Publications by authors named "Lawrence S Honig"

100 Publications

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Nat Med 2021 Jul 21;27(7):1187-1196. Epub 2021 Jun 21.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
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http://dx.doi.org/10.1038/s41591-021-01369-8DOI Listing
July 2021

Patterns of tau pathology identified with F-MK-6240 PET imaging.

Alzheimers Dement 2021 May 31. Epub 2021 May 31.

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Introduction: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of F-MK-6240 in a clinical sample and determined the relationships among F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers.

Methods: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ) , tau, and phosphorylated tau (p-tau).

Results: F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aβ . F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants.

Discussion: F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.
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http://dx.doi.org/10.1002/alz.12384DOI Listing
May 2021

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology.

Alzheimers Dement 2021 May 21. Epub 2021 May 21.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [ F]Florbetaben and [ F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.
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http://dx.doi.org/10.1002/alz.12350DOI Listing
May 2021

Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease.

J Alzheimers Dis 2021 ;80(3):1051-1065

Taub Institute, Columbia University Irving Medical Center, New York, NY, USA.

Background: Olfactory impairment is evident in Alzheimer's disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood.

Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation.

Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42).

Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01).

Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.NCT Registration Numbers: NCT03373604; NCT02831283.
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http://dx.doi.org/10.3233/JAD-201149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044007PMC
September 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Plasma p-tau181, p-tau217, and other blood-based Alzheimer's disease biomarkers in a multi-ethnic, community study.

Alzheimers Dement 2021 08 13;17(8):1353-1364. Epub 2021 Feb 13.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Introduction: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia.

Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD.

Results: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis.

Discussion: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.
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http://dx.doi.org/10.1002/alz.12301DOI Listing
August 2021

Anterolateral entorhinal cortex volume is associated with memory retention in clinically unimpaired older adults.

Neurobiol Aging 2021 02 2;98:134-145. Epub 2020 Nov 2.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Gertrude H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY. Electronic address:

The entorhinal cortex is subdivided into anterolateral entorhinal cortex (alERC) and posteromedial entorhinal cortex (pmERC) subregions, which are theorized to support distinct cognitive roles. This distinction is particularly important as the alERC is one of the earliest cortical regions affected by Alzheimer's pathology and related neurodegeneration. The relative associations of alERC/pmERC with neuropsychological test performance have not been examined. We examined how alERC/pmERC volumes differentially relate to performance on 1) the Modified Rey Auditory Learning Test (ModRey), a verbal memory test designed to assess normal/preclinical populations, 2) the Montreal Cognitive Assessment (MoCA), and 3) the National Alzheimer's Coordinating Center neuropsychological battery. We also examined whether alERC/pmERC volumes correlate with Alzheimer's disease cerebrospinal fluid (CSF) biomarkers. In 65 cognitively healthy (CDR = 0) older adults, alERC, but not pmERC, volume was associated with ModRey memory retention. Only alERC volume differentiated between participants who scored above and below the MoCA cutoff score for impairment. Evaluating the MoCA subdomains revealed that alERC was particularly associated with verbal recall. On the National Alzheimer's Coordinating Center battery, both alERC and pmERC volumes were associated with Craft story recall and Benson figure copy, but only alERC volume was associated with Craft story retention and semantic fluency. Neither alERC nor pmERC volume correlated with CSF levels of amyloid or tau, and regression analyses showed that alERC volume and CSF amyloid levels were independently associated with ModRey retention performance. Taken together, these results suggest that the alERC is important for memory performance and that alERC volume differences are related to a pattern of neuropsychological test performance (i.e., impairments in episodic memory and semantic fluency) typically seen in clinical Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870549PMC
February 2021

Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.

Sci Transl Med 2020 11;12(571)

Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Endosomal trafficking has emerged as a defective biological pathway in Alzheimer's disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD's endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD's trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.
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http://dx.doi.org/10.1126/scitranslmed.aba6334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901670PMC
November 2020

Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks.

J Alzheimers Dis 2020 ;76(3):967-979

Genentech, Inc., South San Francisco, CA, USA.

Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody.

Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated.

Methods: In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported.

Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level.

Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.
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http://dx.doi.org/10.3233/JAD-200134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505005PMC
June 2021

Leukocyte Telomere Length Is Unrelated to Cognitive Performance Among Non-Demented and Demented Persons: An Examination of Long Life Family Study Participants.

J Int Neuropsychol Soc 2020 10 28;26(9):906-917. Epub 2020 Apr 28.

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Objective: Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia.

Method: Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age ≤ 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage.

Results: Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p < 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p < 0.005), who scored significantly lower on all cognitive domains (p < 0.005).

Conclusions: Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population.
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http://dx.doi.org/10.1017/S1355617720000363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983066PMC
October 2020

Research criteria for the diagnosis of prodromal dementia with Lewy bodies.

Neurology 2020 04 2;94(17):743-755. Epub 2020 Apr 2.

From the Newcastle University (I.G.M., A.J.T., P.D., J.P.T.); Mayo Clinic (T.J.F.), Jacksonville; University of Strasbourg (F.B.); Mayo Clinic (B.F.B., K.K.), Rochester; Nagoya University (H.F.), Kawasaki Memorial Hospital; Istituto Neurologico "Carlo Besta" (C.M., P.T.), Milan; Cambridge University (F.M.S.); McGill University (R.B.P.); King's College London and Stavanger University Hospital (D.A.); University of Exeter (C.B.); University of Chieti-Pescara (L.B.); Istanbul Faculty of Medicine (M.E.); University of Miami Miller School of Medicine (J.E.G.); University of California (D.G., D.P.S.), San Diego; Feinberg School of Medicine (J.G.G.); Massachusetts General Hospital (S.N.G.); Columbia University Irving Medical Center (L.S.H., K.S.M.); Osaka University (M.I.); Lou Ruvo Center of Brain Health (J.B.L.), Cleveland Clinic; University of Sydney (S.J.G.L.); Sunnybrook Health Sciences Centre (M.M.), University of Toronto; VA Puget Sound & University of Washington (D.W.T.); University College London (Z.W.).

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.
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http://dx.doi.org/10.1212/WNL.0000000000009323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274845PMC
April 2020

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Acta Neuropathol Commun 2020 01 29;8(1). Epub 2020 Jan 29.

Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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http://dx.doi.org/10.1186/s40478-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990558PMC
January 2020

Cerebrospinal fluid amyloid levels are associated with delayed memory retention in cognitively normal biomarker-negative older adults.

Neurobiol Aging 2019 12 15;84:90-97. Epub 2019 Aug 15.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address:

Alzheimer's disease is defined by abnormal levels of amyloid and tau biomarkers. Even cognitively normal older adults with clinically relevant amyloid and tau levels perform worse on memory tests. However, it is unclear if the relationship between biomarker level and memory extends below clinical thresholds. We hypothesized that even subclinical biomarker levels are associated with memory when measured with neuropsychological tests designed to detect dysfunction in preclinical disease states. In a group of cognitively normal, "biomarker-negative" older men and women, we investigated the relationship between cerebrospinal fluid biomarker levels and memory measured with the ModRey, a list-learning task designed to assess memory in preclinical and cognitively normal adults. Cerebrospinal amyloid levels were associated with ModRey memory retention, the proportion of information retained after a delay period. When older adults with mild impairment were included, cerebrospinal fluid tau levels were also associated with ModRey retention. The association of amyloid and tau levels with memory was independent of each other. These results suggest cognitive changes associated with Alzheimer's disease pathology might occur earlier than currently thought.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.010DOI Listing
December 2019

Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial.

Lancet Neurol 2019 06;18(6):549-558

Biogen, Cambridge, MA, USA. Electronic address:

Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy.

Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094.

Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported.

Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092.

Funding: Bristol-Myers Squibb, Biogen.
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http://dx.doi.org/10.1016/S1474-4422(19)30139-5DOI Listing
June 2019

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis 2019 07 3;127:492-501. Epub 2019 Apr 3.

Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
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http://dx.doi.org/10.1016/j.nbd.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588425PMC
July 2019

Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers.

Neurosurgery 2019 10;85(4):E662-E669

Department of Neurological Surgery, Columbia University Medical Center, New York, New York.

Background: Though it is well known that normal pressure hydrocephalus (NPH) patients can cognitively improve after ventriculoperitoneal shunting (VPS), one of the major dilemmas in NPH is the ability to prospectively predict which patients will improve.

Objective: To prospectively assess preoperative predictors of postshunt cognitive improvement.

Methods: This was a prospective observational cohort including 52 consecutive patients with approximately 1-yr follow-up. Patients underwent neuropsychological testing at baseline, postlumbar drainage, and postshunt. Cerebrospinal fluid (CSF) biomarkers and cortical biopsies were also collected to examine their relationship with postshunt cognitive improvement.

Results: Rey Auditory Verbal Learning Test-L (RAVLT-L) was the only neuropsychological test to demonstrate statistically significant improvement both postlumbar drain and postshunt. Improvement on the RAVLT-L postlumbar drain predicted improvement on the RAVLT-L postshunt. Patients with biopsies demonstrating Aβ+ Tau+ had lower ventricular CSF Aβ42 and higher lumbar CSF pTau compared to Aβ- Tau- patients. A receiver operating curve analysis using lumbar pTau predicted Aβ+ Tau+ biopsy status but was not related to neuropsychological test outcome.

Conclusion: The RAVLT can be a useful preoperative predictor of postoperative cognitive improvement, and thus, we recommend using the RAVLT to evaluate NPH patients. CSF biomarkers could not be related to neuropsychological test outcome. Future research in a larger patient sample will help determine the prospective utility of CSF biomarkers in the evaluation of NPH patients.
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http://dx.doi.org/10.1093/neuros/nyz102DOI Listing
October 2019

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

Alzheimers Dement (Amst) 2019 Dec 22;11:180-190. Epub 2019 Feb 22.

The University of Melbourne and the Florey Institute, Parkville, VIC, Australia.

Introduction: Quantitative measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.

Methods: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.

Results: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.

Discussion: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
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http://dx.doi.org/10.1016/j.dadm.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389727PMC
December 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Acta Neuropathol 2019 06 9;137(6):879-899. Epub 2019 Feb 9.

German Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
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http://dx.doi.org/10.1007/s00401-019-01962-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533145PMC
June 2019

A comprehensive screening of copy number variability in dementia with Lewy bodies.

Neurobiol Aging 2019 03 24;75:223.e1-223.e10. Epub 2018 Oct 24.

Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541211PMC
March 2019

Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia.

J Alzheimers Dis 2018 ;65(4):1417-1425

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD).

Objective: The goal was to determine the overall accuracy of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD.

Methods: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42, tTau, and pTau and the ATI in relation to the final clinical diagnosis.

Results: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72.

Conclusions: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice.
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http://dx.doi.org/10.3233/JAD-180548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218126PMC
August 2019

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study.

J Alzheimers Dis 2018 ;64(3):689-707

Janssen Research & Development LLC, Pennington, NJ, USA.

Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized.

Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab.

Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies.

Results: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups.

Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.
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http://dx.doi.org/10.3233/JAD-171157DOI Listing
July 2019

Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade.

J Alzheimers Dis 2018 ;64(s1):S611-S631

Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.

The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.
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http://dx.doi.org/10.3233/JAD-179935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371153PMC
June 2019

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

Lancet Neurol 2018 06 30;17(6):548-558. Epub 2018 Apr 30.

Department of Neurological-Psychiatric Nursing, Medical University of Gdansk, Gdansk, Poland.

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.

Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin.

Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46-0·63; p=3·54 × 10), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30-1·71; p=1·58 × 10). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2.

Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals.

Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.
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http://dx.doi.org/10.1016/S1474-4422(18)30126-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237181PMC
June 2018

Gene Therapy in Alzheimer Disease-It May Be Feasible, but Will It Be Beneficial?

Authors:
Lawrence S Honig

JAMA Neurol 2018 07;75(7):791-793

Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York.

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http://dx.doi.org/10.1001/jamaneurol.2017.4029DOI Listing
July 2018

Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

N Engl J Med 2018 01;378(4):321-330

From the Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York (L.S.H.); Gérontopôle, Centre Hospitalier Universitaire Toulouse, Unité Mixte de Recherche INSERM Unité 1027 Université Toulouse III-Paul Sabatier, Toulouse, France (B.V.); Austin Health Continuing Care Clinical Service Unit, Heidelberg, and the University of Melbourne, Melbourne, VIC - both in Australia (M.W.); Fundació ACE, Alzheimer Research Center and Memory Clinic, Institut Català de Neurociències Aplicades, Barcelona (M. Boada); Kingshill Research Centre, Victoria Hospital, Swindon, United Kingdom (R.B.); the Division of Geriatric Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada (M. Borrie); Clinic for Medicine of the Elderly, Diakovere Henriettenstift, Hannover, Germany (K.H.); Karolinska Institutet Alzheimer's Disease Research Center and Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Huddinge, Sweden (N.A.); the Department of Pathophysiology and Transplantation, Neurology Unit, Dino Ferrari Center, University of Milan, Fondazione Ca' Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Milan (E. Scarpini); Eli Lilly (H.L.-S., M.C., A.H., K.S., V.P.H., C.C., R.K., M.M., R.D., K.J.S., E. Siemers) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (R.A.D.) - both in Indianapolis; and Avid Radiopharmaceuticals, Philadelphia (M.M.).

Background: Alzheimer's disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.

Methods: We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).

Results: A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.

Conclusions: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).
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http://dx.doi.org/10.1056/NEJMoa1705971DOI Listing
January 2018

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study.

Lancet Neurol 2018 01 16;17(1):64-74. Epub 2017 Dec 16.

Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.

Methods: In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage.

Findings: This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14-2·70; p=1·05 × 10), SNCA (rs7681440; OR 0·73, 0·66-0·81; p=6·39 × 10), an GBA (rs35749011; OR 2·55, 1·88-3·46; p=1·78 × 10). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27-1·79; p=2·32 × 10); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%.

Interpretation: Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.

Funding: The Alzheimer's Society and the Lewy Body Society.
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http://dx.doi.org/10.1016/S1474-4422(17)30400-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805394PMC
January 2018

Frequency of variants in autopsy-proven multiple system atrophy.

Mov Disord Clin Pract 2017 Jul-Aug;4(4):574-581. Epub 2017 Apr 3.

Columbia University Medical Center, New York, New York.

Background: Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA.

Objectives: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City.

Methods: The glucocerebrosidase gene was fully sequenced in the 17 autopsy-proven MSA cases with extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test if the MSA cases in the brain bank are enriched for variants, we compared the variant frequency in MSA to all brain bank cases with pure Alzheimer's disease (AD) at Columbia University for whom genotype was available (n=82).

Results: 4/17 (23.5%) MSA cases carried glucocerebrosidase gene variants, including an individual homozygous for N370S, and one each who were heterozygous carriers of N370S, T369M and R496H. Among the comparator cases with pure AD, 3 of the 82 autopsies (3.7%) carried variants (P = 0.0127, Fisher exact test), including one case each of N370S homozygote, and R496H and T369M heterozygous variant.

Conclusion: We found a higher frequency of glucocerebrosidase variants among pathologically diagnosed MSA cases in our brain bank compared to AD autopsies. This study demonstrates the need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.
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http://dx.doi.org/10.1002/mdc3.12481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614491PMC
April 2017
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