10-08, MAF = 0.006, sex-interaction P = 9.8 × 10-07) and chr11p.15.2 (rs192346166, ß = 0.94, SE = 0.17, P = 3.7 × 10-08, MAF = 0.004, sex-interaction P = 1.3 × 10-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-ß proteinopathy while the other mediated the effect of amyloid-ß in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

Novel CYP1B1-RMDN2 Alzheimer's disease locus identified by genome-wide association analysis of cerebral tau deposition on PET.

Determining the genetic architecture of Alzheimer's disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. The CYP1B1-RMDN2 locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, while APOE4 rs429358 accounted for 3.6%. rs2113389 was associated with higher tau and faster cognitive decline. Additive effects, but no interactions, were observed between rs2113389 and diagnosis, APOE4 , and Aß positivity. CYP1B1 expression was upregulated in AD. rs2113389 was associated with higher CYP1B1 expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship between CYP1B1 and tau deposition but not Aß. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.

Utility of Amyloid Positron Emission Tomography Imaging in Older Adults With Epilepsy and Cognitive Decline.

In older adults with cognitive decline and epilepsy, diagnosing the etiology of cognitive decline is challenging. We identified 6 subjects enrolled in the Imaging Dementia-Evidence of Amyloid Imaging Scanning (IDEAS) study and nonlesional epilepsy. Three cognitive neurologists reviewed each case to determine the likelihood of underlying Alzheimer's disease (AD) pathology. Their impressions were compared to amyloid PET findings. In 3 cases the impression was concordant with PET findings. In 2 cases "possibly suggestive," the PET reduced diagnostic uncertainty, with 1 having a PET without elevated amyloid and the other PET with intermediate amyloid. In the remaining case with lack of reviewer concordance, the significance of PET with elevated amyloid remains uncertain. This case series highlights that in individuals with a history of epilepsy and cognitive decline, amyloid PET can be a useful tool in evaluating the etiology of cognitive decline when used in an appropriate context.