Authors: Caselli, Richard J. | Reiman, Eric M.
Article Type: Review Article
Abstract: Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased ε4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, amyloid-β, and phospho-tau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate …and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with ε4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in ε4 carriers beginning around age 55–60 years whose severity again parallels ε4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible. Show more
Keywords: APOE, normal aging, preclinical, prevention
DOI: 10.3233/JAD-2012-129026
Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S405-S416, 2013
Authors: Chen, Yanxi | Su, Yi | Wu, Jianfeng | Chen, Kewei | Atri, Alireza | Caselli, Richard J. | Reiman, Eric M. | Wang, Yalin
Article Type: Research Article
Abstract: Background: Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer’s disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ plaques. Objective: To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio. Methods: We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aβ42/40 trained a random forest classifier to perform a binary classification of participant …brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer’s Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results: Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model’s superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors. CONCLUSIONS: Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer’s disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI. Show more
Keywords: Aβ positivity, amyloid PET, blood-based biomarkers, image features, MRI
DOI: 10.3233/JAD-231162
Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1415-1426, 2024
Authors: Burns, Christine M. | Kaszniak, Alfred W. | Chen, Kewei | Lee, Wendy | Bandy, Daniel J. | Caselli, Richard J. | Reiman, Eric M.
Article Type: Research Article
Abstract: Background: The association between longitudinal changes in serum glucose level and longitudinal changes in [18 F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer’s disease (AD) risk are unknown. Objective: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer’s disease (AD). Methods: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ 4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm …was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. Results: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ 4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ 4 status and baseline and advancing age. Conclusions: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD. Show more
Keywords: Alzheimer’s disease, blood glucose, longitudinal studies, positron emission tomography
DOI: 10.3233/JAD-170767
Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 833-840, 2018
Authors: Valla, Jon | Yaari, Roy | Wolf, Andrew B. | Kusne, Yael | Beach, Thomas G. | Roher, Alex E. | Corneveaux, Jason J. | Huentelman, Matthew J. | Caselli, Richard J. | Reiman, Eric M.
Article Type: Research Article
Abstract: In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had …lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology. Show more
Keywords: Alzheimer's etiology, bioenergetics, biomarkers, cytochrome c oxidase, differential vulnerability, neocortex
DOI: 10.3233/JAD-2010-100129
Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 307-313, 2010
Authors: Reiman, Eric M. | Langbaum, Jessica B.S. | Fleisher, Adam S. | Caselli, Richard J. | Chen, Kewei | Ayutyanont, Napatkamon | Quiroz, Yakeel T. | Kosik, Kenneth S. | Lopera, Francisco | Tariot, Pierre N.
Article Type: Research Article
Abstract: There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk …of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE) ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit—information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials. Show more
Keywords: Brain imaging, cerebral spinal fluid, biomarkers, surrogate markers, presymptomatic Alzheimer's disease, early-onset Alzheimer's disease, late-onset Alzheimer's disease, presenilin 1, apolipoprotein E, clinical trials
DOI: 10.3233/JAD-2011-0059
Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 321-329, 2011
Authors: Wu, Jianfeng | Su, Yi | Chen, Yanxi | Zhu, Wenhui | Reiman, Eric M. | Caselli, Richard J. | Chen, Kewei | Thompson, Paul M. | Wang, Junwen | Wang, Yalin
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of age-related dementia, affecting 6.2 million people aged 65 or older according to CDC data. It is commonly agreed that discovering an effective AD diagnosis biomarker could have enormous public health benefits, potentially preventing or delaying up to 40% of dementia cases. Tau neurofibrillary tangles are the primary driver of downstream neurodegeneration and subsequent cognitive impairment in AD, resulting in structural deformations such as hippocampal atrophy that can be observed in magnetic resonance imaging (MRI) scans. Objective: To build a surface-based model to 1) detect differences between APOE subgroups in patterns …of tau deposition and hippocampal atrophy, and 2) use the extracted surface-based features to predict cognitive decline. Methods: Using data obtained from different institutions, we develop a surface-based federated Chow test model to study the synergistic effects of APOE , a previously reported significant risk factor of AD, and tau on hippocampal surface morphometry. Results: We illustrate that the APOE -specific morphometry features correlate with AD progression and better predict future AD conversion than other MRI biomarkers. For example, a strong association between atrophy and abnormal tau was identified in hippocampal subregion cornu ammonis 1 (CA1 subfield) and subiculum in e4 homozygote cohort. Conclusion: Our model allows for identifying MRI biomarkers for AD and cognitive decline prediction and may uncover a corner of the neural mechanism of the influence of APOE and tau deposition on hippocampal morphology. Show more
Keywords: Alzheimer’s disease, APOE, Federated Chow test, hippocampal morphometry, tau deposition
DOI: 10.3233/JAD-230034
Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1153-1168, 2023
Authors: Wu, Jianfeng | Su, Yi | Zhu, Wenhui | Jalili Mallak, Negar | Lepore, Natasha | Reiman, Eric M. | Caselli, Richard J. | Thompson, Paul M. | Chen, Kewei | Wang, Yalin
Article Type: Research Article
Abstract: Background: Amyloid-β (Aβ) plaques and tau protein tangles in the brain are the defining ‘A’ and ‘T’ hallmarks of Alzheimer’s disease (AD), and together with structural atrophy detectable on brain magnetic resonance imaging (MRI) scans as one of the neurodegenerative (‘N’) biomarkers comprise the “ATN framework” of AD. Current methods to detect Aβ/tau pathology include cerebrospinal fluid (invasive), positron emission tomography (PET; costly and not widely available), and blood-based biomarkers (promising but mainly still in development). Objective: To develop a non-invasive and widely available structural MRI-based framework to quantitatively predict the amyloid and tau measurements. Methods: With MRI-based hippocampal multivariate …morphometry statistics (MMS) features, we apply our Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP) method combined with the ridge regression model to individual amyloid/tau measure prediction. Results: We evaluate our framework on amyloid PET/MRI and tau PET/MRI datasets from the Alzheimer’s Disease Neuroimaging Initiative. Each subject has one pair consisting of a PET image and MRI scan, collected at about the same time. Experimental results suggest that amyloid/tau measurements predicted with our PASCP-MP representations are closer to the real values than the measures derived from other approaches, such as hippocampal surface area, volume, and shape morphometry features based on spherical harmonics. Conclusion: The MMS-based PASCP-MP is an efficient tool that can bridge hippocampal atrophy with amyloid and tau pathology and thus help assess disease burden, progression, and treatment effects. Show more
Keywords: Alzheimer’s disease, amyloid deposition, Braak12 tau-SUVR, Braak34 tau-SUVR, Centiloid, dictionary and correntropy-induced sparse coding, hippocampal multivariate morphometry statistics, tau deposition
DOI: 10.3233/JAD-220812
Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 637-651, 2023
Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.
Article Type: Correction
DOI: 10.3233/JAD-169007
Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1249-1249, 2016
Authors: Coon, Keith D. | Siegel, Andrew M. | Yee, Stephanie J. | Dunckley, Travis L. | Mueller, Claudius | Nagra, Rashed M. | Tourtellotte, Wallace W. | Reiman, Eric M. | Papassotiropoulos, Andreas | Petersen, Floyd F. | Stephan, Dietrich A. | Kirsch, Wolff M.
Article Type: Research Article
Abstract: The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the …IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder. Show more
Keywords: Iron, iron regulatory protein 2, neurodegeneration, neurodegenerative disease, iron metabolism, Alzheimer's disease
DOI: 10.3233/JAD-2006-9301
Citation: Journal of Alzheimer's Disease, vol. 9, no. 3, pp. 225-233, 2006
Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.
Article Type: Research Article
Abstract: Tau becomes excessively phosphorylated in Alzheimer’s disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, …followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage. Show more
Keywords: Braak NFT stage, colon, HT7, liver, PHF-1, propagation, skin, spread, submandibular gland, T231
DOI: 10.3233/JAD-150859
Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 345-356, 2016
