G2DBridge: A Multimodal Framework Linking Genetics to Disease through Imaging Intermediates

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

Recent genetic studies showed that polygenic risk score (PRS) could be used to identify individuals at high risk of Alzheimer's disease (AD). Despite this success, early detection and intervention of AD still remain challenging. In this study, we suggest a novel PRS approach that is weighted by predicted tissue-specific gene expression levels. We used whole-genome sequencing and phenotypic data of 446 European participants (207 late-onset AD cases and 239 cognitively normal controls) from the Alzheimer's disease Neuroimaging Initiative (ADNI) (Table 1). We performed transcriptome-wide association studies (TWAS) in 13 brain regions by using MetaXcan (weights from GTEx V8) and GWAS summary statistics (IGAP stage 1 excluding ADNI participants) and integrated these 13 TWAS results using MultiXcan. To generate transcriptome-based weighting (TW)-PRS, expression weights in each gene were mapped to SNPs in the gene, and these were applied as additional weights to the SNPs' beta coefficients in the GWAS summary statistics. Then, PRS was derived based on the weighted GWAS summary statistics using PRSice-2. Finally, we evaluated prediction performance of a set of different models that incorporated demographic information and TW-PRS. A total of 17,588 gene expression weights were obtained from 13 brain tissues. These gene expression weights covered about 220,000 SNPs. Among them, expression weights were applied to about 140,000 SNPs overlapped with GWAS summary statistics. An AD prediction using conventional PRS yielded a pseudo-R2 of 0.0462 (P=1.30E-04). Compared with the conventional PRS, the TW-PRS improved the performance and statistical power with a pseudo-R2 of 0.0574 (P=1.74E-05). As shown in Table 2, a fully adjusted model achieved an AUC of 0.794 in which TW-PRS were significant even when APOE ε4 status and demographic information were adjusted (P=2.33E-05). This study proposes a novel TW-PRS approach that combines predicted tissue-specific transcriptomic weights and PRS. Expression weights of brain regions critical to AD progression enhanced the performance of conventional PRS. Our finding suggests that tissue-specific transcriptomic factors may be independent and complementary to conventional PRS and provide additional information for tissue-specific regulatory effects in AD.

APOE is the largest genetic risk factor for Alzheimer's disease (AD), but there is a substantial polygenic component. Polygenic risk scores (PRS) can summarize small effects across the genome but may obscure differential risk across molecular processes and pathways that contribute to heterogeneity of disease presentation. We examined polygenic risk impacting specific AD-associated pathways and its relationship with clinical status and biomarkers of amyloid, tau, and neurodegeneration (A/T/N). We analyzed data from 1,411 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We applied pathway analysis and clustering to identify AD-associated "pathway clusters" and construct pathway-specific PRSs (excluding the APOE region). We tested associations with diagnostic status, abnormal levels of amyloid and ptau, and hippocampal volume. Thirteen pathway clusters were identified, and eight pathway-specific PRSs were significantly associated with AD diagnosis. Amyloid-positivity was associated with endocytosis and fibril formation, response misfolded protein, and regulation protein tyrosine PRSs. Ptau positivity and hippocampal volume were both related to protein localization and mitophagy PRS, and ptau-positivity was also associated with an immune signaling PRS. A global AD PRS showed stronger associations with diagnosis and all biomarkers compared to pathway PRSs. Pathway PRS may contribute to understanding separable disease processes, but do not add significant power for predictive purposes. These findings demonstrate that AD-phenotypes may be preferentially associated with risk in specific pathways, and defining genetic risk along multiple dimensions may clarify etiological heterogeneity in AD. This approach to delineate pathway-specific PRS can be used to study other complex diseases.

The Alzheimer’s disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institute of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer’s disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond.

The Recruitment and Retention of Alzheimer's Disease Diversity Genetic Cohorts in the Alzheimer's Disease Sequencing Project (READD-ADSP) was established to bridge thegap inAlzheimer's disease and related dementias (ADRD) research in Africa. We examined the role of Community Advisory Boards (CABs) in improving participant recruitment and retention in ADRD research in Africa, by exploring how culturally sensitive engagement, community trust-building, and stakeholder involvement influence research participation. Amulti-site, multi-phased qualitative study approachthat involved establishment of CABs, initial planning meetings and community engagement cum recruitment activities. Twenty-one CABs (141 members) were established across 14 study sites in 9 African Dementia Consortium (AfDC)member countries. Co-creation planning meetings, culturally sensitive outreaches for brain health, dementia awareness creation, and recruitment were held. Establishing CABs within the READD-ADSP project has proven instrumental in co-creating culturally appropriate and community-centered strategies for recruitment and retention in ADRD research in Africa. The Recruitment and Retention of Alzheimer's Disease Diversity Genetic Cohorts in the Alzheimer's Disease Sequencing Project (READD-ADSP) project utilizes a community-engaged research (CER) framework to develop a community engagement program and establish Community Advisory Boards (CABs) to enhance participant recruitment and retention. There is a need to standardize CER practices and promote context-sensitive and culturally appropriate CE activities across African Dementia Consortium (AfDC) sites to ensure cultural sensitivity and enhance recruitment and retention. The project seeks to empower CABs to promote national dementia policies by collaborating with policy-makers and advancing equitable dementia scienced and care in Africa.

Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.

Medial temporal lobe atrophy scores translated to clinical practice: Editorial comment on ‘Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut‐offs'

Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans

Fibrillar tau is a defining hallmark of Alzheimer's disease, gradually accumulating and spreading throughout the brain. The synapse plays a key role in this process-both by facilitating the spread of tau between neurons and by serving as a direct target of tau-induced neurotoxicity. However, few studies in humans have explored synaptic density both as a facilitating factor and as a target of tau pathology. In this dual PET tracer study, we used 18F-SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET to assess synaptic density and 18F-MK6240 tau-PET to assess fibrillar tau in 59 amyloid-PET-positive patients and 25 amyloid-PET-negative cognitively normal individuals from the Chinese Preclinical Alzheimer's Disease Study (CPAS). Spatial correlation analyses revealed that brain regions with higher SV2A tracer uptake in cognitively normal individuals exhibited higher 18F-MK6240 uptake in Alzheimer's disease. These findings were independently replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI), where normal SV2A-PET maps from CPAS were correlated with tau-PET data from 372 Aβ+ participants, including longitudinal follow-up in 204 cases. In both cohorts, regions with higher normal synaptic density showed greater tau burden, and in ADNI, higher synaptic density in normal brain also predicted faster tau accumulation over time. Gene-set enrichment analyses of transcriptomic data mapped onto regional tau-PET uptake further showed that areas of high 18F-MK6240 uptake were enriched in genes encoding synapse-related proteins. Together, these findings suggest that synapse-rich regions are especially prone to tau accumulation. We also investigated the downstream impact of tau on synaptic integrity. Notably, regions with higher 18F-MK6240 uptake showed reduced SV2A tracer uptake, indicating synaptic loss, not only in the same regions but also in areas connected to those with high tau. Stronger loss of SV2A tracer uptake was observed in the regions with stronger resting-state functional connectivity to epicenters of high 18F-MK6240 uptake in the Alzheimer's disease group. The connectivity-dependent synaptic loss could not be fully explained by tau levels in the connected target regions but was found to be partially mediated by them. These findings suggest that tau pathology contributes to synaptic loss both locally and in distant, connected brain regions. Overall, our results highlight the central importance of the synapse in Alzheimer's disease: synapses appear to both facilitate fibrillar tau accumulation and become impaired through its toxic effects. Understanding the synapse's role in tau pathology may open new avenues for therapeutic interventions aimed at slowing down tau progression and neurodegeneration.

BackgroundVascular dysfunction plays a role in Alzheimer's disease (AD) pathophysiology. While sodium is vital for vascular function, its involvement in AD pathology needs clarification.MethodWe analyzed 353 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), examining serum sodium levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), and cognitive function. An additional independent sample (N = 471) with CSF sodium‐related proteins and AD biomarkers was studied. Linear regression models evaluated associations between serum sodium and AD pathology, neurodegeneration, and cognition. Spearman's correlation analyzed relationships between CSF sodium‐related proteins and AD biomarkers.ResultHigher serum sodium levels correlated with increased AD pathology, reduced hippocampal volume, and greater cognitive decline (all p < 0.05). Amyloid PET showed this relationship in AD‐susceptible regions, including neocortex and limbic system. High serum sodium groups showed higher tau pathology, lower hippocampal volume, and worse cognitive decline per unit increase in amyloid PET versus low serum sodium groups (all p < 0.05). Among 14 CSF sodium‐related proteins, six correlated with CSF AD pathology and amyloid PET, while two correlated with hippocampal volume and cognitive function. Sodium channel subunit beta‐2 (SCN2B) and beta‐3 (SCN3B) showed strongest correlations.ConclusionSerum sodium plays a crucial role in AD progression, revealing a potential network of sodium dysregulation in AD pathology. Targeting sodium may provide a novel therapeutic approach for slowing AD progression, particularly in impeding amyloid‐related downstream events.

An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

Due to a change in disease spectrum in aged countries, the primary role of geriatricians should be directed to an appropriate management and prevention of 1) cognitive decline and dementia, 2) swallowing and aspiration pneumonia and 3) falls and fractures. Management of dementia constitutes a central part in the practice of geriatric medicine in order to support independence of life in elderly people. The current paradigm of cognitive function-based testing for the diagnosis and treatment of Alzheimer's disease (AD) is going to drastically shift to a biomarker-based test approach, a shift that will correspond to the emergence of disease-modifying drugs. In addition, a new molecular imaging technique that visualizes neuronal protein deposits or pathological features has been developed in Japan and the U.S.A. Based on these achievements, the Alzheimer's Disease Neuroimaging Initiative (ADNI) was proposed and initiated in 2005. The ADNI is a long-term observational study being conducted in the U.S.A., Europe, Australia, and Japan using identical protocols. The objectives of ADNI are: 1) to establish methodology which will allow standard values related to long-term changes in imaging data, such as MRI and PET, in patients with AD and mild cognitive impairment and normal elderly persons; 2) to obtain clinical indices, psychological test data, and blood/cerebrospinal fluid biomarkers to demonstrate the validity of image-based surrogate markers; and 3) to establish optimum methods to monitor the therapeutic effects of disease-modifying drugs for AD. Patient enrollment in the Japanese ADNI has begun in July 2008. Imaging of AD pathology not only acts as a reliable biomarker with which to assay curative drug development by novel pharmaceutical companies, but it also helps health promotion toward AD prevention.

Introduction:Structural variants (SV), genomic alterations spanning more than 50 base pairs, can significantly impact gene expression and protein function. However, their contribution to Alzheimer’s Disease (AD) remains poorly understood. Leveraging a novel SV calling pipeline, we identified SVs with high accuracy in a diverse sample of the Alzheimer’s Disease Sequencing Project (ADSP) and investigated the role of SVs in AD.Results:We analyzed SVs in 16,841 individuals from ADSP whole genome sequencing data using BioGraph, a semi-assembly-based method that employs graph-based representation for accurate SV detection. We identified 456,644 high-quality SVs, 65% of which were novel. Of these, 272,728 SVs directly impact genes, including 86 AD-related genes. Association analyses were performed within three ancestry groups, including 3,371 African (AFR), 6,327 European (EUR), and 2,126 Latin (LAT). Multiple deletions and insertions were observed in moderate to high linkage disequilibrium with known AD loci, including TPCN1 and TMEM106B. In EUR, genome-wide association analysis identified two significant low-frequency deletions associated with AD, located in introns of CCDC12 and CCDC88B, both encoding coiled-coil domain-containing proteins. Gene-based analyses further identified rare pathogenic SVs in several known AD genes, including PSEN1 in LAT and ABCA7 in AFR.Conclusions:Using a novel graph-based SV calling pipeline, we identified high-quality SVs across a large and ancestrally diverse cohort. Our analyses revealed both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.

INTRODUCTIONBiomarkers for Alzheimer's disease neuropathologic change (ADNC) have been instrumental in developing effective disease‐modifying therapeutics. However, to prevent/treat dementia effectively, we require biomarkers for non‐AD neuropathologies; for this, neuropathologic examinations and annotated tissue samples are essential.METHODSWe conducted clinicopathologic correlation for the first 100 Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) cases.RESULTSClinical syndromes in this cohort showed 95% sensitivity and 79% specificity for predicting high/intermediate ADNC, a 21% false positive rate, and a ∼44% false negative rate. In addition, 60% with high/intermediate ADNC harbored additional potentially dementing co‐pathologies.DISCUSSIONThese results suggest that clinical presentation imperfectly predicts ADNC and that accurate prediction of high/intermediate ADNC does not exclude co‐pathology that may modify presentation, biomarkers, and therapeutic responses. Therefore, new biomarkers are needed for non‐AD neuropathologies. The ADNI NPC supports this mission with well‐characterized tissue samples (available through ADNI and the National Institute on Aging) and “gold‐standard” diagnostic information (soon to include digital histology).HighlightsThe Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) brain donation cohort now exceeds 200 cases.ADNI NPC data in National Alzheimer's Coordinating Center format are available through the Laboratory of Neuro Imaging.Digitized slide files from the ADNI NPC will be available in 2025.Requests for ADNI brain tissue samples can be submitted online for ADNI/National Institute on Aging evaluation.Clinical diagnoses of Alzheimer's disease (AD)/AD and related dementias (ADRD) do not always predict post mortem neuropathology.Neuropathology is essential for the development of novel AD/ADRD biomarkers.

IntroductionIt is important to study apathy in Alzheimer's disease (AD) to better understand its underlying neurobiology and develop effective interventions. In the current study, we sought to examine the relationships between longitudinal apathy and regional tau burden in cognitively impaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.MethodsThree hundred and nineteen ADNI participants with mild cognitive impairment (MCI) or AD dementia underwent flortaucipir (FTP) tau positron emission tomography (PET) imaging and clinical assessment with the Neuropsychiatric Inventory (NPI) annually. Longitudinal NPI Apathy (NPI‐A) scores were examined in relation to baseline tau PET signal in three a priori selected regions implicated in AD and AD‐related apathy (supramarginal gyrus, entorhinal cortex [EC] and rostral anterior cingulate cortex [rACC]). Secondary models were adjusted for global cognition (Mini‐Mental State Examination score) and cortical amyloid (florbetapir PET).ResultsHigher baseline supramarginal gyrus and EC tau burden were each significantly associated with greater NPI‐A over time, while rACC tau was associated with higher NPI‐A but did not predict its trajectory over time. These results were retained for supramarginal and EC tau after adjusting models for global cognition and cortical amyloid.DiscussionOur findings suggest that baseline in vivo tau burden in parietal and temporal brain regions affected in AD, and less so in a medial frontal region involved in motivational control, is associated with increasing apathy over time in older adults with MCI and AD dementia. Future work studying emergent apathy in relation to not only core AD pathology but also circuit level dysfunction may provide additional insight into the neurobiology of apathy in AD and opportunities for intervention.HighlightsTau (Flortaucipir PET) in regions implicated in AD was associated with increasing apathy over timeCortical amyloid was also found to be a robust predictor of the trajectory of apathyEvidence of synergy between regional tau and amyloid in overall higher levels of apathy