Publications by authors named "Eric M Reiman"

286 Publications

Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure.

Adv Sci (Weinh) 2021 Aug 2:e2101462. Epub 2021 Aug 2.

Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because the blood-brain barrier (BBB) leakage is a well-known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/β) levels, respectively. In addition, single-cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid-based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.
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http://dx.doi.org/10.1002/advs.202101462DOI Listing
August 2021

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.

Aging (Albany NY) 2021 07 12;13(13):17097-17117. Epub 2021 Jul 12.

Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, USA.

Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer's Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.
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http://dx.doi.org/10.18632/aging.203297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312464PMC
July 2021

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers.

Neuroimage Clin 2021 Jul 4;31:102749. Epub 2021 Jul 4.

Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA; Arizona State University, Tempe, AZ, USA; University of Arizona, Tucson, AZ, USA; Translational Genomics Research Institute, Phoenix, AZ, USA. Electronic address:

Background: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.

Methods: F florbetapir and C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.

Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).

Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.
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http://dx.doi.org/10.1016/j.nicl.2021.102749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278433PMC
July 2021

A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with and CNOT3.

Genes (Basel) 2021 May 26;12(6). Epub 2021 May 26.

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in . The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 ( = -0.27, 95% CI = (-0.35, -0.19), = 1.29 × 10) and rs10881463 ( = -0.20, 95% CI = (-0.27, -0.13), = 3.40 × 10). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4-NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.
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http://dx.doi.org/10.3390/genes12060815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228534PMC
May 2021

Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau.

EMBO Mol Med 2021 Jun 5;13(6):e14022. Epub 2021 May 5.

Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.

Alzheimer's disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer's disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ("BioFINDER-2", N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
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http://dx.doi.org/10.15252/emmm.202114022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185545PMC
June 2021

Brain proteome-wide association study implicates novel proteins in depression pathogenesis.

Nat Neurosci 2021 Jun 12;24(6):810-817. Epub 2021 Apr 12.

Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA.

Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study (GWAS) results (N = 500,199) with human brain proteomes (N = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis-regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS (N = 307,353) and another human brain proteomic dataset (N = 152). Eleven of the 19 genes also had cis-regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes (N = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies.
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http://dx.doi.org/10.1038/s41593-021-00832-6DOI Listing
June 2021

Improved Prediction of Imminent Progression to Clinically Significant Memory Decline Using Surface Multivariate Morphometry Statistics and Sparse Coding.

J Alzheimers Dis 2021 ;81(1):209-220

School of Computing, Informatics, and Decision Systems Engineering, Arizona State University, Tempe, AZ, USA.

Background: Besides their other roles, brain imaging and other biomarkers of Alzheimer's disease (AD) have the potential to inform a cognitively unimpaired (CU) person's likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79%sensitivity/78%specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures.

Objective: To improve the same prediction by using different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI).

Methods: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years ("progressors") and 80 matched adults who remained CU for at least 4 years ("nonprogressors"). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI.

Results: We achieved 92%prediction accuracy in the Arizona cohort, 92%prediction accuracy in the ADNI cohort, and 90%prediction accuracy when combining the two demographically distinct cohorts, as compared to 79%(Arizona) and 72%(ADNI) prediction accuracy using hippocampal volume.

Conclusion: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers.
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http://dx.doi.org/10.3233/JAD-200821DOI Listing
January 2021

National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome.

Neurology 2021 05 15;96(18):848-863. Epub 2021 Mar 15.

From the Boston University CTE Center (D.I.K.), Department of Neurology, Boston University School of Medicine, Boston; Brain Injury Program (D.I.K.), Encompass Health Braintree Rehabilitation Hospital, Braintree, MA; University of Washington Memory & Brain Wellness Clinic (C.B.), Department of Neurology, University of Washington School of Medicine, Seattle; Department of Neurology (D.W.D., C.H.A.), Mayo Clinic, Scottsdale, AZ; Boston University CTE Center (J.M., M.L.A.), Boston University Alzheimer's Disease Center, Department of Neurology, Boston University School of Medicine; Boston University CTE Center (M.L.M.), Boston University School of Medicine, MA; Departments of Neurology (L.J.B.), Ophthalmology, and Population Health, New York University Grossman School of Medicine; Departments of Neurosciences and Psychiatry University of California San Diego (S.J.B.), La Jolla; Departments of Neurology and Psychiatry (W.B.B.), New York University Grossman School of Medicine; Center for Neuroscience and Regenerative Medicine (D.L.B.), Uniformed Services University of the Health Sciences, Department of Neurology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; Boston University CTE Center (R.C.C.), Boston University Alzheimer's Disease Center, Departments of Neurology and Neurosurgery, Boston University School of Medicine, MA; Departments of Rehabilitation Medicine and Neurology (K.D.-O.C.), Icahn School of Medicine, Mount Sinai, New York; Department of Neurology (Y.E.G.), Barrow Neurological Institute, Phoenix, AZ; Rancho Los Amigos National Rehabilitation Center (B.D.J.), Downey, CA; Department of Neurology (B.D.J.), Keck School of Medicine of USC. Los Angeles, CA; Departments of Psychiatry and Neurology (T.W.M.), Indiana University School of Medicine, Indianapolis; Veterans Affairs Northwest Mental Illness (E.R.P.), Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA; Department of Psychiatry and Behavioral Sciences (E.R.P.), University of Washington School of Medicine, Seattle; Mayo Clinic Alzheimer's Disease Research Center (R.C.P.), Mayo Clinic, Rochester, MN; Department of Psychiatry and Psychology (J.V.W.), Mayo Clinic, Scottsdale, AZ; Department of Physical Medicine and Rehabilitation (R.D.Z.), Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston; Faculty of Psychology and Neuroscience (É.M.F.), Maastricht University, the Netherlands, Department of Psychiatry, University of Cambridge, United Kingdom; National Institute of Neurological Disorders and Stroke (D.J.B.), National Institutes of Health; National Institute of Neurological Disorders and Stroke (W.J.K.), Bethesda, MD; Boston University CTE Center (Y.T.), Boston University Alzheimer's Disease Center, Boston University School of Medicine, Department of Biostatistics, Boston University School of Public Health; Boston University CTE Center (A.C.M.), Boston University Alzheimer's Disease Center, Departments of Neurology and Pathology & Laboratory Medicine, Boston University School of Medicine; VA Boston Healthcare System (A.C.M.), US Department of Veteran Affairs, MA; Psychiatry Neuroimaging Laboratory (M.E.S.), Departments of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Chambers-Grundy Center for Transformative Neuroscience (J.L.C.), Department of Brain Health, University of Nevada School of Integrated Health Sciences; Cleveland Clinic Lou Ruvo Center for Brain Health (J.L.C.), Las Vegas, NV; Banner Alzheimer's Institute (E.M.R.), Arizona State University; Department of Psychiatry (E.M.R.), University of Arizona, Phoenix, AZ; and Boston University CTE Center (R.A.S.), Boston University Alzheimer's Disease Center, Departments of Neurology, Neurosurgery, and Anatomy & Neurobiology, Boston University School of Medicine, MA.

Objective: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE).

Methods: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298).

Results: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features.

Conclusions: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.
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http://dx.doi.org/10.1212/WNL.0000000000011850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166432PMC
May 2021

Predicting future cognitive decline with hyperbolic stochastic coding.

Med Image Anal 2021 05 24;70:102009. Epub 2021 Feb 24.

School of Computing, Informatics, and Decision Systems Engineering, Arizona State University, Tempe, AZ, 85287 USA. Electronic address:

Hyperbolic geometry has been successfully applied in modeling brain cortical and subcortical surfaces with general topological structures. However, such approaches, similar to other surface-based brain morphology analysis methods, usually generate high dimensional features. It limits their statistical power in cognitive decline prediction research, especially in datasets with limited subject numbers. To address the above limitation, we propose a novel framework termed as hyperbolic stochastic coding (HSC). We first compute diffeomorphic maps between general topological surfaces by mapping them to a canonical hyperbolic parameter space with consistent boundary conditions and extracts critical shape features. Secondly, in the hyperbolic parameter space, we introduce a farthest point sampling with breadth-first search method to obtain ring-shaped patches. Thirdly, stochastic coordinate coding and max-pooling algorithms are adopted for feature dimension reduction. We further validate the proposed system by comparing its classification accuracy with some other methods on two brain imaging datasets for Alzheimer's disease (AD) progression studies. Our preliminary experimental results show that our algorithm achieves superior results on various classification tasks. Our work may enrich surface-based brain imaging research tools and potentially result in a diagnostic and prognostic indicator to be useful in individualized treatment strategies.
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http://dx.doi.org/10.1016/j.media.2021.102009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049149PMC
May 2021

Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease.

medRxiv 2021 Feb 18. Epub 2021 Feb 18.

The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal β-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.
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http://dx.doi.org/10.1101/2021.02.15.21251511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899461PMC
February 2021

Genetic control of the human brain proteome.

Am J Hum Genet 2021 03 10;108(3):400-410. Epub 2021 Feb 10.

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008492PMC
March 2021

Associations between plasma neurofilament light, in vivo brain pathology, and cognition in non-demented individuals with autosomal-dominant Alzheimer's disease.

Alzheimers Dement 2021 05 1;17(5):813-821. Epub 2021 Feb 1.

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Neurofilament light (NfL) is a promising biomarker of early neurodegeneration in Alzheimer's disease (AD). We examined whether plasma NfL was associated with in vivo amyloid beta and tau, and cognitive performance in non-demented presenilin-1 (PSEN1) E280A mutation carriers.

Methods: Twenty-five mutation carriers and 19 non-carriers (age range: 28 to 49 years) were included in this study. Participants underwent 11C Pittsburgh compound B (PiB)-PET (positron emission tomography), flortaucipir-PET, blood sampling, and cognitive testing.

Results: Mutation carriers exhibited higher plasma NfL levels than non-carriers. In carriers, higher NfL levels were related to greater regional tau burden and worse cognition, but not amyloid beta load. When we adjusted for age, a proxy of disease progression, elevated plasma NfL levels were only correlated with worse memory recall.

Conclusions: Findings support an association between plasma NfL, cognition, and tau pathology in non-demented individuals at genetic risk for developing AD dementia. Plasma NfL may be useful for selecting individuals at increased risk and tracking disease progression in AD.
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http://dx.doi.org/10.1002/alz.12248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158654PMC
May 2021

Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis.

Nat Genet 2021 02 28;53(2):143-146. Epub 2021 Jan 28.

Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD), but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.
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http://dx.doi.org/10.1038/s41588-020-00773-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130821PMC
February 2021

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

Alzheimers Res Ther 2021 01 15;13(1):27. Epub 2021 Jan 15.

Massachusetts General Hoospital, Harvard Medical School, Boston, MA, USA.

Background: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.

Methods: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.

Results: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.

Conclusions: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.
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http://dx.doi.org/10.1186/s13195-020-00765-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811244PMC
January 2021

Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer's disease and implicate its dynamic role in disease progression.

Clin Epigenetics 2020 12 9;12(1):189. Epub 2020 Dec 9.

ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.

Background: While Alzheimer's disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention.

Methods: We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters).

Results: When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances.

Conclusions: Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.
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http://dx.doi.org/10.1186/s13148-020-00984-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724832PMC
December 2020

Patch-Based Surface Morphometry Feature Selection with Federated Group Lasso Regression.

Proc SPIE Int Soc Opt Eng 2020 Oct 3;11583. Epub 2020 Nov 3.

School of Computing, Informatics, and Decision Systems Engineering, Arizona State University, 699 S Mill Ave, Tempe, USA.

Collectively, vast quantities of brain imaging data exist across hospitals and research institutions, providing valuable resources to study brain disorders such as Alzheimer's disease (AD). However, in practice, putting all these distributed datasets into a centralized platform is infeasible due to patient privacy concerns, data restrictions and legal regulations. In this study, we propose a novel federated feature selection framework that can analyze the data at each individual institution without data-sharing or accessing private patient information. In this framework, we first propose a federated group lasso optimization method based on block coordinate descent. We employ stability selection to determine statistically significant features, by solving the group lasso problem with a sequence of regularization parameters. To accelerate the stability selection, we further propose a federated screening rule, which can identify and exclude the irrelevant features before solving the group lasso. Here, we use this framework for patch based feature selection on hippocampal morphometry. Shape is characterized through two different kinds of local measures, the radial distance and the surface area determined via tensor-based morphometry (TBM). The method is tested on 1,127 T1-weighted brain magnetic resonance images (MRI) of AD, mild cognitive impairment (MCI) and elderly control subjects, randomly assigned to five independent hypothetical institutions for testing purpose. We examine the association of MRI-based anatomical measures with general cognitive assessment and amyloid burden to identify the morphometry changes related to AD deterioration and plaque accumulation. Finally, we visualize the significance of the association on the hippocampal surfaces. Our experimental results successfully demonstrate the efficiency and effectiveness of our method.
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http://dx.doi.org/10.1117/12.2575984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694696PMC
October 2020

Developing univariate neurodegeneration biomarkers with low-rank and sparse subspace decomposition.

Med Image Anal 2021 01 21;67:101877. Epub 2020 Oct 21.

School of Computing, Informatics, and Decision Systems Engineering, Arizona State University, P.O. Box 878809 Tempe, AZ 85287, USA. Electronic address:

Cognitive decline due to Alzheimer's disease (AD) is closely associated with brain structure alterations captured by structural magnetic resonance imaging (sMRI). It supports the validity to develop sMRI-based univariate neurodegeneration biomarkers (UNB). However, existing UNB work either fails to model large group variances or does not capture AD dementia (ADD) induced changes. We propose a novel low-rank and sparse subspace decomposition method capable of stably quantifying the morphological changes induced by ADD. Specifically, we propose a numerically efficient rank minimization mechanism to extract group common structure and impose regularization constraints to encode the original 3D morphometry connectivity. Further, we generate regions-of-interest (ROI) with group difference study between common subspaces of Aβ+AD and Aβ-cognitively unimpaired (CU) groups. A univariate morphometry index (UMI) is constructed from these ROIs by summarizing individual morphological characteristics weighted by normalized difference between Aβ+AD and Aβ-CU groups. We use hippocampal surface radial distance feature to compute the UMIs and validate our work in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. With hippocampal UMIs, the estimated minimum sample sizes needed to detect a 25% reduction in the mean annual change with 80% power and two-tailed P=0.05are 116, 279 and 387 for the longitudinal Aβ+AD, Aβ+mild cognitive impairment (MCI) and Aβ+CU groups, respectively. Additionally, for MCI patients, UMIs well correlate with hazard ratio of conversion to AD (4.3, 95% CI = 2.3-8.2) within 18 months. Our experimental results outperform traditional hippocampal volume measures and suggest the application of UMI as a potential UNB.
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http://dx.doi.org/10.1016/j.media.2020.101877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725891PMC
January 2021

Human Autopsy-Derived Scalp Fibroblast Biobanking for Age-Related Neurodegenerative Disease Research.

Cells 2020 10 30;9(11). Epub 2020 Oct 30.

Banner Sun Health Research Institute, Sun City, AZ 85351, USA.

The Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program at Banner Sun Health Research Institute (BSHRI) is a longitudinal clinicopathological study with a current enrollment of more than 900 living subjects for aging and neurodegenerative disease research. Annual clinical assessments are done by cognitive and movement neurologists and neuropsychologists. Brain and body tissues are collected at a median postmortem interval of 3.0 h for neuropathological diagnosis and banking. Since 2018, the program has undertaken banking of scalp fibroblasts derived from neuropathologically characterized donors with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Here, we describe the procedure development and cell characteristics from 14 male and 15 female donors (mean ± SD of age: 83.6 ± 12.2). Fibroblasts from explant cultures were banked at passage 3. The results of mRNA analysis showed positive expression of fibroblast activation protein, vimentin, fibronectin, and THY1 cell surface antigen. We also demonstrated that the banked fibroblasts from a postmortem elderly donor were successfully reprogramed to human-induced pluripotent stem cells (hiPSCs). Taken together, we have demonstrated the successful establishment of a human autopsy-derived fibroblast banking program. The cryogenically preserved cells are available for request at the program website of the BSHRI.
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http://dx.doi.org/10.3390/cells9112383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692621PMC
October 2020

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 01;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer's Disease and Cognitive Decline.

J Alzheimers Dis 2020 ;78(2):721-734

Banner Alzheimer's Institute, Phoenix, AZ, USA.

Background: Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer's disease (AD) is unknown.

Objective: To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study.

Methods: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years.

Results: Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers.

Conclusion: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity-findings that would need to be confirmed in larger studies.
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http://dx.doi.org/10.3233/JAD-200132DOI Listing
May 2021

Risk Factors for Alzheimer's Disease and Related Dementia Diagnoses in American Indians.

Ethn Dis 2020 24;30(4):671-680. Epub 2020 Sep 24.

IREACH, Washington State University, Seattle, WA.

The burden of Alzheimer's disease and related dementias (ADRD) has increased substantially in the United States, particularly in health disparity populations. Little is known about the epidemiology of ADRD in American Indian (AI) adults, although they have a high prevalence of ADRD risk factors including hypertension, diabetes, obesity, and smoking. Using electronic health records from a large health care organization during 2016-18, we describe characteristics of AI patients aged ≥55 years with and without an ADRD diagnosis, assess ADRD risk factors and contrast findings with results from age- and sex-matched non-Hispanic White (NHW) patients. To identify factors associated with ADRD diagnoses, we estimated population-averaged prevalence rate ratios to approximate relative risk (RR) using generalized estimating equations models adjusted for age, sex, and marital and rural residency status. The age-adjusted prevalence of ADRD diagnosis was 6.6% of AI patients, compared with 4.4% in NHW patients. Patient age and diagnosis of hypertension, depression, hyperlipidemia, or diabetes were significantly associated with higher risk of ADRD diagnosis in AIs (RR range: 1.1-2.8) whereas female sex or being married/having a partner were associated with lower risk of ADRD diagnosis (each RR=.7). ADRD risk factors were generally similar between AI and NHW patients, except for sex and marital status. However, the adjusted risk of ADRD was approximately 49% higher in AI patients. To our knowledge, our study is the first to examine ADRD diagnoses and comorbidities in AIs across a large geographical region in southwest United States. Future efforts to confirm our findings in diverse AI communities are warranted.
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http://dx.doi.org/10.18865/ed.30.4.671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518528PMC
April 2021

Examining Sex Differences in Markers of Cognition and Neurodegeneration in Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombian Alzheimer's Prevention Initiative Biomarker Study.

J Alzheimers Dis 2020 ;77(4):1743-1753

Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

Background: Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer's disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy).

Objective: Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD.

Methods: We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20-44; 11 females), 11 symptomatic carriers (age range 42-56; 8 females), and 23 matched non-carriers family members (age range 20-50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted.

Results: There were no differential associations between age, CERAD Total Score, CERAD Word List-Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups.

Conclusion: Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers.
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http://dx.doi.org/10.3233/JAD-200723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075106PMC
January 2020

The Latin American Spanish version of the Face-Name Associative Memory Exam is sensitive to cognitive and pathological changes in preclinical autosomal dominant Alzheimer's disease.

Alzheimers Res Ther 2020 09 10;12(1):104. Epub 2020 Sep 10.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer's disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers.

Methods: A total of 35 cognitively intact mutation carriers (age range 26-41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27-44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation.

Results: Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = - .436, p = .018) and regional tau in the entorhinal (r = - .394, p = .031) and inferior temporal cortex (r = - .563, p = .001) were associated with lower LAS-FNAME Total Scores.

Conclusions: Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.
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http://dx.doi.org/10.1186/s13195-020-00671-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488408PMC
September 2020

Visual short-term memory relates to tau and amyloid burdens in preclinical autosomal dominant Alzheimer's disease.

Alzheimers Res Ther 2020 08 21;12(1):99. Epub 2020 Aug 21.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Rm 10.014, Boston, MA, 02129, USA.

Background: Over the past decade, visual short-term memory (VSTM) binding tests have been shown to be one of the most sensitive behavioral indicators of Alzheimer's disease (AD), especially when they require the binding of multiple features (e.g., color and shape). Recently, it has become possible to directly measure amyloid and tau levels in vivo via positron emission tomography (PET). To this point, these behavioral and neurochemical markers have not been compared in humans with AD or at risk for it.

Methods: In a cross-sectional study, we compared VSTM performance to tau and amyloid concentrations, measured by PET, in individuals certain to develop AD by virtue of their inheritance of the presenilin-1 E280A mutation. These included 21 clinically unimpaired subjects and 7 subjects with early mild cognitive impairment (MCI), as well as 30 family members who were not carriers of the mutation.

Results: We found that VSTM performance correlated strongly with tau in entorhinal cortex and inferior temporal lobe, and also with amyloid when examining asymptomatic carriers only. The condition requiring binding was not preferentially linked to tau-in fact, the non-binding "shape only" condition showed a stronger relationship.

Conclusions: The results confirm VSTM's status as an early marker of AD pathology and raise interesting questions as to the course of binding-specific versus non-binding aspects of VSTM in early AD.
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http://dx.doi.org/10.1186/s13195-020-00660-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442980PMC
August 2020

Longitudinal white matter and cognitive development in pediatric carriers of the apolipoprotein ε4 allele.

Neuroimage 2020 11 18;222:117243. Epub 2020 Aug 18.

Advanced Baby Imaging Lab, Rhode Island Hospital, Providence, RI, USA; Department of Pediatrics, Warren Alpert Medical School at Brown University, Providence RI, USA; Maternal, Newborn, and Child Health Discovery and Tools, Bill and Melinda Gates Foundation; Seattle WA, USA.

We have previously demonstrated cross-sectional differences in magnetic resonance imaging (MRI) measurements of white matter myelin and gray matter in infants with or without the apolipoprotein ε4 allele, a major genetic risk factor for late-onset Alzheimer's disease (AD). In this study, we sought to compare longitudinal MRI white matter myelin and cognitive-behavioral changes in infants and young children with and without this allele. Serial MRI and cognitive tests were obtained on 223 infants and young children, including 74 ε4 carriers and 149 non-carriers, 2-68 months of age, matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated brain mapping algorithms and non-linear mixed models were used to characterize and compare trajectories of white matter myelin and cognitive-behavioral test scores. The APOE ε4 carriers had statistically significant differences in white matter myelin development, in the uncinate fasciculus, temporal lobe, internal capsule and occipital lobe. Additionally, ε4 carriers had a slightly greater rate of development in early learning composite a surrogate measure of IQ representative of expressive language, receptive language, fine motor, and visual skills, but displayed slightly lower non verbal development quotient scores a composite measure of fine motor and visual skills across the entire age range. This study supports the possibility that ε4 carriers have slightly altered rates of white matter and cognitive development in childhood. It continues to raise questions about the role of APOE in human brain development and the relevance of these developmental differences to the predisposition to AD.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779366PMC
November 2020

Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.

JAMA 2020 08;324(8):772-781

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).

Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.

Design, Setting, And Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).

Exposures: Plasma P-tau217.

Main Outcomes And Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]).

Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).

Conclusions And Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.
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http://dx.doi.org/10.1001/jama.2020.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388060PMC
August 2020

Applying surface-based morphometry to study ventricular abnormalities of cognitively unimpaired subjects prior to clinically significant memory decline.

Neuroimage Clin 2020 5;27:102338. Epub 2020 Jul 5.

School of Computing, Informatics, and Decision Systems Engineering, Arizona State University, Tempe, AZ, USA. Electronic address:

Ventricular volume (VV) is a widely used structural magnetic resonance imaging (MRI) biomarker in Alzheimer's disease (AD) research. Abnormal enlargements of VV can be detected before clinically significant memory decline. However, VV does not pinpoint the details of subregional ventricular expansions. Here we introduce a ventricular morphometry analysis system (VMAS) that generates a whole connected 3D ventricular shape model and encodes a great deal of ventricular surface deformation information that is inaccessible by VV. VMAS contains an automated segmentation approach and surface-based multivariate morphometry statistics. We applied VMAS to two independent datasets of cognitively unimpaired (CU) groups. To our knowledge, it is the first work to detect ventricular abnormalities that distinguish normal aging subjects from those who imminently progress to clinically significant memory decline. Significant bilateral ventricular morphometric differences were first shown in 38 members of the Arizona APOE cohort, which included 18 CU participants subsequently progressing to the clinically significant memory decline within 2 years after baseline visits (progressors), and 20 matched CU participants with at least 4 years of post-baseline cognitive stability (non-progressors). VMAS also detected significant differences in bilateral ventricular morphometry in 44 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (18 CU progressors vs. 26 CU non-progressors) with the same inclusion criterion. Experimental results demonstrated that the ventricular anterior horn regions were affected bilaterally in CU progressors, and more so on the left. VMAS may track disease progression at subregional levels and measure the effects of pharmacological intervention at a preclinical stage.
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http://dx.doi.org/10.1016/j.nicl.2020.102338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371915PMC
June 2021

Associative memory and in vivo brain pathology in asymptomatic presenilin-1 E280A carriers.

Neurology 2020 09 1;95(10):e1312-e1321. Epub 2020 Jul 1.

From the Departments of Psychiatry (E.G.V., J.M., C.V.-C., A.A., J.S., Y.T.Q.), Neurology (A.P.S., D.R., R.S., K.A.J., Y.T.Q.), and Radiology (K.A.J.), Massachusetts General Hospital, Harvard Medical School, Boston; Grupo de Neurociencias (A.B., Y.B., F.L., Y.T.Q.), Universidad de Antioquia, Medellín, Colombia; Center for Alzheimer Research and Treatment (K.P., D.R., R.S., K.A.J.), Department of Neurology, Brigham and Women's Hospital, Boston, MA; and Banner Alzheimer's Institute (P.N.T., E.M.R.), Phoenix, AZ.

Objective: To determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls.

Methods: Twenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden.

Results: Free and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology.

Conclusions: FCSRT scores were associated with in vivo markers of AD-related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.
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http://dx.doi.org/10.1212/WNL.0000000000010177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538214PMC
September 2020

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.

Lancet Neurol 2020 06 26;19(6):513-521. Epub 2020 May 26.

Grupo de Neurociencias de Antioquia of Universidad de Antioquia, Medellín, Colombia.

Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.

Methods: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers.

Findings: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset.

Interpretation: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies.

Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.
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http://dx.doi.org/10.1016/S1474-4422(20)30137-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417082PMC
June 2020

The Alzheimer's Prevention Initiative Composite Cognitive Test: a practical measure for tracking cognitive decline in preclinical Alzheimer's disease.

Alzheimers Res Ther 2020 05 27;12(1):66. Epub 2020 May 27.

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Background: There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5 years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial.

Methods: This study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n = 868) compared to those who remained cognitively unimpaired during the same time period (n = 989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer's Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11 years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score.

Results: The optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities + 2.24*MMSE Orientation to Time + 2.14*MMSE Orientation to Place + 0.53*Logical Memory Delayed Recall + 1.36* Word List-Delayed Recall + 0.68*Judgment of Line Orientation + 1.39*Raven's Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was - 1.10 over 1 year.

Conclusions: The APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11 years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.
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http://dx.doi.org/10.1186/s13195-020-00633-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254761PMC
May 2020
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