bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer Disease candidate variants are associated with cerebral amyloid angiopathy
Authors: Godrich Dana , Pasteris Jeremy , Martin Eden R. , Schellenberg Gerard D. , Pericak‐Vance Margaret A. , Cuccaro Michael L. , Scott William K. , Kukull Walter A. , Montine Thomas J. , Beecham Gary W. ,   the Alzheimer's Disease Genetics Consortium
Published: December 2022

AbstractBackgroundThe hallmark lesions of Alzheimer Disease (AD) include tangles and plaques; however, these seldom appear alone. Lesions of AD‐related dementias such as vascular dementias and Lewy body dementias often co‐occur with AD. These co‐occurring lesions and total lesion burden are associated with a higher likelihood of dementia and severe cognitive impairment. Even amongst other lesions, cerebral amyloid angiopathy (CAA) presents a strong risk for more severe cognitive impairment. CAA also shows moderate correlations to AD (rho = 0.31), suggesting that CAA pathology could present an underlying or related process of AD pathology. We hypothesize that there is a genetic overlap between CAA and AD and therefore we investigate the influence of known AD genes on CAA.MethodData come from 3,495 autopsied individuals with neuropathology and array data from the National Alzheimer’s Coordinating Centers (NACC). CAA was measured according to NACC neuropathology form guidelines. We used ordinal logistic regression to model APOE genotype and 22 other known AD variants with CAA severity while adjusting for sex, age at death, and AD pathology. For the 22 other known AD variants, we tested the lead variants reported by Kunkle et al. and labeled by closest gene. We modeled APOE by carrier status and genotype.ResultWe confirmed associations for APOE with CAA severity, when modeling APOE as e4 dosage (OR=2.34, p<0.001) or by genotype (e3/e4: OR=1.96, p<0.001; e4/e4: OR=5.76, p<0.001). However, we did not see a significant association between CAA severity and APOEe2 carriers, as others have reported. Association persisted when including AD pathology terms in the model, even when extending to interaction‐based models. Genetic variations in 7 of the 22 known AD genes (BIN1, HLA‐DRB1, TREM2, CLU, PICALM, SORL1, SLC24A4) showed significant associations with CAA while accounting for AD pathology.ConclusionWe confirmed strong associations of APOEe4 with CAA in a large clinical population. We modeled other known AD genes and 7 of them showed significant associations with CAA, demonstrating genetic overlap between AD and CAA pathologies. This study suggests that there is genetic overlap between CAA and AD pathology that could point to shared disease mechanisms for the targeting and treatment of AD.
Longitudinal changes in the expression of Alzheimer’s disease‐related pattern and default mode network
Authors: Perovnik Matej , Tang Chris C , Šalamon Sandi , Eidelberg David ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundThe Alzheimer’s disease‐related pattern (ADRP) is an imaging biomarker of AD, for which expression levels correlate with cognitive impairment in individual patients. The default mode network (DMN) is a dominant metabolic network expressed in healthy individuals. Longitudinal changes in ADRP and DMN expression levels have not been comprehensively studied in patients with AD or mild cognitive impairment (MCI), or in cognitively normal (CN) subjects.MethodWe obtained longitudinal data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database of participants who were CN (n=59), or who had MCI (n=128) at baseline and underwent 3 or more FDG PET scans (nscans=704) and had CSF amyloid and APOE information available. Groups were divided based on the conversion status, i.e., if they developed MCI/dementia at follow‐up. There were 36 stable and 23 converting CN participants and 73 stable (sMCI) and 55 converting (cMCI) participants. Amyloid positivity was defined as CSF Aβ42 < 880 pg/mL and APOE positivity as presence of one or more APOE4 allele. We used an automated algorithm to calculate standardized ADRP and DMN expression levels for each scan. Repeated measurements ANOVA (RMANOVA) was used to evaluate longitudinal changes in network expression in each group, as well as network interactions with conversion status, amyloid and APOE positivity.ResultsADRP expression increased over time, but at with different rates in the CN, sMCI and cMCI groups (p<0.001). The interaction effect was significant between CN and cMCI (p<0.001) and sMCI and cMCI (p=0.009), but not between CN and sMCI (p=0.51). There was no significant interaction between group and time on DMN expression (p=0.60). Analysis of each group separately revealed no significant interaction between APOE4 status and time on ADRP or DMN expression levels (all p>0.10). There was a significant interaction between conversion status and time on ADRP and DMN in CN group (p<0.04). There was also a significant main effect of time on ADRP and DMN in cMCI group (p<0.04) and a significant interaction between amyloid and time on DMN expression (p=0.03).ConclusionADRP progression was faster in cMCI compared to CN and sMCI. The longitudinal changes in DMN were not significantly different across groups.
Evaluation of pathologies associated with hyperhomocysteinemia in human autopsy brain tissue
Authors: Weekman Erica M , Winder Zachary , Rogers Colin B , Abner Erin L , Patel Ela , Dugan Adam , Fister Shuling X , Wasek Brandi , Bottiglieri Teodoro , Fardo David W. , Wilcock Donna M 
Published: December 2022

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) are one of the leading causes of dementia; VCID affects roughly 10‐40% of all dementia patients. A major, yet underrecognized, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy). Defined as elevated levels of plasma homocysteine (a non‐protein‐forming amino acid), most late‐life HHcy is caused by impaired B vitamin absorption. Although HHcy has been recognized as a risk factor for VCID, studies aimed at identifying pathologies associated with HHcy have been lacking.MethodTo determine pathologies associated with HHcy, we identified 31 autopsied research volunteers with antemortem homocysteine levels; 13 cases had normal plasma homocysteine levels (>14μmol/L) and 18 had high plasma homocysteine levels (<14μmol/L). We then measured levels of homocysteine and related metabolites in both plasma samples taken closest to autopsy and frontal cortex. Next, we determined whether the level of plasma homocysteine was associated with several markers identified via immunohistochemistry, including Aβ, PHF‐1, IBA‐1 and GFAP. Plasma and brain protein markers for inflammation and angiogenesis were also measured to determine associations with plasma homocysteine. Finally, we used the Human Neuroinflammation NanoString panel to determine gene expression changes of inflammatory markers associated with high homocysteine levels in the frontal cortex and occipital lobe.ResultPlasma metabolite analysis showed patients who had elevated levels of homocysteine also had increased levels of several homocysteine cycle metabolites such as cysteine, S‐adenosyl‐homocysteine, cystathionine and choline. Flt1, an angiogenic marker, and IL5, an inflammatory marker, had a positive correlation with increased plasma homocysteine. No correlation between IBA‐1 or GFAP immunohistochemistry with plasma homocysteine was found. Gene expression showed that most genes were downregulated in the presence of high plasma homocysteine, including many significant genes involved in apoptosis, growth factor and cytokine signaling, and the innate and adaptive immune response.ConclusionThese preliminary data show that increased plasma homocysteine correlates with protein inflammatory and angiogenic markers and with a significant downregulation of inflammation‐related gene expression markers in the brain. Overall, this could reflect impaired normal immune function, providing possible mechanisms by which hyperhomocysteinemia induces cognitive deficits and cerebrovascular damage.
Re‐examining the impact of adjusting for education and sex the RBANS delayed memory score: Implications on the cut‐offs used to detect cognitive impairment in prodromal Alzheimer’s disease. Data from the EPAD‐LCS study.
Authors: Sánchez‐Benavides Gonzalo , Buongiorno Mariateresa , Brugulat‐Serrat Anna , Cañas‐Martínez Alba , Canals‐Gispert Lidia , Minguillón Carolina , Milà‐Alomà Marta , Grau‐Rivera Oriol ,   EPAD Consortium
Published: December 2022

AbstractBackgroundthe RBANS is a multilingual brief cognitive battery commonly used in both clinical practice and research. Its delayed memory index has been used as entry criteria for clinical trials in early stages of Alzheimer’s disease (AD). Although several studies reported a significant effect of education and sex in RBANS scores, the published normative data only provide adjustments by age. We aimed at exploring the impact of sex and education in the age‐adjusted scores and studying the percentage of change in the classification of memory impairment, along with the association with AD biomarker status after adjusting for education and sex.MethodsWe analyzed data from the EPAD baseline Longitudinal Cohort Study (n = 1,716 [Clinical Dementia Rating [CDR] = 0 n = 1,233; CDR = 0.5 n = 483]), see Table 1. We used multiple regression to assess the impact of years of education and sex on the age‐adjusted delayed memory index within the CDR = 0 sample. The coefficients obtained were used to generate sex‐, education‐ and age‐adjusted scores. The whole sample was classified as having/not having memory impairment (<85 points) with published and full adjusted scores. Within CDR = 0.5 group, the concordance between presence of memory impairment and pathologic amyloid‐β (A+; cut‐off = 1000 pg/ml) and p‐tau levels (T+; cut‐off = 27 pg/ml) in cerebrospinal fluid was assessed.ResultsEducation and sex (being a woman) had significant positive effects (p<0.001) on the age‐adjusted delayed memory scores (Partial eta2 = 0.035 and 0.010). We observed a change of up to 10 points after sex and education adjustment (mean[SD] change = 0.83 [2.6]). The use of fully adjusted scores increased the number of individuals classified as having memory impairment by 1.7%. Within the CDR = 0.5 group, these scores identified 2.5% individuals with memory impairment that were considered within the normal range using the regular norms, and increased the concordance between memory impairment and A+T+ biomarkers by almost 5% (regular norms = 65.2%, adjusted norms = 69.7%).ConclusionAlthough small, education and sex exert a relevant effect in the delayed memory score of the RBANS and improve clinical and biomarker concordance of the conclusions on the cognitive status derived from them. Adding education and sex adjustments to the RBANS measures may improve the selection of individuals for clinical trials.
Insulin and hippocampal subregion volume in older adults
Authors: Twisselmann Alicia M , Tubi Meral A , Hall Brandon J , Hazra Nalini , Matsiyevskiy Elizabeth , Wheeler Koral , Johnson Leigh , Yaffe Kristine , Toga Arthur W. , O'Bryant Sid E. , Braskie Meredith N ,   for the HABS‐HD Study Team
Published: December 2022

AbstractBackgroundType 2 diabetes (DM) is a risk factor for Alzheimer's disease (AD) and other dementias. DM, which is more common in Mexican Americans (MA) than non‐Hispanic Whites (NHW), is associated with high blood glucose levels and often with hyperinsulinemia. Hippocampal volume is an early neuroimaging marker of AD. We examined the relationship of blood insulin with hippocampal subregion volumes in MA and NHW.MethodIn a sample of 1588 older adults without dementia (age: 50‐92 years; 826 MA, 762 NHW; 387 DM, 1201 non‐DM; 1344 cognitively normal, 244 mild cognitive impairment; 613M/975F) from the Health and Aging Brain Study ‐ Health Disparities (HABS‐HD) cohort, we assessed whether fasting plasma insulin and glucose levels were associated with the volume of left and right hippocampal body subregions (CA1, CA23DG, subiculum) using hippocampal high resolution 3T MRI scans (Siemens 3T). We further examined the significant insulin relationship with CA23DG volume by ethnicity and diabetes diagnostic group. We used a multiple linear regression model, covarying for age, sex, cognitive diagnosis, diabetic status, years of education, number of MRI slices segmented, and intracranial volume. All p values were FDR corrected for multiple comparisons across regions.ResultHigher insulin levels were associated with a smaller volume in right and left CA23DG (right: FDR p=0.015, left: FDR p=0.015) across all participants. Glucose levels were not significantly associated with hippocampal subregion volume (Table 1). When we further investigated the significant relationship between insulin and CA23DG volume by ethnic group and diabetic status, we found that higher insulin was associated with lower CA23DG volume in NHW (right: p=0.014, left: p=0.013), MA (right only: p=0.034, left: p=0.115), and in non‐diabetics (right: p=0.027, left trend: p=0.056) (Figure 1).ConclusionHigher insulin levels were associated with lower CA23DG volume in older adults without dementia, with the strength of the negative association between blood insulin levels and hippocampal subfield volume varying by diabetic status.
A Quantitative‐EEG Assessment of Alpha‐1062, a Novel Pro‐Drug of Galantamine for the Treatment of Mild to Moderate Dementia Associated with Alzheimer’s Disease.
Authors: Kay Denis G , Stijl‐’t Hart Ellen , Bakker Charlotte , Linkenkaer‐Hansen Klaus , Sancilio Frederick D , Ortiz J. Bryce , Groeneveld Geert Jan , Poil Simon‐Shlomo 
Published: December 2022

AbstractBackgroundAcetylcholinesterase inhibitors (AChEIs) enhance cognitive functioning in Alzheimer’s disease (AD). The use of AChEIs at therapeutic doses is limited by gastrointestinal (GI) side effects, such as nausea, vomiting and diarrhea. Alpha‐1062 is a pharmacologically inactive prodrug of the AChEI galantamine specifically designed to reduce or eliminate GI side effects and provide increased safety. In addition to its activity as an AChEI, galantamine exhibits a second important mechanism of action, binding allosterically to nicotinic cholinergic receptors enhancing their responsiveness to acetylcholine. In Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) trials in young and elderly healthy subjects, Alpha‐1062 demonstrated both evidence of an improved GI side effect profile and enhanced cognition. Here we extend the findings of the SAD and MAD studies with an additional analysis of the effects of Alpha‐1062 on quantitative‐EEG (qEEG) data collected as part of the MAD study.MethodsSubjects (n = 12/dose) were administered two doses per day of Alpha‐1062 for 7 consecutive days. Pharmaco‐EEG measurements were performed for 4 min eyes closed / 4 min eyes open, on day 1 and day 7 at various timepoints both pre‐dose and post‐dose using a standard 10‐20 electrode montage with 21 channels. qEEG data analysis was conducted using qEEG indices developed using a machine learning algorithm based on the analysis of 39 AD patients administered galantamine (Sci Rep
7, 5775 [2017]). These were an AD index and a galantamine index, which were expected to be sensitive to the effects of Alpha 1062 administration.ResultsIn healthy elderly subjects, Alpha‐1062 administration improved response on the AD index (p <0.05) compared to placebo, at the pre‐dose timepoint on day 7. The AD index was also reduced at all post‐dose timepoints on day 7 relative to placebo. Changes in several other relevant measures of qEEG function suggested Alpha‐1062 improved brain function.ConclusionThese data demonstrate the potential benefit Alpha‐1062 in the treatment of AD. Alpha‐1062 was safe in the dose range investigated, and influenced pharmaco‐EEG outcomes in healthy elderly subjects that were consistent with the previously documented positive effects in tests related to sustained attention and working memory.
Autopsy Results from the ENGAGE Trial of Aducanumab: Lessons from Co‐pathology
Authors: Horiki Sheena , VandeVrede Lawren , La Joie Renaud , Ljubenkov Peter A. , Koestler Mary , Rojas Julio C. , Rabinovici Gil D. , Boxer Adam L. , Seeley William W. 
Published: December 2022

AbstractBackgroundAducanumab, a monoclonal antibody that clears amyloid aggregates, received FDA approval for early‐stage Alzheimer’s Disease (AD). Clinicopathologic studies from patients treated with aducanumab are as yet unavailable, and may inform clinical use. Therefore, we report the clinical course, PET, and autopsy results from two patients treated with aducanumab.MethodsPatients were seen at UCSF and enrolled in ENGAGE (NCT02477800). Florbetapir (FBP) PET was obtained, including the initial six‐month treatment interval. Additional data, including flortaucipir (FTP) PET, was available through UCSF ADRC. PET was analyzed locally, and neuropathological analyses were performed by the UCSF Neurodegenerative Disease Brain Bank.ResultsPatient 1: 77‐year‐old male (ApoE3/3) with vascular risk factors; onset age 63 with slowed processing, memory loss, and executive dysfunction. Fourteen doses aducanumab (6mg/kg) were administered in ENGAGE and 3 doses (1mg/kg) in EMBARK (NCT04241068). FBP demonstrated 8% reduction in amyloid centiloids (67.8→62.7). FTP encompassing four‐year interval from diagnosis to ENGAGE closure showed increase in metatemporal SUVR (1.175→1.273), with progression of cortical atrophy on MRI. He died of myocardial infarction (FBP‐to‐autopsy interval: 577d). Autopsy revealed intermediate ADNC (Thal 3, Braak 5, CERAD frequent), and substantial vascular pathology including chronic multifocal microinfarcts.Patient 2: 64‐year‐old female (ApoE4/4); onset age 55 with rapid forgetting, executive dysfunction, prominent anxiety, and dream enactment. Fourteen doses aducanumab (10mg/kg) were administered prior to early‐termination due to disease progression. FBP showed 38% reduction in amyloid centiloids (42.1→26.2). After discontinuation, she developed dysautonomia, parkinsonism, and paranoia, later dying in status epilepticus (FBP‐to‐autopsy interval: 1120d). Autopsy revealed high ADNC (Thal 5, Braak 6, CERAD frequent), extensive cortical Lewy bodies disease (LBD, Braak 6), moderate cerebral amyloid angiopathy, and amygdalar TDP‐43 (LATE‐NC Stage 1).ConclusionVascular disease and LBD, both common co‐pathologies in AD, likely contributed to the clinical phenomenology and course of these patients. In the first case, low‐dose aducanumab did not substantially reduce amyloid, and the patient later died from unrelated heart disease. In the second case, despite substantial amyloid clearance on high‐dose, co‐morbid LBD led to clinical progression and discontinuation. Additional autopsy studies are needed to clarify the neuropathological effects of aducanumab, and the role of AD co‐pathology.
Plasma biomarkers associations with cognitive change in preclinical Alzheimer’s disease
Authors: Milà‐Alomà Marta , Sánchez‐Benavides Gonzalo , Ashton Nicholas J. , Ortiz‐Romero Paula , Montoliu‐Gaya Laia , Benedet Andréa Lessa , Karikari Thomas K , Rodriguez Juan Lantero , Brugulat‐Serrat Anna , Escalante Armand González , Vanmechelen Eugeen , Day Theresa A. , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Dage Jeffrey L. , Zetterberg Henrik , Gispert Juan Domingo , Blennow Kaj , Suárez‐Calvet Marc ,   for the ALFA Study
Published: December 2022

AbstractBackgroundBlood biomarkers to detect Alzheimer’s disease pathology are needed as screening tools and to predict the onset of cognitive decline. Although there is increasing data on their potential usefulness across AD continuum, comprehensive comparisons of their ability to predict cognitive decline in cognitively unimpaired (CU) populations are still lacking.MethodWe studied 214 CU individuals from the ALFA+ cohort (Table 1), which had baseline measurements of plasma p‐tau181, p‐tau217, p‐tau231, t‐tau, GFAP, NfL and Ab42/40. All biomarkers were measured with Simoa, except for plasma p‐tau217 and t‐tau that were MSD‐based assay measures (Eli Lilly and Company ). Longitudinal measures of cognition (Preclinical Alzheimer Cognitive Composite [PACC]) at 3 years’ follow‐up were available. All participants remained CU at follow‐up.We tested the associations of baseline plasma biomarkers with PACC scores change (delta score computed as V2‐V1) using linear regression models adjusted by age, sex, education and time between neuropsychological visits. We further stratified by CSF Aβ‐status (Aβ+ if CSF Aβ42/40 <0.071) and interaction terms between each biomarker and Aβ‐status were evaluated. Finally, we studied the associations between baseline plasma biomarkers and cognitive change specifically in participants that displayed the steepest (<1SD) cognitive decline (“decliners”).ResultIn the whole sample, higher baseline plasma p‐tau181 (P=0.003) and t‐tau (P=0.007) were significantly associated with lower PACC scores at follow‐up. In CSF Aβ‐positive individuals, plasma p‐tau181, p‐tau231, t‐tau and NfL at baseline were significantly associated with cognitive decline while no significant associations were found in the Aβ‐negative group. The interaction with CSF Aβ status was significant only for plasma p‐tau231 (P=0.028) (Figure 1). In individuals that displayed a steeper decline (n = 33 [16% of the sample], Table 2), plasma p‐tau181, p‐tau217 and t‐tau were significantly associated with longitudinal change in PACC scores (Figure 2).ConclusionIn preclinical AD, baseline plasma levels of p‐tau181, tau231, t‐tau and NfL are associated with cognitive decline at follow‐up. In the group of decliners, higher p‐tau181, p‐tau217 and t‐tau at baseline associate with cognitive change. These results have important implications for the consideration of plasma biomarkers for clinical trials targeting asymptomatic individuals or individuals with subtle cognitive decline.