bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of ethnoracial differences in self‐ and study partner‐reported subjective cognitive decline in the A4 Study screen data
Authors: Robinson Talia L , Klinger Hannah , Buckley Rachel F. , Deters Kacie D , Quiroz Yakeel T. , Rentz Dorene M. , Sperling Reisa A. , Amariglio Rebecca E.
Published: December 2022

Background

Subjective cognitive decline (SCD) may represent an early clinical manifestation of Alzheimer’s disease (AD) pathology. There is evidence of an association between amyloid deposition and SCD. Given disparities in risk of AD and cognitive impairment across ethnoracial groups, there is need to evaluate SCD, cognition, and markers of AD across diverse samples, as well as study partners as reporters of SCD.

Method

Participants included 267 non‐Hispanic Black, 5241 non‐Hispanic White, 225 Hispanic White, and 228 Asian individuals who presented for screening for the Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study (N = 5961). Participants completed the Preclinical Alzheimer Cognitive Composite (PACC) and self‐ and study partner‐report of SCD (Cognitive Function Instrument/CFI). A subsample of participants underwent amyloid PET (N = 4416). In a series of within‐group linear regressions, we evaluated the relationships between 1) self‐reported SCD and cognitive performance 2) study partner‐ and self‐reported SCD, and 3) participant amyloid status and SCD.

Result

Asian participants self‐reported the highest SCD and non‐Hispanic White participants reported the lowest. Controlling for age, education, and gender, PACC performance was significantly associated with self‐reported SCD in non‐Hispanic White (R2 = 0.039, b = ‐0.141, p < .0001), non‐Hispanic Black (R2 = 0.055, b = ‐0.158, p < .01), and Asian samples (R2 = 0.093, b = ‐0.318, p < .0001), with better PACC performance associated with lower CFI. PACC was not significantly associated with CFI in the Hispanic sample (R2 = .003, b = ‐0.097, p = .0636). Self‐ and study partner report of SCD were significantly correlated in all groups. Amyloid burden was associated with greater self‐reported SCD in non‐Hispanic White (R2 = 0.018, b = 0.452, p < .001) and Asian samples (R2 = 0.046, b = 1.58, p < .01), but not in the non‐Hispanic Black (R2 = 0.020, b = ‐.501, p = .277) and Hispanic participants (R2 = 0.016, b = 0.638, p = .169).

Conclusion

SCD appears similarly related to cognitive performance across most groups, and there is alignment between self‐ and study‐partner report of SCD across groups. There is evidence of variability in the association between AD biomarkers and SCD across racial groups, albeit in a smaller subsample with PET imaging. Future work should evaluate sociocultural factors that may contribute to differences in the value of SCD in individuals at risk for symptomatic AD.
Aβ1‐42 oligomers induce pericyte dysfunction via p75 Neurotrophin Receptor
Authors: Bobinger Hanna V. , Bauman Allison J. , Randall Ryleigh B. , Saiyasit Napatsorn , Nelson Amy R.
Published: December 2022

Background

Amyloid beta (Aβ) aggregates and tau tangles are hallmark pathologies of Alzheimer’s disease (AD). There is growing evidence that vascular dysfunction may contribute to the pathophysiology of AD. Pericyte injury and/or deterioration leading to blood‐brain barrier (BBB) breakdown occur in normal aging and are associated with cognitive impairment in AD patients. Furthermore, there is reduced cerebral blood flow in AD. Because vascular resistance occurs in capillaries, we hypothesize that Aβ1‐42 causes aberrant pericyte contraction and cell death via p75 neurotrophin receptor (p75NTR).

Method

p75NTR levels were quantified via Western blotting in mouse vascular brain pericytes treated with either artificial cerebrospinal fluid (aCSF) as a control or 72 nM Aβ1‐42 oligomers for either 20 minutes or 24 hours. Furthermore, LIVE/DEAD assays were performed to quantify pericyte deterioration after exposure to 72 nM Aβ1‐42 for various time points. In mouse models, changes in red blood cell (RBC) flow due to pericyte contraction around capillaries were measured using intravital microscopy in the somatosensory cortex of anesthetized C57 mice and applying either topical aCSF or 72 nM Aβ1‐42.

Result

After 20 minutes of aCSF or Aβ1‐42 treatment, there is a statistically significant increase in p75NTR levels (n = 3, p = 0.016, two‐tailed t‐test), while there is a statistically significant decrease by 43% in p75NTR levels after 24 hours (n = 6, p = 0.0028, two‐tailed t‐test). After 48 hours of aCSF or Aβ1‐42 treatment, 75.6% of the control pericytes were viable, whereas only 65.3% of the Aβ1‐42 treated pericytes were viable. Preliminary in vivo studies revealed that 72 nM Aβ1‐42 treatment stalled RBC flow.

Conclusion

Pericytes were confirmed to express p75NTR. Aβ1‐42 treatment upregulates p75NTR expression after 20 minutes while downregulating its expression after 24 hours. This suggests that acute increases in p75NTR levels may mediate increased pericyte contraction and play a role in reduced cerebral blood flow during the progression of AD. Because the details of this mechanism are unknown, future in vivo studies will involve pericyte‐specific p75NTR knock‐out mice.
The Clu‐rs2279590_h2kb variant increases axonal and neuritic damage in 5xFAD mice
Authors: Milinkeviciute Giedre , Tran Katelynn , Tran Kristine M , Phan Jimmy , Da Cunha Celia , Javonillo Dominic I , Neumann Jonathan , Alcantara Joshua A , Walker Amber , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N
Published: December 2022

Background

Genome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer's disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The rs2279590 SNP risk allele is located within a putative enhancer element in intron 7 of CLU. Indeed, deletion of a 115bp region including this SNP reduces expression of CLU and neighboring genes (EPHX2 and PTK2B) on Chromosome 8. The region surrounding rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.

Method

CRISPR was used to substitute a 2kb region of human CLU (intron 7 to exon 9) containing the enhancer region and the GWAS AD‐risk rs2279590 SNP variant for the orthologous region of Clu within the C57BL/6J mouse genome. Clu‐rs2279590_h2kb mice were crossed with 5xFAD mice and aged to 4 months to study the effects of the partially humanized Clu allele on development of AD‐related pathologies in 5xFAD mice. Coronal brain sections were immunolabeled to visualize dense‐core plaques (Thioflavin‐S), microglia (IBA1), reactive astrocytes (GFAP), axonal and neuritic damage (neurofilament light chain (NfL) and LAMP1, respectively). Confocal images of hippocampal and cortical regions were analyzed using Imaris software. In addition, Aβ and NfL levels were quantified in the brain tissue and plasma NfL measured using meso scale discovery (MSD) technology.

Result

Four‐month‐old 5xFAD hemizygous, Clu‐rs2279590_h2kb homozygous mice had reduced microglial density and volume compared to 5xFAD hemizygous controls. No change was found in astrocyte density or reactivity. Despite comparable plaque load between 5xFAD and 5xFAD x Clu‐rs2279590_h2kb mice, neuritic and axonal damage was elevated in the brain of 5xFAD x Clu‐rs2279590_h2kb mice compared to 5xFAD, while plasma NfL level did not differ. Insoluble Aβ42 levels mirrored plaque density.

Conclusion

Despite the lack of impact on Aβ plaque deposition, and moderate influence on gliosis, four‐month‐old 5xFAD hemizygous, Clu‐rs2279590_h2kb homozygous mice display elevated axonal and neuritic damage compared to 5xFAD hemizygous controls.
Association between sub‐classified white matter hyperintensities (WMH) volume and and cognitive function in patients with Alzheimer`s disease
Authors: Na Min Chull , Yang Hyun‐ju , Park Joon Hyuk
Published: December 2022

Background

WMH in MRI are common among the elderly. WMH are associated with increased cognitive impairment and risk of Alzheimer`s disease (AD). Although WMH contribute to AD pathology, their clinical implications are not fully understood. This study aimed to assess whether WMH predict AD and investigate the association between WMH (including subclassified WMH volume) and cognitive function in AD.

Method

This study enrolled 171 patients with AD. All participants underwent clinical evaluations including brain MRI study and neuropsychological tests using the CERAD‐K neuropsychological assessment battery. In addition, Charlson comorbidity index, the Korean version of the Geriatric Depression Scale short from were administered. WMH volume was calculated using automated quantification method with SPM and MATLAB image processing software. WMH were classified according to the distance from the ventricular surface. WMH located in juxtaventricular areas, within 3 mm from the ventricular surface, were classified as juxtaventricular with matter hyperintensities (JVWMH). WMH located within 3–13 mm or farther than 13 mm from the ventricular surface were classified as periventricular white matter hyperintensities (PVWMH) or deep white matter hyperintensities (DWMH), respectively. WMH volume data were right‐skewed. Consequently, WMH volume data were logarithmic transformed.

Result

The AD group had a higher mean WMH volume(20.7 ± 18.2 ml). Multivariate linear regression analysis showed that total WMH volume in AD was associated with poor performance in categorical verbal fluency test (p = 0.008) and word list memory test (p = 0.023). JVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.013) and digit span test forward (p = 0.037). PVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.011) and word list memory test (p = 0.021), whereas DWMH volume showed no association with cognitive dysfunction in AD.

Conclusion

Total WMH, JVWMH and PVWMH were associated specifically with executive function, immediate memory, and working memory, independently of hippocampal atrophy in AD. WMH were associated with AD risk and cognitive dysfunction differentially according to the distance from the ventricular surface.
Cognitive functioning and simulated driving in older adults with and without cognitive impairment
Authors: Brush David M. , Persad Carol , Song Woojin , Jansohn Eva , Giordani Bruno
Published: December 2022

Background

Age‐related changes in cognitive functions affect complex task engagement such as driving. Studies have demonstrated high occurrences of driving errors and crashes among older adults, particularly those with mild cognitive impairment (MCI). We have previously demonstrated that fatigue contributes to detriments in driving ability, especially among MCI, and that attention‐maintenance tasks (AMT) improve older cognitively normal (OCN) but not MCI performance. This study considers which cognitive deficits predict driving performance across AMT conditions.

Methods

Participants included 34 OCN and 21 MCI adults age 60+ years diagnosed through consensus conference, who completed tests of memory (HVLT‐R delayed recall), executive functioning (Trail Making Test B; TMB), working memory (CogState One Back Test, ONB), simple reaction time (CogState Detection Test, DET), and choice reaction time (CogState Identification Test, IDN). Computerized driving scenarios were presented on a 45” flat screen monitor, which included a 50‐minute simulated drive designed to induce fatigue, followed by four 10‐minute sessions alternating between driving with and without AMT. Lane position, velocity, lane and velocity variability, and driving errors (e.g., leaving the road, crossing midline) were compared across 10‐minute driving segments. Cognitive measures and diagnosis were used to predict driving performance.

Results

Participants with MCI 1) maintained significantly slower average speed, 2) demonstrated higher variability in lane‐keeping, and 3) had greater velocity variability, only in the non‐AMT condition. OCN participants performed significantly better on all cognitive measures, except DET. Linear regressions showed that TMB, alone, predicted average velocity during the AMT driving condition with no significant predictors for the non‐AMT. Velocity variability during the non‐AMT driving condition was predicted by the main effect of Diagnosis, TMBxDiagnosis, and ONBxDiagnosis interactions. TMB and HVLT‐R predicted velocity variability during the AMT condition. Lane variability during both driving conditions was predicted by DETxDiagnosis and IDNxDiagnosis.

Conclusions

Performance on TMB and its interactions are predominantly important predictors for velocity‐related driving conditions. Reaction time decrements among those with MCI predict lane variability. This suggests that executive functions are particularly needed in maintaining velocity, while monitoring is critical for maintaining lane position. Our findings demonstrate that higher cognitive burden likely accentuates driving difficulty, especially in MCI.
Fluctuations in reaction time performance as a marker of incipient amyloid‐related cognitive decline in clinically unimpaired older adults.
Authors: Jutten Roos J. , Rentz Dorene M. , Amariglio Rebecca E. , Properzi Michael J , Maruff Paul , Johnson Keith A. , Sperling Reisa A. , Papp Kathryn V.
Published: December 2022

Background

Accumulating evidence suggests that fluctuations in reaction time (RT) performance across assessments, usually defined by intraindividual variability in RT (IIV‐RT), are associated with cognitive impairment and decreased neurobiological integrity. Computerized cognitive testing facilitates the study of IIV‐RT, allowing for precise and frequent RT measurements in remote settings. We investigated whether quantifying IIV‐RT over months on various remotely administered computerized RT tasks could aid in the detection of emerging cognitively decline in initially clinically unimpaired (CU) older adults with elevated Alzheimer’s disease (AD) biomarkers.

Method

N = 114 CU individuals (age 77.6±5.1, 61% female, MMSE 29±1.2, n = 33 amyloid‐positive as measured using PiB‐PET imaging) from the Harvard Aging Brain Study (HABS) completed the self‐administered Computerized Cognitive Composite (C3) monthly at‐home on an iPad for up to one year (11.7±3.2 C3 assessments). Baseline C3 assessment coincided with participants’ HABS in‐clinic visit including Preclinical Alzheimer’s Cognitive Composite (PACC) testing, and participants had 1.8±1.2 subsequent years follow‐up PACC testing available. The C3 includes two basic RT tasks (Detection [DET]; Identification [IDN]), and two complex RT tasks (One Card Learning [OCL]; One Back [ONB]) that also require working memory skills. IIV‐RT measures were derived for each task by computing the intraindividual standard deviation between mean RTs across all monthly visits for each participant. Subsequently, IDN and DET IIV‐RT were combined into a basic IIV‐RT composite, and OCL and ONB IIV‐RT into a complex IIV‐RT composite. Linear mixed models were used to investigate the association between both IIV‐RT composites and PACC decline adjusting for covariates (age, sex, education, amyloid status (+/‐)) and their interaction with time.

Result

Greater IIV‐RT on complex RT tasks was associated with steeper decline on the PACC (Time*IIV‐RT ß = ‐1.3, 95%CI[‐2.57 – ‐0.03],p = .04) (Figure 1), which was driven by amyloid‐positive individuals (Time*Amyloid[+]*IIV‐RT ß = ‐3.52, 95%CI[‐6.43 – ‐0.61],p = .02) (Figure 2). In contrast, greater IIV‐RT on basic RT tasks was only associated with baseline PACC performance (IIV‐RT ß = ‐4.29, 95%CI[‐7.32 – ‐1.26],p = .007) but not with PACC change over time.

Conclusion

Our findings suggest that fluctuations in RT performance over monthly‐repeated complex RT tasks may reflect evidence of early amyloid‐related neurodegeneration and provide a marker of incipient cognitive decline in preclinical AD.
Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice
Authors: Eastman Guillermo , Sharlow Elizabeth R , Lazo John S , Sotelo‐Silveira José R , Bloom George S
Published: December 2022

Background

Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre‐symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.

Method

To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2‐/‐) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA‐Seq and Ribo‐Seq (ribosome profiling). Identical starting pools of bulk RNA were used for RNA‐Seq and Ribo‐Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels to disentangle genes specifically regulated at the translation level. Regulated genes were functionally evaluated by gene ontology tools.

Result

Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to APP metabolism associated with neurotoxicity and neuroprotection.

Conclusion

This work represents the first genome‐wide study of brain translatome regulation in animal models of AD, and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.
Network medicine‐based multimodal omics analytic framework identifies immunometabolism endophenotypes underlying sex difference of Alzheimer’s disease
Authors: Cheng Feixiong , Hou Yuan , Zhou Yadi , Xu Jielin , Bekris Lynn M. , Lathia Justin D. , Pieper Andrew A. , Leverenz James B. , Cummings Jeffrey
Published: December 2022

Background

Although Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying these sex differences are not well understood.

Method

We presented a multimodal omics analytic framework to inspect sex differences in susceptibility to inflammation, cellular metabolism, and disease pathophysiology of AD. Specifically, we investigated the interplay between cellular metabolism and immune responses, termed the “immunometabolism endophenotype,” by unique integration of transcriptomics (single‐cell/nuclei RNA‐seq), proteomics (inflammatory biomarker expression), and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer's Disease Research Center (CADRC).

Result

We identified sex‐specific, elevated pro‐inflammatory gene/protein expression in blood (including myeloid‐derived suppressor cells [MDSCs]) and cerebrospinal fluid of phenotypically characterized subjects by AD biomarkers of Amyloid deposition, pathologic Tau, and Neurodegeneration (ATN). We also identified sex‐specific microglial gene signatures in AD patient brains from single‐cell/nuclei RNA‐seq (sc/snRNA‐seq) data analyses. We further found that women lost gene expression of innate and adaptive pathways (i.e., NF‐kappa B signaling, Toll‐like receptor signaling, and HIF signaling) in microglia compared to men with amyloid and tau neuropathology. However, women have elevated expression of innate and adaptive pathways (i.e., IL‐17 signaling and antigen processing and presentation) in excitatory neurons compared to men with tau neuropathology. Integrative sc/snRNA‐seq data analyses showed sex‐specific ligand‐receptor interactions among microglia, astrocytes, and neurons. We also found that women with AD have elevated metabolites of glycerophospholipids and sphingolipids compared to men with AD. A microglia‐specific male‐biased metabolite‐enzyme network is enriched in immune pathways of Type I and II IFN signaling and fructose, mannose, and HIF‐1 metabolic pathways. By contrast, the female‐biased metabolite‐enzyme network is significantly enriched in glycerophospholipids. These findings were further validated by the female‐biased expression of pro‐inflammatory cytokines (i.e., IFNγ, GM‐CSF, IL‐8, and IL‐15) from ATN‐characterized cohorts from our CADRC.

Conclusion

This study establishes proof‐of‐concept of sex‐specific immune responses, cellular metabolism, and microglial immunometabolism underlying sex differences in AD.
Blood‐brain barrier dysfunction is associated with A/T/N biomarkers and cognition in the aging brain
Authors: Tabdili Yasmine , Belmonte Krystal Courtney D , Brathaban Nivetha , Iorio Emma , Park Ryan , VandeBunte Anna M , Casaletto Kaitlin B , Kramer Joel H. , Akassoglou Katerina , Elahi Fanny M
Published: December 2022

Background

Age‐associated dysfunction of the blood‐brain barrier results in increased non‐specific permeability of the barrier and “leakage” of blood proteins into the central nervous system (CNS). Over the past decade, fibrinogen, the blood coagulation factor, has been demonstrated to be necessary and sufficient for triggering brain dysfunction and degeneration in model systems and is now serving as a robust biomarker of pathological BBB leakage. Importantly, BBB leakage may be an early pathological feature of the aging brain, instigating the development of neurodegenerative disease pathologies.

Method

We used colorimetric enzyme‐linked immunosorbent and chemiluminescence immunoassays to quantify CSF concentrations of fibrinogen and A/T/N AD biomarkers in a cohort of 84 deeply phenotyped functionally normal older adults and built linear models to test the associations of fibrinogen (BBB leakage) with A/T/N biomarkers and cognition (processing speed). The “N” biomarkers included three synaptic proteins (neurogranin, SNAP25, and GAP43). We set significance at α=0.05.

Result

We found strong, significant associations of BBB leakage (CSF fibrinogen levels) with all three synaptic proteins, as well as tau and p‐tau. With respect to Aβ, we found a significant association of BBB leakage with Aβ 1‐40, which is the peptide most strongly associated with cerebral amyloid angiopathy, an aging and AD‐related microangiopathy of the CNS. Importantly, we also found a significant association with processing speed–a highly relevant cognitive measure for the aging brain.

Conclusion

In this work, we demonstrate associations between BBB leakage and levels of AD A/T/N biomarkers in the aging brain. Although correlation is not causation, prior mechanistic studies in mice have demonstrated that fibrinogen leakage into the CNS triggers and propagates degenerative brain pathologies, relevant to AD. This is the first in vivo translation and extension of these pathways to the aging brain. Our reported findings have implications for therapeutics, given great interest in development of therapies for BBB leakage in neurodegenerative disorders. This process may start early in the aging brain and therefore trials may consider the inclusion of preclinical disease stages.
Loneliness predicts stronger negative associations between cerebrovascular, but not Alzheimer’s, pathology and cognition
Authors: Lao Patrick J. , Young Christina B , Andrews Ryan M , Gibbons Laura E , Kraal A.Zarina , Turney Indira C , Deters Kacie D , Trelle Alexandra N , Fox‐Fuller Joshua T. , Minto Lex , Seblova Dominika , Mukherjee Shubhabrata , Dotson Vonetta M , Manly Jennifer J , Zahodne Laura B.
Published: December 2022

Background

Alzheimer’s disease (AD) and cerebrovascular disease are the two most common pathologies underlying dementia. Loneliness is associated with faster cognitive decline and greater AD risk independent of pathology. Risk reduction efforts would benefit from knowing whether loneliness exacerbates the cognitive impact of pathology. Our objective was to characterize the interaction between loneliness and AD or cerebrovascular pathology on cognitive performance.

Methods

Participants with neuropathological data were drawn from the Religious Orders Study, the Memory and Aging Project, and the Minority Aging Research Study (Table 1). Loneliness was assessed with a modified version of the de Jong‐Gierveld Loneliness Scale. Amyloid and tau pathology were assessed jointly with the NIA‐Reagan scale as high/intermediate likelihood or low likelihood/no AD. Chronic infarcts and chronic microinfarcts were each assessed as present or not present. Composite domain scores for episodic memory, working memory, semantic memory, perceptual speed, and perceptual orientation were obtained from the study visit proximal to death. Separate general linear models were run for each domain and each pathology, including an interaction between loneliness and pathology and adjusting for covariates.

Results

Greater loneliness was associated with older age and lower education, and loneliness was greater in men compared to women, but not different by race or APOE‐ε4 (2). Loneliness was not associated with AD or cerebrovascular pathology (Table 3). Greater loneliness was independently associated with lower cognitive scores in all domains. Greater pathology was independently associated with lower episodic memory and semantic memory scores, while cerebrovascular disease was not independently associated with cognitive scores. We additionally found that negative associations between microinfarcts and cognitive scores in working memory, semantic memory, and perceptual orientation were stronger among individuals with greater (Table 4).

Conclusions

Negative associations between loneliness and cognition are apparent across domains and independent of pathology. While loneliness does not appear to be related to AD or cerebrovascular pathology directly, it may increase susceptibility to cognitive impairment due to microinfarcts. Social support‐based interventions may benefit optimal brain aging, particularly in older adults exposed to greater loneliness.
Spatial dysregulation of Rho GTPases in Alzheimer’s Disease brain in human and in transgenic mouse model
Authors: Akhtar Shayan Nik , Zhu Yi , Lu Qun
Published: December 2022

Background

Alzheimer disease (AD) is histopathologically characterized by brain accumulation of amyloid plaques, neurofibrillary tangle formation, and loss of synapses. The small GTPases of Rho family such as RhoA, Rac1 and Cdc42 play an important role in neural plasticity by regulating synaptic actin and spine dynamics. However, the functions of these proteins in AD are paradoxical. To understand their contributions in AD pathogenesis, it is important to investigate the relationship between the expression of Rho GTPases and their functional states in signaling.

Method

We characterized the spatial dysregulation of Rho GTPases in human AD brains and that of aged Triple Transgenic (3xTg‐AD) mouse model carrying mutations in amyloid precursor protein, tau protein, and presenilin. For human brains, the paraffin‐embedded tissues were collected from age and gender matched AD and Non‐Dementia (ND) patients. Phosphorylated Rho GTPase antibodies were used as signaling indicators for immunofluorescence microscopy

Result

We observed altered phospho‐RhoA (S188) and phospho‐Rac/Cdc42(S71) expression and distribution in human, wild type (WT), and 3xTg‐AD mouse brains. In the CA3 region and dentate gyrus (DG), pRac/Cdc42 immunostaining showed decreased punctate staining in WT compared to 3xTg‐AD mice. For CA3 pRhoA immunostaining scored a slightly higher level of expression in WT compared to 3xTg‐AD. In the CA2 region, pRac/Cdc42 immunostaining was perinuclear in WT and diffused in 3xTg‐AD, whereas the pRhoA immunostaining pattern was similar between WT and 3xTg‐AD. In the CA1 region, pRac/Cdc42 immunostaining showed perinuclear as well as dendritic localization in WT and 3xTg‐AD, while pRhoA immunostaining between WT and 3xTg‐AD was similar. In human brains,there was no significant difference in pRhoA in cortex between ND and AD whereas pRac/Cdc42 was slightly reduced in AD cortex. However, while Rac signaling was reduced, Cdc42 signaling was increased in ND compared to AD cortex. On the other hand, Rac signaling is decreased in ND DG compared to AD whereas the differences in Cdc42 signaling in DG were not significant.

Conclusion

Small GTPases of Rho family are differentially dysregulated in expression, distribution, and functional states in different areas of the brain in AD patients as well as in AD mouse brains
Examining the impact of a rare protein‐truncating SORL1 variant on AD pathology
Authors: DeRosa Brooke A , Simon Shaina A , Cuccaro Michael L. , Cukier Holly N. , Vance Jeffery M. , Vance Margaret A. , Dykxhoorn Derek M.
Published: December 2022

Background

Recent analyses of rare variants using whole exome sequencing have found an enrichment of SORL1 loss‐of‐function (LoF) variants in early onset Alzheimer’s disease (EOAD). This makes SORL1 one of the highest risk factors for AD, along with other candidate EOAD genes such as APP, PS1, and PS2. SORL1 encodes an endocytic receptor involved in the trafficking of amyloid‐β precursor protein (APP) and the secretion of amyloid‐β. We identified a family with multiple individuals affected with EOAD carrying a single base pair deletion (c.4293del) in SORL1, resulting in a frameshift and premature termination of the protein (p.Cys1431fs; Kunkle et al. JAMA Neurol. 2017). Several recent studies have demonstrated that haploinsufficiency of SORL1 can induce AD‐related phenotypes in cultured neurons. However, the functional consequences of specific variants remain largely undefined. In this study, we used patient‐specific induced pluripotent stem cell (iPSC)‐derived neurons to evaluate the effect of a rare LoF SORL1 variant on AD‐related pathology.

Method

Patient‐specific iPSC lines were derived from two related heterozygous p.Cys1431fs carriers with EOAD. Each line was validated for pluripotency through immunocytochemical staining and RT‐PCR. Karyotypic stability was assessed by G‐banding. To evaluate the functional consequences of the SORL1 deletion, patient and control iPSC lines were differentiated into cortical neurons and assessed for AD‐related phenotypes.

Result

The iPSC lines were successfully differentiated into cortical neurons, characterized by immunostaining for various neuronal markers. Our data show that neurons bearing the p.Cys1431fs SORL1 mutation have increased levels of APP accumulated in EEA1+ endosomes compared to neurons from cognitively intact individuals. Additionally, analysis of synaptic density revealed that neurons carrying the p.Cys1431fs variant show a significant reduction of SYN1+ puncta compared to cognitively intact individuals.

Conclusion

Our results indicate that patient‐derived neurons carrying the p.Cys1431fs variant have cellular defects associated with AD pathology while replicating, at least in part, previous in vitro findings on SORL1 haploinsufficiency.
Verbal recognition declines in later Braak Stages compared to verbal delayed recall
Authors: Arias Jaime Fernandez , Therriault Joseph , Lussier Firoza Z , Pascoal Tharick A , Tissot Cécile , Wang Yi‐Ting , Bezgin Gleb , Servaes Stijn , Kang Min Su , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Poltronetti Nina Margherita , Kunach Peter , Ottoy Julie , Stevenson Alyssa , Mathotaarachchi Sulantha , Massarweh Gassan , Vitali Paolo , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2022

Background

Episodic memory decline is a hallmark of cognitive impairment due to Alzheimer’s Disease (AD). Literature has consistently indicated that delayed recall is compromised early in the disease. Recognition memory seems disrupted at late stages, although findings are mixed. Recent PET studies have demonstrated that the presence of tau in the medial temporal lobe (MTL) relates to early deterioration of delayed recall, but no PET studies have assessed how recognition memory relates to tau. We sought to investigate this relationship across the Braak staging continuum.

Method

Tau PET ([18F]‐MK6240) was acquired for 140 cognitively unimpaired elderly (CU), 54 MCI patients and 33 AD patients. Participants were segregated into Braak stages, based on in vivo PET neuroimaging of tau. Episodic memory was assessed using RAVLT delayed recall and recognition tests. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non‐linearly registered to the ADNI template using Dartel and smoothed with an 8mm FWHM gaussian kernel. Independent samples t‐tests or their nonparametric counterparts were conducted to evaluate differences in memory scores by Braak stage. Voxel‐wise linear regression models were applied, using VoxelStats, with either delayed recall or recognition scores as dependent variables and tau PET as a predictor. Global amyloid, age, sex, education and APOE genotype were entered as covariates.

Results

Pairwise comparisons revealed that recognition memory is spared in early Braak stages. Voxel‐wise analyses in the whole sample unveiled that delayed recall and recognition memory relate to tau in virtually the same cortical areas. However, the strength of the relationships widely varied by memory type. Tau‐PET in anterior MTL and posterior hippocampus shows stronger associations with delayed recall, while tau binding in lateral temporal, temporooccipital and posterior areas exhibits stronger associations with recognition memory.

Conclusion

Our findings support the differentiation between delayed recall and recognition across the AD spectrum. Relationships between delayed recall and tau in the MTL are in concordance with previous research. Moreover, the contrast in the strength of the associations between memory and tau aggregation further supports the notion that delayed recall is already impaired in early Braak stages while recognition is damaged in later Braak stages.
Interactions between brain and bile acid ratio profiles predict baseline cognitive status
Authors: Labus Jennifer S , Liu Cathy , Blach Colette , Arnold Matthias , Kaddurah‐Daouk Rima F. , Mayer Emeran A
Published: December 2022

Background

Alterations in the brain‐gut microbiome system are thought to play an important role in the development of neurodegenerative diseases. While the great majority of secreted primary bile acids (BAs) are reabsorbed in the ileum, about 5% are metabolized by gut microbes and reabsorbed. Alterations in secondary BAs metabolism associated with specific gut‐microbial species, and reflected in altered ratios of primary and secondary BAs have recently been linked with brain atrophy and cognitive decline. The aim of this study was to investigate whether interactions between brain‐derived morphometric phenotypes and BA profiles can predict baseline cognitive status (cognitively normal (CN), mild cognitive impairment (MCI), Dementia (AD)) or conversion status (MCI to AD).

Method

The sample included 1013 CN, MCI, and AD participants from the Alzheimer’s Disease Neuroimaging Initiative cohort. Regional brain morphometry was derived using Freesurfer v5.1 and Desikan‐Killany atlas. Targeted metabolomics profiling quantifed concentrations of 20 BAs from serum samples. Analysis was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO). Data was split into a training and test sets (70/30 split) to determine predictive accuracy.

Result

A correlated brain and BA ratio signature predicted cognitive status (CN vs AD) with high predictive accuracy (see Figure 1). The brain signature of AD, compared to CN was characterized by gray matter atrophy in a limited number of regions including the hippocampus, entorhinal cortex, amygdala and medial temporal regions. The BA ratio signature was characterized by higher ratio of glycolithocholic acid and glycodeoxycholic acid to ursodeoxycholic acid, GLCA:UDCA, GDCA:UDCA along with a lower ratio of cholic acid to GLCA in AD. Predicted conversion from MCI to AD at 2 and 4 years had lower predictive accuracy (BER∼ = 34%)

Conclusion

These findings demonstrate that interactions between brain signatures and secondary BA profiles predict baseline cognitive status with high accuracy. They support the concept that differences in gut microbial metabolism of certain BAs, possibly related to diet, play a role in shaping the brain signature in AD patients. Compared to previously employed univariate approaches, the supervised multi‐omics multivariate integration approach complements and elucidates the interactions along the brain gut microbiome axis that contribute to AD.
Longitudinal clinical and neuropsychological outcomes in limbic predominant age related TDP_43 encephalopathy vs. Alzheimer’s disease from The 90+ Study
Authors: Sajjadi S. Ahmad , Qian Tianchen , Bukhari Syed , Woodworth Davis C. , Montine Thomas J. , Corrada Maria M. , Kawas Claudia H.
Published: December 2022

Background

Limbic predominant age related TDP‐43 encephalopathy‐neuropathologic change (LATE‐NC) is prevalent in the oldest old. Our aim was to determine the association of longitudinal change in clinical and neuropsychological measures in relation to the presence of LATE‐NC and Alzheimer’s disease neuropathologic change (ADNC) in an exclusively oldest‐old cohort.

Methods

323 participants from The 90+ Study with longitudinal evaluations and autopsy data were studied. LATE‐NC was considered present in those with TDP‐43 in hippocampus and/or neocortex and ADNC in those with high‐likelihood ADNC according to NIA‐AA guidelines. Scores in clinical dementia rating sum of the boxes (CDR‐SB) and neuropsychological tests representing global cognition (MMSE and modified MMSE (3MS)), memory (California verbal learning test‐long delay (CVLT)), language (Boston naming test (BNT)), executive function (TRAIL‐B), attention/concentration (digit span backward), and orientation (from MMSE) were used to calculate standardized effect sizes (SES) of LATE‐NC and ADNC on longitudinal change in the scores. Relationships were estimated using linear mixed effect models accounting for age at death, age at the time of testing, sex, and education.

Results

Mean age at death was 97.7 years and 67% were female. Prevalence of LATE‐NC and ADNC in the whole cohort was 28% and 31% respectively and 11.4% had both pathologies. Of 34% who had dementia at death, 42.7% had LATE‐NC and 41.8% had ADNC (Table 1). LATE‐NC alone was associated with decline in global measures [MMSE (SES: ‐0.70), 3MS (SES:‐0.77), CDR‐SB score (SES: 0.89)] and with orientation (SES: ‐0.82). In contrast, ADNC alone was associated with decline in executive function‐ TRAILB (SES: 0.49). Both pathologies, LATE‐NC and ADNC, were related to decline in memory‐CVLT (SES: 0.73 for LATE‐NC & 0.46 for ADNC), language‐BNT (SES: 0.54 for LATE‐NC & 0.45 for ADNC), and attention‐digit span backward (SES: 0.41 for LATE‐NC & SES: 0.36 for ADNC) (Figure 1).

Conclusion

Our results confirm the importance of LATE‐NC in the oldest old and highlight that LATE‐NC and ADNC are associated with partially distinct patterns of clinical and neuropsychological decline that might aid prediction of LATE‐NC during life.
Plasma pTau 181 concentrations in middle‐aged, community‐dwelling, racially and ethnically diverse adults
Authors: Brickman Adam M. , Lao Patrick J. , Banjoko Michael B. , Mayeux Richard , Simoes Sabrina , Manly Jennifer J
Published: December 2022

Background

Plasma biomarkers for Alzheimer’s disease (AD) are becoming more widely available, with pTau181 emerging as among the most sensitive and specific. There is a lack of data characterizing plasma pTau181 concentration in diverse cohorts and in middle age. The purpose of this study was to examine the association of age, sex/gender, race/ethnicity, APOE genotype, and memory with plasma pTau181 in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease study, a population‐representative study of AD risk in middle aged adults.

Method

We included 1041 participants (56±11‐years‐old [range: 28‐88], 68% women, 13±3 years education, 49% Latinx tested in Spanish, 24% Latinx tested in English, 20% non‐Latinx Black, 7% non‐Latinx White, 28% with APOE‐ε4). Blood samples were analyzed for pTau181 concentration (Quanterix Simoa) and APOE genotype, and memory was evaluated with the Selective Reminding Test (SRT). We used general linear models to examine associations of pTau181 concentration with the variables of interest. We also examined differences in memory among subgroups of participants defined with a model‐based clustering approach based on the distribution of Ptau181 concentrations.

Result

PTau181 concentrations were 1.87±1.21 pg/mL (range: 0.071‐16.15). Increased age (β=0.016 [0.009‐0.023], p<0.001) and male sex/gender (β=‐0.274 [‐0.436‐ ‐0.111], p<0.001) were associated with higher pTau181, but APOE‐ε4 genotype (β=‐0.008 [‐0.176‐0.161], p=0.930) was not. PTau181 did not differ between Latinx participants tested in Spanish (reference group) and Latinx participants tested in English (β=0.151 [‐0.048‐0.350], p=0.136), non‐Latinx Black (β=0.150 [‐0.056‐0.357], p=0.153), or non‐Latinx White (β=‐0.031 [‐0.284‐0.345], p=0.849) participants. Higher pTau181 was associated with lower SRT delayed memory scores in an unadjusted model (β=‐0.442 [‐0.661‐ 0.22], p<0.001) and after adjustment for age, sex/gender, race/ethnicity, education, and APOE status (β=‐0.366 [‐0.577– ‐0.154],p<0.001). We identified three clusters of participants, corresponding to relatively low, medium, and high pTau181 concentrations. The highest cluster had poorer memory performance than the other groups in fully adjusted models (F=5.56, p=0.004).

Conclusion

Plasma pTau181 concentrations are associated with memory, sex/gender, and age in midlife. We do not find evidence of race/ethnicity or APOE related differences in pTau181 concentrations in this age group.
Biophysical analysis of TREM2 interactions reveals a shared binding site for Alzheimer’s disease ligands apoE and oligomeric amyloid beta
Authors: Greven Jessica A , Song Jong Hee , Kober Daniel L , Alexander‐Brett Jennifer M , Gross Michael L , Brett Thomas J
Published: December 2022

Background

The development of new innovative treatments to prevent and ameliorate AD requires knowledge of molecular mechanisms that are critical to neuronal health. The triggering receptor expressed on myeloid cells 2 (TREM2) receptor is part of a signaling complex that modulates inflammatory responses, phagocytosis and cell survival in microglia, resident immune cells in the brain that play a critical role in clearing misfolded aggregates. Examples include neurotoxic aggregates consisting largely of amyloid beta (Ab) and apoliproteinE (apoE). Both molecules have emerged as important signaling ligands for TREM2. Although TREM2 signaling in microglia is generally associated with beneficial outcomes, intense or prolonged signaling may produce overactivated microglia leading to neuronal damage. Such events may also contribute to other diseases such as Parkinson’s or cancers. Furthermore, rare TREM2 variants, most notably R47H and R62H, have been identified that are associated with a significantly increased risk of developing AD. Given these significant roles, TREM2 has emerged as an important yet challenging therapeutic target for AD. Although a number of ligands for TREM2 with relevance to AD have been identified, little is known regarding the molecular details of how TREM2 engages them. Detailed knowledge of the molecular mechanisms underlying TREM2 signaling in microglia is urgently needed to facilitate the development of specific, potent, safe and efficacious therapies for AD that target the TREM2 signaling pathway. The objective of this study was to identify the critical surfaces on TREM2 that mediate interactions with both apolipoproteinE (apoE) and oligomeric amyloid b1‐42 (oAb42) using rigorous structural and biophysical methods.

Method

We used structure‐based mutations and comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 interactions with apoE and oAb42.

Result

We found that TREM2 utilizes a distal hydrophobic surface, consisting of the CDR1, CDR2, and CDR3 loops, to engage apoE. Surprisingly, we found that this same surface is utilized to engage oAb42.

Conclusion

Our results indicate that the hydrophobic site on TREM2 (consisting of the CDR1, CDR2, and CDR3 loops) is the critical ligand‐engaging surface on TREM2. They also indicate that therapeutics that either directly bind or allosterically alter the hydrophobic site on TREM2 should modulate TREM2 signaling as potential AD treatments.
Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample
Authors: Naslavsky Michel S , Suemoto Claudia Kimie , Brito Luciano Abreu , Scliar Marília Oliveira , Ferretti‐Rebustini Renata Eloah de Lucena , Rodriguez Roberta Diehl , Leite Renata Elaine P. , Araujo Nathalia Matta , Borda Victor , Tarazona‐Santos Eduardo , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Nitrini Ricardo , Yaffe Kristine , Zatz Mayana , Grinberg Lea Tenenholz
Published: December 2022

Background

Dementia affects more Black individuals, likely due to a combination of environmental and biological factors1,2,3. APOE ε4 allele risk of dementia is different between individuals with European (EUR) and African (AFR) ancestries4,5,6. It is unclear what drives these differences in Alzheimer’s disease (AD) neuropathology among patients with cognitive decline, both outcomes influenced by different sets of biological and environmental factors. We studied the interaction between global and local APOE African ancestry, e4 allele, burden of neuritic plaques (NP) and neurofibrillary tangles (NFT), and cognition in a postmortem sample of admixed individuals with AD pathology.

Method

Community‐dwelling autopsied brains (n=400) without neuropathological changes or with NP scored using CERAD and NFT scored by Braak stage but lacking others comorbid neuropathologies. Subject’s cognitive function prior to death as assessed using Clinical Dementia Rating sum of boxes (CDR‐SOB). APOE genotypes were assessed with allele‐specific amplification. Global ancestry was inferred using Admixture and local ancestry using RFMix, derived from panels of variants interrogated by microarray.

Result

When dichotomously ascertained at 2% of AFR, and adjusting for age, sex, educational attainment and APOE ε4 carrier status, the admixed group is significantly protected of neuritic plaques (NP, beta=‐0.21, p=0.04) but not neurofibrillary tangles (NFT, beta=0.137, p=0.39). However, CDR‐SOB was associated with continuously distributed AFR (Table 1) only among individuals with severe levels of NFT (beta=7.04, p<0.001) and NP (beta=3.9, p<0.001). Stratifying the same analysis between APOE status, only APOE ε4 noncarriers presented significant associations between AFR and CDR‐SOB, but APOE ε4 carriers lost significance. APOE local ancestry inference of showed that non‐European admixed APOE ε4 noncarriers had lower NP burden outcomes (Table 2, beta=‐0.28, p=0.032 and beta=‐0.27, p=0.015 with and without adjusting for AFR, respectively), but worst cognitive decline compared to European APOE of the same genotype group when adjusting by NP levels (beta=1.01, p=0.041, without adjusting for AFR). Lastly, APOE ε has a significant effect on neuropathology, but not cognition, only within European local ancestry contexts (Table 3, beta=0.61, p<0.001).

Conclusion

Our results demonstrate a complex relation between APOE genotypes and local ancestry, AFR global ancestry and AD‐related neuropathology and cognition outcomes.