bluuebunny/crossref_metadata_2025 huggingface dataset:
The Alzheimer’s Disease Sequencing Project: Progress and Update
Authors: Pericak‐Vance Margaret A
Published: January 2025

In response to the National Alzheimer’s Project Act (NAPA) in 2012 the National Institute on Aging (NIA) commenced a new genetics initiative (the Alzheimer’s Disease Sequencing Project [ADSP]) to understand the genetic architecture of Alzheimer’s Disease and Related Dementias (AD/ADRD). The ADSP has three main goals 1) To Identify new genes and genetic variations that contribute to increased risk for or protection against AD/ADRD, 2) to provide insight as to how these genes and variations impact AD/ADRD, 3) to identify potential avenues or approaches to translate genetic results into therapeutic targets. The ADSP has led the field in global inclusion and diversity with the goal of universal success in the treatment and prevention of AD/ADRD. The most recent release of over 36,000 genomes from over 40 cohorts worldwide is evidence to this effect. This first presentation will be a brief introduction and overview of the structure, growth, and progress of the ADSP.
Truncated tau accumulates before hyperphosphorylated tau and in relatively distinct neuronal subpopulations in entorhinal cortex and inferior temporal gyrus in Alzheimer’s disease patients
Authors: Oh Ian Michael , Li Song Hua , Pereira Felipe Luiz , Kaur Prabhleen , Raju Anya , Jerfy Rushil , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Rodriguez Roberta Diehl , Ambrose Andrew J. , Spina Salvatore , Seeley William W. , Miller Bruce L. , Arkin Michelle R. , Grinberg Lea T.
Published: January 2025

Background

Alzheimer’s disease (AD) features stereotypical spread of hyperphosphorylated tau (p‐tau) and beta‐amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always coincide with p‐tau, making the latter an excellent marker of pathological tau burden. We showed in experimental studies that truncated tau (tr‐tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p‐tau in neurons at late AD stages; however, only about 40% of tr‐tau positive neurons also show p‐tau positivity. This makes tr‐tau a potential AD marker previously invisible at neuropathological investigation or potential target of diagnostic tool development. We sought to determine how early in AD tr‐tau is detected and to what degree tr‐tau and p‐tau neuronal populations overlap at early AD stages.

Method

Our analysis included 56 cases (Table 1) from across all AD Braak stages (BB = 0‐6; N = 56). We used multiplex immunofluorescence to probe tr‐tau (D13, D402, TauC3) and p‐tau (PHF1) species in the same tissue slides of postmortem human brain tissue. We then quantified neuronal tau pathology and colocalization in images of entorhinal cortex (EC) and inferior temporal gyrus (ITG) as areas representative of p‐tau pathology in intermediate AD stages.

Result

We detected D13 tr‐tau in lower BB and in greater quantities than p‐tau at low BB (Fig. 1A). The EC accumulated more D13 tr‐tau than the ITG in early BB (Fig. 1B). Overlap between D13 tr‐tau and p‐tau was minimal in both regions from early to late BB, with 0% at BB = 3 in both regions and 16.7% and 16.1% at BB = 5 in EC and ITG, respectively (Fig. 2).

Conclusion

Neuronal D13 tr‐tau deposits develop in AD before p‐tau pathology. Across AD Braak stages, the % of overlapping between D13 tr‐tau and p‐tau positive neuronal populations is moderate at best; these results suggest neuronal accumulation of D13 tr‐tau occurs in a selectively vulnerable manner. This corroborates D13 tr‐tau as a potential biomarker of tau pathology in AD overlooked by p‐tau screening. Future plans include analysis of these pathological markers between clinically typical and atypical variants of AD.
Title: Reducing APOE4 in carriers is a therapeutic goal for Alzheimer Disease: Report of the APOE4 National Institute on Aging (NIA) /Alzheimer Disease Sequencing Project (ADSP) Consortium Working Group
Authors: Vance Jeffery M. , Holtzman David M.
Published: January 2025

As part of the goal of the ADSP to develop effect therapeutic for AD, it has become imperative to develop therapeutic targets for APOE4. The Apolipoprotein E4 gene (APOE4) strongest genetic risk factor for AD and is present in 64% of sporadic, late‐onset AD, with a recent prevalence estimate of 245 million carriers worldwide. A key question is whether APOE4 is a toxic or gain of function allele or alternatively if its effect is due to a loss or partial loss of function.

To answer this question, the APOE4 National Institute on Aging (NIA)/Alzheimer’s Disease Sequencing Project Consortium (ADSP) working group (WG) came together to discuss the question of whether to reduce or increase APOE4 as therapeutic intervention for AD. The WG reviewed both genetic data concerning this question and the various model studies on the effects of reducing or increasing the expression of APOE4.

Studies utilizing ancestry comparisons, single nuclei RNAseq/ATACseq of AD autopsy material and studies of loss of function variants in APOE all provided support that the appropriate therapeutic intervention for APOE4 carriers is to reduce APOE4 expression and APOE4 protein levels. Reviewing studies in animal and cellular models to assess the effects of raising or lowering APOE4 conclusively demonstrated that the presence of APOE4 leads to a toxic gain of function and that lowering it’s levels in the brain is the therapeutic choice. The WG only reviewed African and European ancestries as genomic data is from Asian ancestry is limited.

It was the unanimous conclusion by the WG that lowering APOE4 is the correct therapeutic intervention. The combined studies strongly support that APOE4 exerts a toxic gain of function in regard to not only risk for AD but also on several outcomes linked with AD including amyloid deposition, neurodegeneration that is tau‐mediated and inflammation. Questions that are important to address as intervention moves forward include: What would be the timing and duration of therapy? How does local ancestry influence therapeutic options? Given that APOE is needed for normal physiological function, how far should it be lowered? How would successful outcome be monitored?
Mitigating Barriers to Participant Recruitment and Retention in the READD‐ ADSP Programme: Experience from the African Dementia Consortium
Authors: Akinyemi Rufus O.
Published: January 2025

Achieving greater diversity and inclusion in global dementia research requires the inclusion of underrepresented geographic, ethnic and regional populations such as indigenous Africans. The ADSP is a collaborative global initiative that includes sample collection across diverse populations, data generation including whole genome sequencing in over 120,000 individuals and multi‐omics, the collating of rich phenotypic information, data harmonization, and unified data management and quality control. These datasets are being analyzed to accelerate our understanding of AD neurobiology with implications for better risk prediction and discovery of novel precision diagnostics and therapeutics. The Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD‐ADSP) is a case/control study that is recruiting, retaining and evaluating 13,000 participants of diverse race/ethnicity, including 5,000 indigenous Africans (AF), 4,000 Black Americans (BA), and 4,000 US Hispanic/Latinx (HL). The study in Africa involves multiple sites in 9 African countries operating under the African Dementia Consortium (AfDC). Barriers and facilitators of recruitment have been observed. A total of 652 participants (302 AD cases and 352 controls) have been recruited into the READD – ADSP Africa programme between 22nd June, 2023 and January 22nd January, 2024 from diverse populations in 8 countries in eastern, central and western Africa. Identified barriers to recruitment include non‐existence or poorly managed dementia registries, language diversity, myths around blood donation for research, family dynamics, stigma and unmet expectations regarding incentives for participating in research and concerns about data privacy. These challenges were mitigated through context ‐ sensitive community – engagement programmes involving community advisory boards, leveraging previous research programmes and existing doctor – patient relationships, and use of social media. The collaboration of the ADSP with the African Dementia Consortium (AfDC) to recruit participants into the READD – ADSP program is yielding positive results with progressive recruitment of study participants while innovative and context – sensitive stakeholder engagement strategies are mitigating the barriers to participant recruitment and retention.
Extracellular Vesicles from Human iPSC‐derived NSCs Protect Human Neurons Against Aβ‐42 Induced Neurodegeneration, Mitochondrial Dysfunction and Tau Phosphorylation
Authors: Rao Shama , Madhu Leelavathi N , Babu Roshni S , Nagarajan Advaidhaa , Narvekar Esha , Upadhya Raghavendra , Shetty Ashok K
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid‐beta (Aβ) in the extracellular space, which leads to various adverse effects such as oxidative stress, neuroinflammation, mitochondrial dysfunction, tau phosphorylation, synapse loss, and neurodegeneration. Therefore, therapeutic interventions that can reduce Aβ‐toxicity and slow down the progression of cognitive dysfunction in AD have significance. One promising approach is to use extracellular vesicles (EVs) that are released by neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs). These EVs contain therapeutic proteins and miRNAs that can help protect against Aβ‐induced pathological changes in the brain, providing a potential avenue for neuroprotection.

Method

This study first isolated and characterized EVs secreted from hiPSC‐NSCs by chromatographic methods. Next, mature human neurons generated from 2 different hiPSC lines were exposed to 1‐µM Aβ42 oligomers with different concentrations of hNSC‐EVs. The protective effects of EVs on neurons exposed to Aβ were quantified using MTT and live/dead cell assays and counting of surviving MAP‐2+ neurons. The extent of oxidative stress was investigated via measurements of malondialdehyde (MDA) and protein carbonyls (PCs) and the expression of genes encoding iNos and Cox2. Furthermore, the expression of genes and/or proteins linked to pro‐apoptotic (Bad, Bax) and antiapoptotic (Bcl2) effects, mitochondrial respiratory chain (Nudfs6, Nudfs7, Sdha, Sdhb, Cyc1, Bcs11, Cox6a1, Atp6ap1), autophagy (Beclin 1 and MAPILC3B) were quantified. Total tau and p‐tau were also measured.

Result

The addition of hiPSC‐NSC‐EVs to mature human neuronal cultures exposed to Aβ reduced the extent of Aβ‐induced neurodegeneration. When human neurons were exposed to Aβ‐42 alone, it increased pro‐apoptotic genes (Bad, Bax) and reduced the expression of an antiapoptotic gene (BCL‐2). However, adding hNSC‐EVs to Aβ‐42 exposed neurons normalized the expression of pro‐ and antiapoptotic genes to control levels, reduced oxidative stress markers, prevented Aβ‐42‐induced hyperactivation of mitochondria and decreased autophagy, reduced the phosphorylation of tau.

Conclusion

Treating human neurons with hiPSC‐NSC‐EVs can significantly decrease the various pathological changes caused by Aβ exposure. Supported by a grant from the National Institute for Aging (1RF1AG074256‐01A1 to A.K.S.)
Midlife Neuroinflammatory Dynamics: The Emergence of Alzheimer’s Disease Neuroimmune Profile in the Female Human Brain
Authors: Van Rossum Hannah , Shang Yuan , Brinton Roberta Diaz
Published: January 2025

Background

Inflammation plays a pivotal role in driving the development and progression of Alzheimer’s disease (AD) in the human brain, offering a promising avenue for therapeutic intervention. However, the initiation phase of inflammation and its potential sex differences remain elusive. In this study, we aim to provide translational validity to our preclinical findings by testing two hypotheses: 1) the inflammatory profile of late‐onset AD (LOAD) is initiated and detectable during midlife aging, and 2) sex differences manifest in the brain by midlife.

Method

Human frozen tissue samples were procured from the NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai). We matched samples from 40 brain donors for sex and age, encompassing tissues from the hippocampus, hypothalamus, and corpus callosum. APOE genotyping determined APOE e4 carrier status. The study classified samples into three groups: healthy aging 40‐49 years old (young controls), healthy aging 50‐59 years old (old controls), and AD aged 60‐80 years old (AD). Exploratory analyses utilized Nanostring’s Neuroinflammation Panel, with subsequent replication through deep in‐depth characterization by bulk‐seq at Vanderbilt University Medical Center.

Result

Principal components analysis indicated that transcriptomic profiles are influenced by cofactors such as tissue, sex, and disease state. Unbiased pathway analysis identified the top 5 upregulated pathways in AD compared to healthy aging controls, all associated with the immune system and inflammation. Conversely, the top 5 down‐regulated pathways were linked to synaptic function. Targeted pathway analysis, including peripheral immune cell regulation, interferon, and microglial activation, revealed significant sex and APOE e4 carrier differences in all three brain regions.

Conclusion

This comprehensive characterization provides compelling evidence of sex differences in neuroinflammation emerging during midlife. Notably, the midlife female brain exhibits a profile reminiscent of the inflammatory signature observed in the AD brain. The study presents an opportunity to identify distinct profiles emerging decades before AD diagnosis, and to inform precision medicine interventions that can be implemented to prevent or delay a key driver of AD pathology.
Increasing Amerindian diversity in AD genetics research, A Peruvian perspective
Authors: Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela Z.
Published: January 2025

Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Alzheimer’s Disease Sequencing Project (ADSP), a global genetic initiative established by the National Institute of Aging (NIA) is supporting regional initiatives in Latin America and its admixed population.

Latin America is the largest recently admixed population, with variable Native American, European, and African ancestry proportions, as result of successive settlements and new massive migrations. The Native American population from Latin America are descendants of ancestral Asians who entered America through Beringia 15 000 years ago. By the 14‐15 th century the Native American population was about tens of millions with uneven distribution across the Americas. However, about 90% of the NA populated collapsed due to violence, famine, and infectious diseases. Consequently, the NA from Latin America exhibit lower genetic diversity with higher differences among countries.

Peru is the fifth largest country of South America with a complex geography that comprise the Andes mountains, the Amazon jungle, and the Pacific coast. Peru is an emergent economy dealing with governance disparities, centralism in Lima, the capital city, with notable inequities in income distribution. The “modern mestizo “population in Peru concentrates a high proportion (˜70%) of NA ancestry, mostly derived from the ancient pre‐Inca and Inca civilizations.

Over the past decade, both local and collaborative efforts, have been contributing to the AD genetic research in the Peruvian populations. A combination of regional research teams and multisource ascertainment approaches allowed the recruitment of 250 AD patients and 400 cognitively unimpaired controls from five different regions across Peru (source: PeADI initiative). The studies performed in the Peruvian cohort have been demonstrating the important role of the Amerindian ancestry in the genetic architecture of AD, including the estimation of APOE4 risk higher than non‐Hispanic Whites and Africans, and the recent identification a novel SORL1 variant in a Peruvian AD family.

Despite these significant contributions, performing research in Latin American regions requires strong local brain health programs with community engaged approaches to prevent disparities and contributing to long‐term local capacity building.
Back to the Future! Understanding old mechanisms and discovering new insights via ADSP initiatives
Authors: Bush William S. , Griswold Anthony J.
Published: January 2025

The Alzheimer’s Disease Sequencing Project (ADSP) has used whole genome sequencing, computational approaches, and epidemiological and statistical expertise to accelerate understanding of the fundamental mechanisms of Alzheimer disease and related disorders (ADRD). Going forward, the ADSP will continue growing to over 110,000 participants to further dissect the risk for AD. To move towards novel insights, the ADSP is adopting new approaches while leveraging the rich existing data. New technologies such as long‐read sequencing will reveal complex structural variants in diverse genetic ancestries and enable discovery of novel variants for further exploration. The ADSP Functional Genomics Consortium will expand their work in the generation and integration of multiomic data to better elucidate underlying disease mechanisms thereby enhancing therapeutic target discovery. Harnessing the ADSP data resource will allow examination of genetic heterogeneity by ancestry, identifying both shared and ancestry‐specific genetic variants that modulate AD risk, encompassing variants of all types using a variety of new statistical approaches and integration with large AD‐specific multiomics resources such as through xQTL projects. The phenotypic heterogeneity of AD will also be examined through the collection and harmonization of emerging AD fluid and imaging biomarkers and cognitive testing through the efforts of the ADSP Phenotype Harmonization Consortium. The ADSP AI/ML consortium will develop new analysis approaches for many of these tasks and will construct comprehensive risk models for AD by incorporating genetics, endophenotypes, biomarkers, and social determinants of health. Finally, as we enter an era of new Alzheimer’s therapeutics, the ADSP is poised to uncover genetic predictors of treatment response and adverse events as these are adopted in the general population, enabling personalized medicine approaches for maximizing benefit and minimizing harm. Through expanding sample diversity, integrating diverse datasets, applying cutting‐edge technologies, and forging global collaborative networks, the Alzheimer’s Disease Sequencing Project aims to achieve an unprecedented understanding of Alzheimer’s disease genetics—ultimately translating genetic insights into life‐changing treatments and prevention strategies worldwide.
Machine‐learning derived proxy phenotypes for Alzheimer’s disease genome‐wide association study by proxy
Authors: Goudey Benjamin , Saint‐Jalmes Martin , Liu Shu , Laws Simon M. , Masters Colin L
Published: January 2025

Background

For large genomic studies of middle‐aged individuals, the prevalence of Alzheimer’s disease (AD) is extremely low, making it difficult to conduct genomic analysis of the condition. To enable genome‐wide association studies of AD in such datasets, an approach called Genome‐wide association by proxy (GWAX) uses family history of disease as a proxy for disease status. Borrowing from the machine learning (ML) literature, we treat the development of proxy phenotypes as a pseudo‐labelling task, where an ideal proxy label accurately predicts the lifetime risk of AD. Given this, this work develops ML‐derived proxy phenotypes of AD for downstream GWAX based on survival models of conversion to AD and demonstrates their predictive performance and impact on downstream GWAX.

Method

Using cognitively normal (CN) and mild cognitive impaired (MCI) individuals with at least 2 timepoints in AIBL (n = 426), ADNI (n = 283) and UK Biobank (n = 56,105), we derived two proxy phenotypes of AD: i) a ML‐derived boosting model with age, sex, years of education and AD family history, i.e. number of recorded parents with a history of Alzheimer’s disease and ii) family history alone. The prognostic ability for future AD conversion was measured using concordance index (C‐index) in 10‐fold cross‐validation. The two models were applied to the subset of UK Biobank with white British ancestry (n = 408,165) and a GWAX was conducted on the predicted labels. From this GWAX, PRS was derived and evaluated using area under the ROC curve (AUC).

Results

In 10‐fold cross‐validation, the ML‐derived phenotypes were more predictive of conversion to AD than family history alone (median C‐index: 0.7 vs 0.5, Mann Whitney p‐value <0.001). GWAX of UKB from these proxy phenotypes indicates that the multivariate model detects a higher number of significant regions compared to family history alone. PRS constructed from these ML‐derived phenotypes GWAX show greater power to separate true AD case/control labels when externally validated on ADNI.

Conclusion

Preliminary analysis of ML‐derived proxy phenotypes of AD indicates may be a promising approach to improve AD genomic studies in middle age cohorts. Further analysis of the results and potential biases of this approach are needed to fully characterise this method
Bilingualism contributes to resilience in distinct ADRD syndromes
Authors: Tablante Jonathan , VandeVrede Lawren , Paolillo Emily W. , Mamuyac Eugenie , Grasso Stephanie M , Dronkers Nina , Casaletto Kaitlin B. , Deleon Jessica
Published: January 2025

Background

Previous studies on the effects of bilingualism on Alzheimer’s disease and related disorders (ADRD) are mixed, and there remains an unclear role of bilingualism in preventing the onset of ADRD (resistance) and in mitigating its effects in the presence of changes related to aging or neuropathology (resilience). Furthermore, the effects of bilingualism may differ depending on the underlying neuropathology, and this remains unexplored.

Methods

In this study, we leveraged a cohort of 484 patients (404 monolingual and 80 bilingual speakers) with Frontotemporal Lobar Degeneration‐Modified Clinical Dementia Rating scale (FTLD CDR) box scores, a measure of clinical disease severity, and plasma neurofilament light chain (NfL) levels, a marker of neurodegeneration, at one or more timepoints. The patients were classified into four groups (healthy controls, Alzheimer’s disease (AD), 4‐repeat (4R) tau, and TAR DNA‐binding protein 43 (TDP‐43)). A total of 302 participants (62% of the cohort) were classified into the four groups based on autopsy‐confirmed neuropathology, while the remaining 182 participants (38% of the cohort) were classified based on predicted pathology. We used linear mixed‐effects models to estimate the longitudinal change in FTLD CDR box scores.

Results

We found that bilingual speakers with AD pathology had a slower rate of change in FTLD CDR box scores compared to monolingual speakers (P = 0.003) when controlled for NfL levels as a proxy of neurodegeneration. This effect was not seen in healthy controls or in patients with tau or TDP pathology.

Conclusions

These results point towards a protective, disease‐specific effect of bilingualism in patients with AD‐related neurodegenerative disease, supporting a role of bilingualism in resilience to ADRD. A strength of this study is its exploration of the effects of bilingualism in a largely autopsy‐confirmed cohort of patients with distinct ADRD neuropathologies. The study may explain the mixed findings in previous studies of bilingualism’s effects, emphasizing the need to explore the effect of bilingualism within specific ADRD subtypes. This may clarify the mechanism by which bilingualism modulates the course of ADRD and contributes to cognitive and brain resilience.
Electrophysiological insights into resilient individuals: Examining calcium permeable AMPA receptor responses and neuropathological correlations in Alzheimer’s Disease
Authors: Gutierrez Berenice A , Moreno Naomi , Keene C Dirk , Limon Agenor
Published: January 2025

Background

Alzheimer’s disease (AD) is a common form of dementia characterized by the accumulation of amyloid beta (Aβ) and phosphorylated tau proteins in the brain. While clinical observations are typically used for AD diagnosis, postmortem studies have revealed individuals without dementia symptoms but with high AD pathology, known as resilient individuals. Calcium permeable AMPA receptors (CP‐AMPARs) have been implicated in the calcium dyshomeostasis of AD, but it is unclear whether they are found or behave differently at the electrophysiological level in resilient and control individuals compared to AD patients.

Method

We examined the differences in responses of synaptic CP‐AMPARs from a cohort of postmortem tissue from 30 individuals, including controls (3M, 4F; non‐demented, no neuropathology), age‐matched AD patients (2M, 5F; individuals with AD of the same age as the control group), resilient individuals (2M, 6F; non‐demented with AD neuropathology), and age‐matched AD patients to resilient individuals (2M, 5F; individuals with AD of the same age as the resilient group). We isolated and microtransplanted synaptic membranes from the parietal cortex of each individual into Xenopus laevis oocytes for recordings of AMPARs through two electrode voltage clamp. We induced agonist responses of AMPARs with the use of kainate and glutamate drugs. To differentiate CP‐AMPARs from calcium‐impermeable AMPARs, we used IEM‐1460 drug, which selectively targets GluR2 subunit‐lacking receptors (CP‐AMPARs) over GluA2‐containing receptors (calcium‐impermeable AMPARs). Additionally, we performed immunoblots from the synaptosomal aliquots of each individual to assess the presence of Aβ/Tau oligomers and determine whether there is a correlation between the amount of toxic oligomers and the strength of the CP‐AMPARs responses

Result

Our results suggest that resilient individuals tend to have less CP‐AMPARs synaptic responses compared to individuals with AD and even controls, despite the presence of Aβ/Tau oligomers.

Conclusion

Understanding the differences in synaptic receptors among different groups of individuals provides a foundation for future research into the mechanisms that lead to synaptic alterations in AD.
The moderating effects of sex and amyloid status on the associations between early tau burden and memory
Authors: Lui Kitty K. , Wang Xinran , Stiver Jordan , Wang Xin , Sundermann Erin E. , Betthauser Tobey J. , Jonaitis Erin M. , Langhough Rebecca E. , Johnson Sterling C. , Banks Sarah
Published: January 2025

Background

Older women accumulate more pathological tau than older men in the early stages of Alzheimer’s disease (AD). However, the cognitive effects of early tau deposition may be obscured in women given their superior performance on verbal memory tests, which are commonly used in diagnosing AD. Visuospatial memory may more accurately reflect early tau burden in older women due to less apparent sex differences. In the Wisconsin Registry for Alzheimer’s Prevention (WRAP), we examined whether sex and Aβ status moderated associations between tau and verbal and visuospatial memory in older adults.

Method

Cognitively unimpaired and mild cognitively impaired WRAP participants (n = 196; age = 70.8±4.2; 65.8% female) with [18‐F]MK6240 tau positron emission tomography (PET), [11‐C]Pittsburgh Compound B (PiB) Aβ‐PET, apolipoprotein E ε4 (APOE4) status, and memory scores from the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test‐Revised (BVMT‐R) were included (Table 1). Tau standard uptake value ratio (SUVR) in Braak stages I and II, regions of early tau deposition, were calculated. We used linear models to analyze the effect of sex×Aβ status (distribution volume ratio (DVR)>1.19)×tau interactions on memory, controlling for age at memory assessment, time between memory assessment and PET scans, APOE4 status, and years of education.

Result

Significant sex×Aβ status×tau in Braak stage II interactions were observed on BVMT‐R total learning, BVMT‐R delayed recall, and RAVLT delayed recall (ps<.03), showing that, in Aβ+ women, more tau in Braak stage II was associated with worse performance on these memory outcomes (ps<.01), but not in Aβ+ men (ps>.07; Figure 1). Moreover, in Aβ‐ men, more tau in Braak stage II was related to worse BVMT‐R delayed recall (p = .03), but not in Aβ‐ women (p = .97; Figure 1B).

Conclusion

These findings indicate that, in the presence of Aβ pathology, there are impacts of early tau accumulation on both visuospatial and verbal memory in older women more than in older men. Longitudinal studies with ethnoculturally diverse samples will be necessary to clarify our understanding of the relationship between tau accumulation and memory decline and to increase the generalizability of the results.
Increasing the power of rare variant association analyses with common variant eQTLs in Alzheimer’s disease
Authors: Yang Yuchen , Bush William S.
Published: January 2025

Background

Many independent studies have found rare variants associated with AD. Current gene‐based tests for rare‐variants generally consider the impact of low‐frequency coding variants as an independent effect from the common regulatory variants that surround them. In this work, we propose to increase the statistical power of kernel‐based rare‐variant association tests by accounting for the surrounding cis‐regulatory variants’ effects on gene expression. We intend to identify novel AD associations of genes with rare variants on existing haplotype backgrounds.

Method

We incorporate common variant cis‐eQTLs around the gene or SNP‐set of interest as a fixed effect by estimating their impact on gene expression using GTEx association models. The Sequence Kernel Association Test (SKAT) is then used to test for the residual random effect of coding rare‐variants (MAF<1%). SKAT is known to retain statistical power when a small proportion of test variants are causal, and when these effects are in mixed directions. We perform comprehensive simulation studies that demonstrate the biological conditions under which our method can substantially increase power, including a range of effect sizes for gene expression, providing insight into the relationship between eQTLs and rare variants. Power analyses were performed with both exact p‐values computed via the Davies method and derived empirically through permutation tests.

We then applied our approach to data from the Alzheimer’s Disease Sequencing Project to evaluate gene‐level associations across 6461 genes with 210,000 missense rare variants. We also extend this approach to other set‐based rare variant association tests such as SKAT‐O and variant‐set mixed model association tests.

Result

Simulations show that our method can substantially increase power, while maintaining the type I error in the absence of association. Our proposed method improves the power of SKAT where a low proportion (<10%) of tested variants have small mixed effect sizes (OR<1.0), closely resembling real world variant effects. We confirm previously reported significant associations such as TREM2, and find several novel gene candidates that required this adjustment to be study‐wide significant.

Conclusion

Our approach is useful for discovering rare variation in genes that contribute to AD risk and heritability. This method can be flexibly incorporated into many existing analyses pipelines.
ALLFTD: Characterization of Frontotemporal Lobar Degeneration (FTLD) Disease Trajectories through Longitudinal Assessment
Authors: Heuer Hilary W. , Forsberg Leah K. , Mester Carly T. , Kolander Tyler , Johnson Noah , Brushaber Danielle , Rosen Howard J. , Boeve Brad F. , Boxer Adam L. ,   ALLFTD Consortium
Published: January 2025

Background

The ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. To understand disease trajectories in the context of potential preventative or disease‐modifying therapeutic agents, comprehensive evaluation across multiple time‐points is crucial.

Method

ALLFTD evaluates participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS, PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. ALLFTD has expanded to include 28 expert sites in North America conducting clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants, providing detailed data on participant status and disease progression. Participants are asked to return for annual evaluations. The central data management staff assist sites in retention efforts by providing monthly reports of follow‐up visits that are pending, due, or overdue, based on a 15‐month period from previous visit.

Result

Since enrollment began in January 2020, ALLFTD has conducted 1363 baseline visits, including 339 participants previously enrolled in ALLFTD’s predecessor studies (ARTFL and LEFFTDS). Excluding individuals not anticipated to return due to disease progression (123), participant death (55), or recent enrollment (<15 months; 318), ALLFTD has a retention rate of 83% for a second visit despite early enrollment occurring during COVID restrictions. Retention rates for third and fourth visits are even higher (90% and 97% respectively), suggesting a high degree of engagement in longitudinal participants. Including historic data from ARTFL and LEFFTDS, >1000 participants have multiple visits.

Conclusion

Longitudinal assessment of clinical and biomarker profiles in f‐FTLD and s‐FTLD can inform models of disease onset and progression, allowing analysis of disease trajectories and identification of the most sensitive clinical outcome measures over time. ALLFTD has been successful at recruiting and retaining a large active cohort to obtain detailed clinical and biomarker characterizations; data are available by request.
Neuropsychiatric symptoms and depression across cognitively‐defined AD subgroups at the time of AD diagnosis: data from the National Alzheimer’s Coordinating Center (NACC)
Authors: Choi Seo‐Eun , Scollard Phoebe , Mukherjee Shubhabrata , Gibbons Laura E. , Lee Michael L. , Klinedinst Brandon S , Gallée Jeanne , Sugimoto Taiki , Nakano Connie , Kukull Walter A. , Biber Sarah A , Trittschuh Emily H. , Mez Jesse , Saykin Andrew J. , Crane Paul K.
Published: January 2025

Background

Neuropsychiatric symptoms are uncommon at Alzheimer’s Disease (AD) dementia diagnosis but are exhibited by nearly everyone during the course of dementia. Depressive symptoms are common in AD dementia. We sought to determine correlations between memory, executive functioning, language, neuropsychiatric symptoms, and depressive symptoms at AD dementia diagnosis, and to characterize neuropsychiatric and depressive symptoms across groups defined by substantial relative cognitive impairments, using data from the National Alzheimer’s Coordinating Center (NACC).

Method

Using confirmatory factor analysis, we derived composite Neuropsychiatric Inventory Questionnaire (NPI‐Q) and Geriatric Depression Scale (excluding the memory question) scores. We defined a reference category of people with AD dementia whose memory, executive functioning, and language scores were similar to each other. Other groups were defined based on relative differences in cognitive domain scores. We used multinomial logistic regression to test if neuropsychiatric and depressive symptoms differed across groups.

Result

Our sample included the diagnosis visit for 7,747 people with AD dementia and CDR = 1 (Table 1). Correlations between cognitive domains ranged from +0.29 to +0.50. Correlations between cognitive domains and NPI‐Q composite scores ranged from ‐0.02 to +0.04 and with depressive symptoms from ‐0.09 to +0.14. The correlation between depressive symptoms and the NPI‐Q composite was +0.17. We did not find a difference in NPI‐Q composite scores across groups, but depressive symptom score differed across groups (p<0.0001), with higher scores in people with relatively greater executive functioning impairments and lower scores in people with relatively greater memory impairments, compared to people with similar domain scores (Figure 1, Table 2).

Conclusion

Composite scores for depressive and neuropsychiatric symptoms facilitate well‐powered investigations of relationships with these clinically salient factors. Neuropsychiatric symptoms had trivial correlations with cognitive domain scores at AD dementia diagnosis, and did not differ across groups defined by substantial relative cognitive impairments. Depressive symptoms were weakly correlated with cognitive domain scores, and differed across groups defined by substantial relative cognitive impairments. More research is warranted to further characterize depression and neuropsychiatric symptoms over the course of AD dementia.
Genetic subtypes of Alzheimer’s disease are related to differential biomarker and cognitive trajectories
Authors: Elman Jeremy A. , Schork Nicholas J. , Rangan Aaditya V
Published: January 2025

Background

Alzheimer’s disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. We previously identified a genetic heterogeneity across two levels. The first level, which was disease‐relevant but not disease‐specific, comprised three clusters (termed “constellations”) driven by different correlation patterns in a region of extended LD surrounding the MAPT locus. The second level reflected disease‐specific genetic subtypes of AD. These structures were previously found to replicate in an independent dataset. Here, we investigate whether genetic subtypes demonstrate different patterns of biomarker and cognitive trajectories.

Method

In a discovery dataset from the UK Biobank (AD cases = 2,739, controls = 5,478), we applied principal component analysis (PCA) to AD‐associated variants, allowing us to identify three constellations. Subsequently, a biclustering algorithm identified two distinct disease‐specific genetic signatures among subsets of cases not found in controls. We classified individuals with mild cognitive impairment (MCI; n = 399) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) into constellations and determined whether they were a member of either bicluster (i.e., genetic subtype) or not. Longitudinal change in cognitive performance (Preclinical Alzheimer’s Cognitive Composite; PACC), amyloid (florbetapir PET) and p‐tau (CSF) was compared between the two bicluster groups and with non‐bicluster cases.

Result

The disease‐relevant constellations and disease‐specific bicluster structure was apparent in the ADNI MCI sample. Individuals with genetic signatures resembling bicluster 2 exhibited greater decline on the PACC compared to the non‐bicluster (p = 0.022) and bicluster 1 groups (p = 0.004). Bicluster 1 demonstrated a somewhat greater increase in florbetapir over time compared to the non‐bicluster group, but this difference was not significant (p = 0.129). Bicluster 2 demonstrated a significantly greater increase of CSF p‐tau over time compared to the non‐bicluster group (p = 0.041)

Conclusion

These results provide additional evidence for the existence of AD genetic subtypes in an independent dataset. The genetic subtypes exhibit differential pathological accumulation and cognitive decline over time, suggesting that this genetic variation has meaningful consequences for downstream processes and disease manifestation.
Genetic architecture of Alzheimer’s disease in a West African Cohort: Insights from the READD ‐ ADSP
Authors: Akinyemi Rufus O. , Griswold Anthony J. , Coker Motunrayo , Whitehead Patrice L. , Rajabli Farid , Akinwande Kazeem S. , Diala Samuel , Ogunronbi Mayowa , Scott Kyle , Obiako Reginald , Adams Larry D. , Hamilton‐Nelson Kara L. , Wahab Kolawole , Mena Pedro R. , Akpalu Albert Kwaku , Kunkle Brian W. , Sarfo Fred Stephen , Vance Jeffery M. , Okubadejo Njideka U , Baiyewu Olusegun , Reitz Christiane , Tosto Giuseppe , Owolabi Mayowa O , Bush William S. , Haines Jonathan L. , Kalaria Raj , Byrd Goldie S. , Ogunniyi Adesola , Pericak‐Vance Margaret A. , Consortium African Dementia
Published: January 2025

Background

The “Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD‐ADSP)” is developing a resource to expand ancestral diversity in Alzheimer disease (AD) studies to dissect the genetic architecture of AD across different populations. In addition to US sites, READD‐ADSP includes four US sites and nine countries in sub‐Saharan Africa through the Africa Dementia Consortium (AfDC). The overall goal of READD‐ADSP is to identify genetically driven targets in diverse groups including African Americans and Hispanic/Latinos in US, and Africans. In this preliminary analysis we investigated the ancestral genetic differences and the impact of known AD risk factors within West African cohorts.

Method

Genome‐wide genotyping was performed on 91 AD cases and 97 cognitive unimpaired controls from Nigeria and Ghana. APOE alleles and ABCA7 deletion (rs142076058) were sequenced using Sanger. We calculated global ancestry (principal components) using the PC‐AiR approach that is robust to known and cryptic relatedness. We investigated known AD loci from non‐Hispanic White (NHW) and AA genome wide association studies. For association analysis, we employed a mixed‐model regression approach (SAIGE) where we controlled for age, gender, population substructure (first three principal components), and relatedness.

Result

Principal component analysis identified a distinction between the Ghana and Nigerian cohorts along the first principal component (PC1). Among the genetic loci examined, several showed nominal significance. Notably, the most prominent marker was found in SORL1 (rs17125523; p = 2 × 10‐3). Additionally, we discovered an exonic nonsynonymous marker in the BIN1 gene (rs112318500), which is specific to African ancestry and showed a protective effect. APOE e4 allele showed a significant association with AD risk (OR = 2.5; CI:1.5‐4.2; pv = 0.001), while the e2 indicated a protective trend but did not reach statistical significance. No statistical difference in the frequency of ABCA7 deletion was observed between AD and CU individuals.

Conclusion

Our findings highlight the presence of genetic variations between West African populations that warrant further investigation, potentially offering new insights into the genetic underpinnings of AD. Data collection is ongoing across the AfDC and updated data will be presented.
Vascular‐based risk scores for the prediction of Alzheimer’s disease pathology biomarkers and cognitive status in older adults at‐risk for dementia: Exploratory analysis of sex and ethno‐racial differences
Authors: Udeh‐Momoh Chinedu , Duran Tugce , Hughes Timothy M. , Sai Kiran K. Solingapuram , Bateman James R. , Byrd Goldie S. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N.
Published: January 2025

Background

Vascular‐based dementia risk scores (VDRS) which reliably predict risk of Alzheimer’s disease and related dementias (ADRDs), may be useful to identify at‐risk individuals for secondary prevention trials. Dementia risk scores have typically focused on predicting ADRD‐associated symptoms, with fewer studies assessing capacity for detecting individuals with underlying brain pathologies. We compare the predictive value of two vascular‐based risk scores (CAIDE and Reitz VDRSs) for discriminating AD‐related histopathological and structural abnormalities, further considering race and gender differences.

Method

We included non‐demented (self‐identified) White and Black participants at the Wake Forest ADRC Clinical Core with baseline UDSv3 cognitive testing (used to calculate the Preclinical Alzheimer’s Cognitive Composite ‐ PACC5), clinical adjudication, amyloid (PiB) PET, APOE genotype, and metabolic characterization for diabetes including prediabetes. WHICAP/Reitz scores were calculated using components of sex, education, age, race, ethnicity, hypertension, diabetes, WHR, HDL, smoking and APOE‐ε4 status. CAIDE scores included age, education, sex, systolic BP, BMI, physical activity, total cholesterol, and APOE‐ε4. We assessed differences in VDRS among cognitive, amyloid PET and racial groups.

Result

616 participants (Table 1) had baseline data available for analysis. Of 287 with amyloid PET, 33% were amyloid positive (CL>20). Median Reitz scores differed by cognitive status (Figure 1A), with higher mean scores noted for those with amnestic (aMCI) and non‐amnestic MCI (naMCI) compared to those with normal cognition (naMCI/aMCI: median 17, p<.001). Reitz scores were also significantly higher in amyloid positive vs negative participants (Figure 1C) as well as in Black vs White participants (Figure 2A) (median (IQR): 16 (2,34) vs 12 (0,28), 17 (0,33) vs 14 (0,40) respectively; p<.001), however no sex differences were noted. In contrast, we found no significant differences in CAIDE scores among cognitive and amyloid pathology groups (p>0.05, Figures 1B and 1D), except ethno‐racial groups (p<.001, Figure 2B).

Conclusion

Significant differences in distinct VDRSs were found in relation to brain amyloid pathology levels and clinico‐cognitive status, with ethno‐racial influences potentially contributing to noted differences. Risk composites accounting for these factors will be useful for greater precision around pre‐selection of at‐risk populations towards targeted trials for disease modifying therapies and optimal management of clinical care.