bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic analyses of the plasma proteome and metabolome in the same cohort from participants with African and European ancestry identify ancestry‐specific AD risk associated molecular traits
Authors: Yang Chengran , Gorijala Priyanka , Timsina Jigyasha , Wang Lihua , Wang Ciyang , Liu Ellen , Morris John C , Sung Yun Ju , Cruchaga Carlos
Published: December 2023

Background

Alzheimer disease (AD) has different prevalence across different ancestries. However, the genetic factors underlying AD pathogenesis between diverse populations are largely unknown. The recent AD genome‐wide association study (GWAS) (Bellenguez et al 2022) reported 75 significant genetic loci in European ancestry, while the latest African‐based AD GWAS (Kunkle et al 2021) only reported two loci. It will be important to map these genetic loci into the functional molecular traits, e.g. RNA expression, protein abundance, metabolite levels. Multiple studies integrated such molecular traits with AD risk and termed them as TWAS, PWAS, and MWAS. However, few studies reported more than one molecular trait and in multiple ancestries.

Method

We first identified the plasma proteomic (SomaScan 7K) and metabolomic (Metabolon HD4) QTLs (quantitative trait loci) from participants with African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively. We next associated the genetic variants with the AD risk GWAS (EUR‐Bellenguez‐2022 & AFR‐Kunkle‐2021) using the protein or metabolite as the intermediate molecular trait. We extended the TWAS framework to test the disease association with the genetically predicted levels of proteins (PWAS) and metabolites (MWAS).

Result

We identified over 3,000 pQTLs and 400 mQTLs. Out of these findings, approximately 40% were novel QTLs compared to the previous studies. We found ancestry‐specific proteins and metabolites associated with AD risk. For example, proteins BIN1, TREM2, APOE, were only significant in EUR‐PWAS results but not AFR‐PWAS using the ancestry‐matched disease associations. Conversely, Spondin‐1 and RNF24 were only nominally significant in AFR‐PWAS. Similarly, metabolites glucuronide and sphingosine were only significant in EUR‐MWAS, whereas ethylmalonate was only nominally significant in AFR‐MWAS. There were 146 and 10 proteins associated with AD‐risk in EUR and AFR, respectively. 55 proteins can be used as drug targets. 119 proteins were not nominated by previous AD risk GWAS. Three and one metabolites were associated with AD‐risk in EUR and AFR, respectively. One metabolite can be used as drug target.

Conclusion

We uncovered ancestry‐specific genetic architectures for proteomics and metabolomics. Our study serves as the first multi‐omic genetic study on multi‐ancestries for AD and can help guide the future ancestry‐specific therapy.
Identifying Individualized Neurophysiological Causal Features for Working Memory Performance: Implications for Non‐Invasive Brain Stimulation
Authors: Mirjalili Mina , Zomorrodi Reza , Daskalakis Zafiris J. , Blumberger Daniel M. , Hill Sean , Rajji Tarek K.
Published: December 2023

Background

Non‐invasive brain stimulation (NIBS) has been extensively used to target specific neural oscillations with the aim of improving working memory performance. However, current NIBS paradigms have two main limitations: first, lack of personalization and second, a need for a randomized controlled trial (RCT) to infer causality between targets of NIBS and subsequent performance. RCT is a powerful measure to infer causality, but its implementation is expensive, time consuming, and sometimes simply not possible. Therefore, our aim was to use computational models and observational data to discover causal relations between neural oscillations and working memory performance to identify potential targets and stimulation parameters for personalized NIBS paradigms.

Method

We used electroencephalography (EEG) data of 66 young healthy participants collected while performing a 3‐back working memory task. Using graphical causal modeling, we extracted individualized causal brain oscillations of 3‐back performance and compared the causal features between two groups: high and low performers.

Result

Total number of causal features in high performers was higher than low performers. Among the causal features, right temporal gamma oscillation was ∼5 times (z‐score = 3.87, p = 0.003) more frequently a causal feature among high performers than low performers. However, the power of causal temporal gamma oscillation was not different between the two groups.

Conclusion

Our findings suggest that a potential approach to improve working memory performance using NIBS is to induce more causal gamma oscillations by, for example, generating more local gamma entrainment over the right temporal cortex and not necessarily by increasing gamma power.
Hippocampal subregion‐specific proteomic differences between Alzheimer disease (AD) and primary age‐related tauopathy (PART)
Authors: Walker Jamie M. , Orr Miranda E. , Orr Timothy C. , Crary John F. , Woodoff‐Leith Emma , Teixeira‐Yokoda Raquel , Gupta Meenakshi , Daoud Elena , Kautz Tiffany F , Richardson Timothy E.
Published: December 2023

Background

Although Alzheimer disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R‐tau immunopositive Alzheimer‐type neurofibrillary degeneration, they differ in the spatial development of neurofibrillary tangles (NFTs) in the hippocampus. PART displays an early predilection for neurofibrillary degeneration in the CA2 subregion of the hippocampus, whereas AD typically develops NFTs in the entorhinal cortex and CA1 subregion initially (Figures 1‐2).

Method

Using Nanostring’s GeoMx™ Digital Spatial Profiling (DSP), we compared hippocampal subregion protein expression differences between AD and PART. The DSP panel allows for spatial analysis of the level of expression of 73 different proteins in multiple regions of interest (ROIs) on formalin‐fixed paraffin embedded sections. Our ROIs were NFT‐bearing neurons and non‐NFT‐bearing neurons in the entorhinal cortex, CA1 and CA2 hippocampal subregions, as well as the neuronal microenvironments in these regions.

Result

Analyses identified several proteins displaying differential expression in tangle‐bearing neurons when comparing AD to PART. These included higher levels of synaptic and neuronal markers in PART, such as Synaptophysin, MAP2, Calbindin and NRGN, as well as higher levels of proteins involved in degradation pathways, such as CTSD, GPNMB, Park7 and FUS. PART also displayed higher levels of Neprilysin in CA2, and higher IDE in CA1, which are proteins that help degrade β‐amyloid (Figure 3). Many of these proteins were also differentially expressed in the non‐tangle bearing neurons. In addition, AD demonstrated higher levels of p‐tau T231, S214, S199, and S396 in non‐tangle bearing neurons of CA1, as well as higher expression of Aβ1‐40. In the microenvironment, NEFL, NRGN, CLEC7a, GPNMB, and CTSD were higher in PART, while p‐tau S396 and BACE1 were higher in AD.

Conclusion

In conclusion, PART cases displayed higher levels of neuronal and synaptic markers, suggesting better maintenance of neuronal and synaptic integrity than AD, as well as higher levels of proteins important for degradation of detrimental proteins. AD cases expressed higher levels of certain p‐tau epitopes, especially in and around CA1 non‐tangle bearing neurons. In addition, AD displayed higher levels of BACE1, whereas PART displayed higher levels of CTSD, Neprilysin and IDE, which could explain the differences in β‐amyloid deposition in these cases.
Sleep Phenotypes predict self‐reported measures of cognition and mild cognitive impairment in diverse Hispanics/Latinos
Authors: Ramos Alberto R , Tarraf Wassim , Gonzalez Kevin A , Gallo Linda C , Wallace Douglas M , Redline Susan , Mossavar‐Rahmani Yasmin , Pike James R. , Zeng Donglin , González Hector M , Decarli Charles
Published: December 2023

Background

The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) showed that self‐reported cognitive decline (SCD) is associated with objectively assessed cognition. In HCHS/SOL, sleep phenotypes using empirically derived latent class/cluster analyses are associated with brain vascular outcomes. Since these measures may predict cognitive decline and dementia, we examined the associations between sleep phenotypes, SCD and mild cognitive impairment (MCI) among a diverse sample of Hispanics/Latinos living in the United States.

Method

HCHS/SOL is prospective cohort study designed using a multisite (Bronx, NY, Chicago, IL, Miami, FL, San Diego, CA) multistage probability sample. SCD was measured as part of SOL‐INCA, an HCHS/SOL ancillary study. SOL‐INCA obtained repeated cognitive tests, seven‐years apart and the Everyday Cognition Short Form (ECog‐12). The ECog‐12 is a self‐rated questionnaire of current multiple cognitively relevant functional abilities compared to 10‐years ago administered to 5,563 SOL‐INCA participants aged ≥ 50 years. We used latent class analysis using 15 common sleep related symptoms, home sleep apnea test and four comorbidities to derive three sleep phenotypes: (1) Minimally Symptomatic group (49.6%), (2) Disturbed Sleep group (17.1%), and (3) Daytime Sleepiness group (33.3%). We used survey regression to evaluate associations between visit‐1 sleep phenotypes and the ECog‐12 (linear) cognitive domains (memory, language, executive function, and global) and MCI (logistic) using the minimally symptomatic sleep group as the reference. Models were adjusted for age, education, sex, background, field center, insurance, body mass index, cigarette use, alcohol use, cardiovascular disease, language preference, and respiratory event index.

Result

Average age was 64.34±8.25 years and 55% were female. In fully adjusted models, participants with disturbed sleep had worse global cognition β = 0.18 [0.14;0.22], memory β = 0.21 [0.16;0.26], language β = 0.23 [0.17;0.29], and executive function β = 0.16 [0.12;0.21]. Compared to the reference, we observed stronger associations in participants with daytime sleepiness; global cognition β = 0.22 [0.16;0.27], memory β = 0.26 [0.19;0.32], language β = 0.26 [0.19;0.34], and executive function β = 0.20 [0.15;0.26]. Adults with disturbed sleep, OR = 1.44 [1.08;1.93], and daytime sleepiness OR = 1.67 [1.16;2.40] had higher odds of MCI.

Conclusion

Empirically derived sleep phenotypes capturing disturbed sleep and sleepiness had associations with self‐reported cognitive function and MCI in this sample of U.S. Hispanic/Latino adults.
The Cingulate Island Sign in a Mixed Memory Population: Prevalence and Diagnostic Accuracy
Authors: Feng Linda Ruohua , Waldemar Gunhild , Hasselbalch Steen G. , Vogel Asmus , Henriksen Otto Mølby , Law Ian , Frederiksen Kristian Steen
Published: December 2023

Background

Visual rating of the cingulate island sign (CIS) on [18F]fluorodeoxyglucose ([18F]FDG) position emission tomography (PET) has a high specificity for dementia with Lewy bodies (DLB) in selected populations such as DLB versus Alzheimer’s disease (AD). This study aims to uncover the prevalence of CIS in an unselected memory clinic population, diagnostic accuracy to detect DLB, and the relationship between CIS and disease severity.

Method

We assessed the CIS on [18F]FDG‐PET with the visual CIS rating scale (CISRs) in 1000 consecutive patients with a syndrome diagnosis of dementia or mild cognitive impairment (MCI) with no restrictions in terms of etiological diagnosis.

Result

Possible (CISRs score 1‐2) or definite CIS (CISRs score 3‐4) was found in 24.3% of the cohort and 7.8% had definite CIS. The prevalence of definite or possible CIS was highest in DLB (n = 57 (74.0%)) followed by AD/AD + vascular dementia (AD/AD + VaD) (n = 158, (26.0%)) and other non‐neurodegenerative diseases (n = 6 (9.5%)). The prevalence of CIS across disease severities showed no statistically significant difference (p = 0.23). To differentiate DLB from non‐DLB with MCI or mild dementia the cut‐off which yielded the highest balanced accuracy was at CISRs score ≥ 1 (balanced accuracy = 77.1%) and in moderate or severe dementia a cut‐off at CISRs score ≥ 2 yielded the highest balanced accuracy (80.6%). The positive predictive value of definite CIS for DLB was 48.5% in MCI or mild dementia and 31.3% in moderate or severe dementia.

Conclusion

CIS on [18F]FDG‐PET is most prevalent in DLB followed by AD/AD + VaD. The prevalence of CIS across disease severities showed no significant difference. CISRs is useful in differentiating DLB from a variety of other diagnosis in a mixed memory cohort, and the diagnostic accuracy was comparable at early and late stages of dementia.
Impaired Astrocytic Synaptic Function by Peripheral Cholesterol Metabolite 27‐Hydroxycholesterol
Authors: Loera‐Valencia Raúl
Published: December 2023

Background

Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes involved in synaptic dysfunction during Alzheimer´s disease (AD). AD patients have imbalanced cholesterol metabolism shown by high levels of a side‐chain oxidized cholesterol known as 27‐hydroxycholesterol (27‐OH). Evidence from our laboratory has shown that elevated 27‐OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear.

Method

Our results suggest that elevated 27‐OH decrease the astrocyte function in vivo in one model of brain cholesterol imbalance. To study the relationship between astrocytes and neurons we have developed a 3D co‐culture system (3D‐NAMs) that allows all of the cell types from mice embryos differentiate together in vitro.

Result

We have validated our 3D‐NAMs and show that it reproduces effects of 27‐OH observed in 2D and in vitro. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures but are present in 27‐OH overproducing mice. We uncover a mechanism of GLT‐1 dysfunction that leads to astrocyte activation, neuronal hyperexcitability and synaptic dysfunction based on the effects of 27‐OH on astrocytes.

Conclusion

We propose 3D‐NAMs as tools that can give information about mechanisms of disease and will help elucidate the effectiveness and safety of drug interventions and report a new simple mechanism based on GLT‐1 downregulation in the presence of elevated 27‐OH as the culprit of hyperexcitability in neurons under hypercholesterolemia metabolic conditions.
Interaction of genetic and cardiovascular risk factors identifies pathways involved in Alzheimer’s Disease
Authors: Lee Annie J , Raghavan Neha S , Bhattarai Prabesh , Reyes‐Dumeyer Dolly , De Jager Philip L , Bennett David A. A , Schneider Julie A , Menon Vilas , Wang Yanling , Lantigua Rafael A , Medrano Martin , Mejia Diones Rivera , Jiménez‐Velázquez Ivonne Z. , Kukull Walter A. , Brickman Adam M. , Manly Jennifer J. , Tosto Giuseppe , Mayeux Richard , Kizil Caghan , Vardarajan Badri N
Published: December 2023

Background

Cardio and cerebrovascular diseases co‐exist in up to a third of the Alzheimer’s disease (AD) patients, and the presence of cardiovascular/cerebrovascular risk factors (CVRFs) are associated with the risk of AD in middle age and later. The relationship between CVRFs such as hypertension, body mass index, diabetes and coronary heart disease, and AD is well known, but there has been limited mechanistic evidence directly linking these vascular risk factors in AD to the presence of ischemic microvascular pathology. Each of these vascular factors has the capacity to impair the blood‐brain barrier and glio‐vascular units. Arterial pulses and flow are required for glymphatic clearance of molecules including amyloid β. Few studies have directly linked genetic variation related to the risk factors and the molecular mechanisms underlying the interplay of CVRF and genetics in AD. APOE plays a role in the metabolism of cholesterol and other lipids in the brain. Other genetic variants that have been found to interact with cardio and cerebrovascular risk factors include the CLU, PICALM, CR1, BIN1, ACE, AGT, and ALDH2.

Methods

We analyzed several large multi‐ethnic AD cohorts to understand the role of cardiovascular risk in the disease. We created a CVRF score comprised of hypertension, diabetes, heart disease and body‐mass‐index and tested the interaction of the score with genetic variants in conferring risk of AD.

Results

We found that genetic variants in FMNL2, BRINP1, RFC2, and IGFN1 interact with enhanced risk score for CVRFs, to modify the risk of developing AD. FMNL2 and BRINP1 brain expression is increased in patients that have pathological hallmark of AD and have chronic infarcts. Causal mediation analysis found that both amyloid and tau pathology increased FMNL2 expression which in turn resulted in higher risk of AD, suggesting that AD brains enhance the activity of this gene.

Conclusions

We propose that that FMNL2 is part of a larger set of genetic and molecular network that underlies the interaction between CVRF and AD. Clinical studies and basic science with animal models could be harmonized to discover new disease mechanisms, which could open new clinical directions and drug development efforts.
Sex/gender differences in subjective cognitive decline’s association to cognition and depression
Authors: Joyce Jillian , Chapman Silvia , Gifford Katherine A. , Shagalow Shaina , Waltrip Leah H. , Zeiger Peter , Kann Michael , Ravichander Aanya , Rizer Sandra , Marder Karen , Jefferson Angela L. , Cosentino Stephanie
Published: December 2023

Background

Despite the fact that women are more likely to develop Alzheimer’s disease (AD) than men, and develop pathological changes at an earlier age, women often receive diagnoses later. This disparity is possibly due to women’s verbal memory advantage, and the fact that verbal memory tests are often the gold‐standard for diagnostics. Further, a recent meta‐analysis found that female sex/gender was associated with greater depression which is often a differential diagnosis for dementia (Eikelboom 2022). Understanding sex/gender differences in Subjective Cognitive Decline (SCD) is critical to closing the care gap, as SCD is thought to be a preclinical stage of AD where intervention may be most effective. Integration of challenging cognitive testing, including non‐verbal memory tests, along with measurement of depression, is key for defining this preclinical stage. In this study, we compare SCD’s associations with non‐verbal and verbal list‐learning and depression as a function of sex/gender.

Method

97 cognitively unimpaired older adults were recruited for this study. Participants completed surveys regarding SCD and depression (Geriatric Depression Scale [GDS]) and cognitive testing. Non‐verbal memory was assessed with the Biber Figure Learning Test – Extended (BFLT‐E), a challenging non‐verbal figure‐learning test. Verbal memory was assessed with the Loewenstein‐Acevedo Scales for Semantic Interference and Learning (LASSI‐L). Both tests are associated with early AD changes. Linear regressions were conducted and stratified by sex/gender to assess the relationships of cognition and mood with SCD. Models of cognitive performance included age and education as covariates.

Result

Verbal list‐learning (LASSI‐L) predicted SCD in men (R2= .416, β = ‐.390, p = .017), but not in women (R2
= .217, β = ‐.173, p = .167). Non‐verbal figure‐learning, as measured by the BFLT‐E, predicted SCD in women (R2
= .267, β = ‐.342, p = .006), but not in men (R2
= .175, β = ‐.334, p = .078). Similarly, depression predicted SCD in women (R2
= .109, β = .330, p = .007), but not in men (R2
= .003, β = .055, p = .763).

Conclusion

Results demonstrate that in AD risk states such as SCD, cognitive dysfunction may manifest differently for women than men. Clinical care settings should consider integration of non‐verbal memory tests such as BFLT‐E along with regular screening of depression in order to address the inequities in diagnostics for women.
Microbial infection and associated inflammasome in the retina of Alzheimer’s disease patients
Authors: Gaire Bhakta Prasad , Koronyo Yosef , Rentsendorj Altan , Fuchs Dieu‐Trang , Subedi Lalita , Jallow Ousman , Black Keith L , Arditi Moshe , Crother Timothy R , Koronyo‐Hamaoui Maya
Published: December 2023

Background

Recent advances in Alzheimer’s disease (AD) research revealed that AD pathology is not confined to the brain but also occur in the neurosensory retina. Data have further suggested parallels between retinal and brain AD biomarkers. While the exact etiology of AD pathogenesis is undefined, an emerging theory has linked AD with microbial infection as a plausible cause for AD progression. The presence of several microbes including Chlamydia pneumoniae (Cp), Borrelia burgdorferi, Porphyromonas gingivalis, and Toxoplasma gondii have been reported in the post‐mortem brain of AD patients and murine models. However, the existence and role of microbial infection in AD retina has never been studied.

Method

We employed a range of histological, biochemical, and genetic techniques to detect bacterial infection and other associated biomarkers in postmortem retinas of patients with mild cognitive impairment (MCI) or AD dementia, compared to retinas from age‐matched individuals who displayed normal cognition (NC). We assessed the presence and burden of Cp and correlated with gliosis, inflammasome, and apoptosis markers.

Result

We discovered the presence of Cp inclusions in postmortem retinas of patients with MCI and AD as compared to age‐ and sex‐matched NC individuals. Our experimental evidence revealed Cp‐infected retinal neuronal cells in AD patients, with no increase in retinal Cp infection in MCI versus CN and a significant 4‐fold increase in of Cp immunoreactivity in retinas of AD patients versus MCI and CN subjects. These data possibly indicate that Cp infection mainly occur during the dementia phase of AD and is less observable at the early functional impairment stages of AD. Retinal microglia were found to aggregate around and engulf Cp‐infected cells. Alongside Cp infection, retinal tissues from MCI and AD patients exhibited increased NLRP3 inflammasome and gliosis. Our data suggest Cp‐triggered inflammasome activation, that can lead to neuronal degeneration. We further found a relationship between the severity of retinal Cp infection and brain pathology; retinal Cp burden was associated with brain neurofibrillary tangles, neuropil threads, Braak stage.

Conclusion

Cp‐triggered chronic inflammation could be a detrimental process leading to retinal degeneration in AD, suggesting potential new therapeutic avenues involving early antibiotic treatment or inflammasome attenuation.
Genetic and Environmental Influences of Plasma Biomarkers and Their Relation to APOE status and Mild Cognitive Impairment
Authors: Gillespie Nathan A. , Panizzon Matthew S. , Elman Jeremy A. , Neale Michael C. , Reynolds Chandra A. , Franz Carol E , Kremen William S.
Published: December 2023

Background

Before onset of Alzheimer’s dementia, aggregation of amyloid‐beta (Aβ) is thought to drive accumulation of Tau, followed by neurodegeneration (indexed here by neurofilament light chain [NFL]). Why or how Aβ increases Tau accumulation remains unclear. Using genetically informative twins aged 61.4 to 73.3 years, we sought to: (1) identify genetic and environmental influences on plasma Aβ (Aβ40, Aβ42, Aβ42/40), total Tau (t‐Tau), and NFL; (2) determine if their genetic and environmental influences are correlated with one another; (3) determine if Aβ40 and Aβ42 causally impact Tau levels; (4) measure associations between biomarkers and APOE‐ε4 status; and (5) measure associations between these biomarkers and mild cognitive impairment (MCI).

Method

Data were from 1,035 male twins in the Vietnam Era Twin Study of Aging. Average age was 67.1 years (SD = 2.6). Twin models were used to estimate heritability, genetic and environmental correlations, model the direction of causation between biomarkers, and associations with APOE‐ε4 status. Mixed effect linear regressions were applied to regress MCI on biomarkers.

Result

Heritability for Aβ40, Aβ42, t‐Tau and NFL ranged from 43% to 51%, whereas Aβ42/40 heritability was not significantly different from zero. Phenotypic correlations between t‐Tau and Aβ40 (rP = 0.01) and Aβ42 (rP = 0.14) were small. Genetic correlations between t‐Tau and Aβ40 (rG = ‐0.05) and Aβ42 (rG = 0.05) were also very small. In contrast, genetic correlations between NFL and Aβ40 and Aβ42 were higher (rG ranging = 0.31‐0.37). We found no evidence to suggest that Aβ40 or Aβ42 causally impacts t‐Tau. APOE‐ε4 accounted for a significant, but very small amount of variance in Aβ40 and Aβ42. Finally, none of the biomarkers was significantly associated with MCI, which affected 15.1% of the sample.

Conclusion

Both Aβ40 or Aβ42 appear heritable, but have very little phenotypic and genetic association with t‐Tau. The associations between the amyloid‐beta biomarkers and t‐Tau are mostly explained by non‐shared environmental factors, and the direction of causation is unclear. The small associations between APOE‐ε4 and the biomarkers, including their lack of association with MCI, may stem from the low sensitivity of plasma biomarkers, the relatively young age or the low proportion of MCI cases in this community‐dwelling sample.
Proteomics correlates of amyloid beta and tau in CSF: A monozygotic twin study
Authors: Visser Pieter Jelle , Braber Anouk , Campo Marta , Teunissen Charlotte E. , Tijms Betty M.
Published: December 2023

Background

Early Alzheimer’s disease (AD) is characterised in cerebrospinal fluid (CSF) by a decreased concentration of amyloid beta 1‐42 and an increased concentration of total tau (t‐tau). Insights in early AD development may provide clues for primary and secondary prevention. We aimed to investigate which other proteins were associated with abnormal amyloid beta 1‐42 and t‐tau in cognitively normal monozygotic twins. We tested to what extend proteins associated with abnormal amyloid and t‐tau have a common genetic background by performing cross‐twin cross‐trait (CTCT) analysis.

Method

We included 126 twins (54 pairs) from the EMIF‐AD PreclinAD study. We assessed 690 proteins by OLINK multiplex panels and t‐tau, abeta42, abeta40 by ELISA. We used the abeta42/40 ratio as measure of amyloid pathology. We correlated the abeta42/40 ratio and t‐tau levels with the other proteins. For proteins that showed an association with abeta42/40 or t‐tau we performed Cross‐Twin Cross‐Trait (CTCT) analysis by correlating the concentration of abeta42/40 or t‐tau in one twin with the concentration of the protein in the co‐twin (figure 1). Enrichment analysis was performed using Gene Ontology.

Result

Average age was 70 years. A lower abeta42/40 ratio was associated with increased levels of 114 proteins. These proteins were enriched for neurogenesis (p = 1.7E‐9) and apoptosis (p = 1.7E‐10). Only one protein showed a CTCT association. A lower abeta42/40 ratio was associated with lower levels of just 3 proteins. Increased t‐tau levels were associated with increased concentrations of 414 proteins. These proteins were enriched for nervous system development (p = 9.7*10‐21) and included 103 of the 114 proteins that correlated negatively with abeta42/40. Of the 414 proteins, 335 correlated with t‐tau in CTCT analysis. One of these proteins was BACE1 (see figure 2). Increased t‐tau levels were also associated with lower levels of 21 proteins which were enriched for leukocyte migration (p = 5.47*10‐3), of which 5 correlated with t‐tau in CTCT analysis.

Conclusion

A lower Abeta42/40 ratio and higher t‐tau level were both associated with an increased concentration of neuroplasticity related proteins. CTCT analysis showed that only t‐tau and plasticity proteins shared a common genetic architecture supporting the role of t‐tau in aberrant plasticity.
Innate immunity protein IFITM3 is involved in Alzheimer’s disease‐associated microglial response
Authors: Jain Tanya , Frost Georgia , Li Yueming
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disorder that has complex neuropathology which includes an accumulation of amyloid beta (Aβ) plaques, hyper‐phosphorylated tau tangles, and neuroinflammation. Amyloid plaques consist Aβ peptides, which are sequentially cleaved by α or β‐secretase and then γ‐secretase (GS) from amyloid precursor protein (APP). Our lab has previously identified interferon response protein IFITM3 as a GS modulatory protein that is upregulated in the human AD brain as well as in the 5xFAD mouse brain. We have shown that IFITM3 regulates GS activity in neurons, and a deficit in IFITM3 results in decreased GS cleavage of APP, leading to reduced amyloid plaque deposition in the 5xFAD mouse.

Method

We have generated 5xFAD;IFITM3−/−;TREM2−/− mice and have established stem cell‐derived IFITM3‐/‐ microglial cells. We have used a panel of mouse behavioural and immunohistochemical tests and in vitro microglial assays to investigating the function of IFITM3 in the phagocytic clearance of Aβ by microglia, its interplay with TREM2 and downstream signaling in the context of neuroinflammation.

Result

We have found that IFITM3 is highly expressed and inducible in glial cells, particularly astrocytes and microglia. We have shown that 5xFAD;IFITM3−/− mice have partially rescued cognition compared to 5xFAD mice, and have an upregulation of several microglial genes. In our in vitro microglial model, we have found that IFITM3−/− microglia display enhanced uptake of Aβ peptide, enhanced lysosomal degradation, and enhanced TREM2 expression and signalling.

Conclusion

We have determined a novel role of IFITM3 in microglia using cellular assays and mouse models. We have also found evidence of an interplay of IFITM3 with TREM2.
Quantification of the Brain Iron Metabolism in the Cognitively Declined Adults Using 7T MRI
Authors: Alipour Akbar
Published: December 2023

Background

The extracellular aggregation of beta‐amyloid (AB) plaques is one of the hallmark pathology of Alzheimer’s diseases (AD) that develops years prior to clinical symptoms. However, inconsistency in the rate of cognitive decline among subjects with AB pathology and ineffectiveness of anti‐amyloid therapeutics to mitigate cognitive impairment suggest that other parameters, such as patterns of brain iron, may impact the risk of cognitive decline. In this study we leveraged improved MRI signal at 7T to explore susceptibility changes in the iron‐enriched regions among individuals with AD/MCI and healthy controls (HCs) through quantitative susceptibility mapping (QSM) with unprecedented resolution.

Method

In vivo MRI experiment was performed in AD/MCI and age‐matched healthy subjects. Scanning was conducted on a 7T MRI scanner using 1Tx/32Rx Nova head coil. To calculate QSM, a 3D high‐resolution spoiled gradient echo (GRE) sequence was used (voxels size = 0.3×0.3×1.5 mm3). QSM was used to measure susceptibility in the major iron‐enriched structures (Fig. 1), including red nucleus (RN), substantia nigra (SN), globus pallidus (GP), Caudate nucleolus (CN), putamen (PT), and dentate nucleus (DN).

Result

We found a significantly higher magnetic susceptibility in GP and DN in patients with AD/MCI compared with HCs (Fig. 2). Overall mean susceptibility values for the RN, SN, CN, GP, PT, and DN in AD/MCI and HCs is summarized in Table 1. In AD/MCI the highest susceptibility values were found in the GP (233.5±12.7) and DN (214.7±10.4), verses 174.6±11.8 and 168.9±11.6 for GP and DN in the HCs, respectively. There were small differences in the susceptibility values between the other ROIs.

Conclusion

We reported an initial result for QSM at 7T in the AD/MCI subjects and appropriate age matched HCs. The main aim of the study was to investigate whether susceptibility values measured using ultra‐high resolution QSM differ in the iron‐enriched regions between these two populations. A significant susceptibility value was reported in the AD/MCI compared with the HC in GP and DN regions. This observation clearly deserves further investigations in larger cohorts.
Food Insecurity and Executive Function among Older Mexican Adults: Indirect Effects through Depressive Symptoms
Authors: Saenz Joseph , Renteria Miguel Arce , Avila Jaqueline Contrera
Published: December 2023

Background

Recent work has linked food insecurity with worse cognitive outcomes, with executive function being a domain affected most consistently. The mechanisms underlying this association are largely unknown and few have investigated how changes in food insecurity over time (never food insecure, newly food insecure, formerly food insecure, or chronically food insecure) relate with cognitive outcomes. Food insecurity is also related with worsening depressive symptoms, which may impact executive function. This study evaluates how changes in food insecurity in late‐life relate with executive function, and whether this association is mediated by depressive symptoms among older adults in Mexico.

Method

Data includes the 2012‐2015 Mexican Health and Aging Study (MHAS) and 2016 Mex‐Cog subsample of the MHAS (n = 1,581 age 55+). Food insecurity was classified as never food insecure (not food insecure in 2012 or 2015), newly food insecure (food insecure in 2015 but not 2012), formerly food insecure (food insecure in 2012 but not 2015), or chronically food insecure (food insecure in 2012 and 2015). Executive function and depressive symptoms (CES‐D) were obtained from the Mex‐Cog. Direct/indirect (through depression) effects of food insecurity were tested using structural equation modeling with bootstrap confidence intervals controlling for demographic and socioeconomic confounders.

Result

Approximately half of the sample were never food insecure, 16% were newly food insecure, 15% were chronically food insecure, and 18% were formerly food insecure. SEM results indicated partial mediation. Significant direct effects were observed, with chronic and former food insecurity related with 0.12 and 0.11 standard deviations lower executive function, respectively, compared to the never food insecure. Both chronic and former food insecurity exhibited significant indirect effects via depressive symptoms with indirect effects making up 21% and 15% of the total effects of chronic and former food insecurity on executive function.

Conclusion

Food insecurity may represent an important modifiable risk factor for poorer executive function outcomes. Although food insecurity had a direct impact on executive function, part of its detrimental effect was through worsening depressive symptoms. This study highlights the importance of considering experiences of food insecurity over time and the co‐existence of both food insecurity and depressive symptoms.
Interpretable Deep Learning and MultiOme data repurposing in Alzheimer’s target and drug discovery: NIA Artificial Intelligence and Machine Learning Consortium
Authors: Cheng Feixiong
Published: December 2023

Background

High‐throughput DNA/RNA sequencing technologies have rapidly led to a robust body of genetic and genomic data in the Alzheimer’s Disease Sequencing Project (ADSP); however, approaching AD with a simplistic single‐target approach has been demonstrated effective for developing symptomatic therapies but ineffective when attempted for disease modification. Therapeutic approaches by specifically modulating genetic risk genes are essential for development of disease‐modifying treatments in AD. However, existing data, including genetics, genomics, transcriptomics, proteomics, and interactomics, have not yet been fully utilized and integrated to explore the roles of targeted therapeutic development for AD.

Method

We will introduce how our team combines tools from artificial intelligence (AI), network medicine, endophenotype models, multi‐omics (genomics, transcriptomics, and proteomics), and electronic health records (EHRs), to identify potential drug targets and repurposable drugs for AD. The fundamental premise of our method is that AD risk genes exhibit distinct functional characteristics compared to non‐risk genes and, therefore, can be distinguished by their aggregated human brain‐specific functional genomic features from various quantitative trait loci (X‐QTL), including expression QTL (eQLT), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL).

Result

Via applying our deep learning model to the latest AD GWAS data, we identified 156 putative AD‐risk genes that were differentially expressed in AD‐associated microglia and astrocytes from large single‐nuclei RNA‐sequencing data of human postmortem brains with AD. Combining network‐based prediction and retrospective case‐control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is significantly associated with reduced likelihood of AD incidence, after adjusting for various confounding factors. Importantly, gemfibrozil (an approved lipid regulator) is significantly associated with reduced risk of AD compared to simvastatin (another approved anti‐lipid medicine under Phase II AD trials), using an active user design (odds ratio 0.57, 95% CI 0.51‐0.63, P < 0.0001).

Conclusion

From a translational perspective, the deep learning and network‐based approaches presented here, if broadly applied would significantly catalyze effective treatment development in AD and other neurodegenerative diseases from the human genome sequencing findings.
Exploring Biomarker Signatures of the Peripheral Immune Response in Alzheimer’s Disease: NIA Artificial Intelligence and Machine Learning Consortium
Authors: Bekris Lynn M.
Published: December 2023

Background

Alzheimer’s disease (AD) has been linked to multiple immune system‐related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, a soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage‐dependent manner. Multiple studies have reported an altered peripheral immune response in AD. Less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The overall objective of this study was to explore the relationship between plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2‐related inflammatory activity differs by AD stage or ATN Research Framework category.

Method

Cohorts included participants from the Cleveland Clinic‐based Dementia with LewyBody Consortium (DLBC), the Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease biobank (LRCBH‐biobank) and the Cleveland Alzheimer’s Disease Research Center (CADRC). Patients were clinically characterized based on cerebrospinal fluid AD‐related biomarkers, clinical symptoms, and consensus review. Analytes measured included: plasma sTREM2 and a panel of 38 inflammatory factors (Luminex/Millipore). Linear regression, Spearman correlation, Correlation Matrices, and Network analyses were some of the methods utilized.

Result

We observed different patterns of inflammatory activity across AD stages. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups (cognitively normal and A‐T‐N‐) that was lost in later AD‐related stages (MCI or AD and A+T‐N‐, A+T+N‐ and A+T+N+). Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor‐2, GM‐CSF, and IL‐1β) were notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a disease stage alteration in the relationship with sTREM2. Additionally, preliminary analyses indicate sex differences in peripheral TREM2‐related inflammatory activity.

Conclusion

These findings suggest that sTREM2‐related inflammatory activity alterations are AD stage specific and potentially sex specific. This novel information could enhance therapeutic strategies focused on targeting the immune response in AD.
Cerebrospinal fluid biomarkers at presentation associate with etiologic diagnosis and treatment responsiveness in patients with rapidly progressive dementia
Authors: Kuchenbecker Lindsey A , Tipton Philip W , Martens Yuka A , Brier Matthew R , Satyadev Nihal , Dunham S Richard , Lazar Evelyn , Dacquel Maxwell V , Bu Guojun , Geschwind Michael D , Morris John C , Schindler Suzanne E. , Fagan Anne M. , Graff‐Radford Neill R , Day Gregory S.
Published: December 2023

Background

The causes of rapidly progressive dementia are heterogeneous, including neurodegenerative, vascular, and autoimmune/inflammatory diseases. Overlap in presenting symptoms and signs, results of cognitive testing, and findings on brain imaging and other common diagnostic tests confounds the etiologic diagnosis, contributing to diagnostic delays, missed opportunities for treatment, and poorer outcomes in patients with RPD. New tools and approaches are needed to improve diagnostic accuracy, with particular emphasis on improving early recognition of patients with potentially treatable causes of RPD.

Methods

Established and emerging biomarkers of Alzheimer disease neuropathology (Aβ42/40, p‐tau181, p‐tau231), neuroaxonal and neuronal injury (neurofilament light [NfL], VILIP‐1, total tau), neuroinflammation (YKL‐40, sTREM2, GFAP, MCP‐1), and synaptic dysfunction (SNAP‐25, neurogranin) were measured in cerebrospinal fluid obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative (n = 35), vascular (n = 9), and autoimmune/inflammatory (n = 34) diseases, and 72 age‐ and sex‐similar cognitively normal individuals (controls). Causes of RPD were further classified as potentially treatment‐responsive or nonresponsive, referencing the extant literature. Biomarker levels were compared across etiologic diagnoses and by treatment responsiveness, referencing control values. Analyses were adjusted for the effects of age (ANCOVA).

Results

Alzheimer disease biomarkers (low Aβ42/40 and elevated p‐tau181 and p‐tau231) were associated with neurodegenerative causes of RPD (ANCOVA, p = 0.02 p = 0.30, p = 0.15), while high NfL (p = 0.61), low VILIP‐1 (p = 0.009), and elevated markers of inflammation (sTREM2, p = 0.009; YKL‐40, p<0.001) identified patients with autoimmune/inflammatory diseases (Figure). MCP‐1 levels were highest in patients with vascular causes of RPD (p = 0.08). 44 patients (56.4%) had potentially treatment‐responsive causes of RPD. Treatment responsiveness was associated with higher levels of CSF Aβ42/40 (p = 0.003), NfL (p<0.001), sTREM2 (p<0.001) and YKL‐40 (p<0.001); and lower levels of p‐tau‐181 and p‐tau231 (p<0.001, p<0.001) and VILIP‐1 (p<0.001).

Conclusion

Selected biomarkers measured in CSF at presentation associate with etiologic diagnosis and treatment responsiveness in patients with neurodegenerative, vascular, and autoimmune/inflammatory causes of RPD. Biomarker panels may be adapted to improve recognition of patients with treatment‐responsive causes of RPD early in the symptomatic course when treatments may be most effective.
Neurofibrillary tangle distribution in posterior cortical atrophy and early‐onset Alzheimer disease
Authors: Dickinson Sophie M. , Smirnov Denis , Estrella Melanie , Headley Alison , Goodwill Vanessa , Pizzo Donald , Galasko Douglas R. , Salmon David P. , Hiniker Annie
Published: December 2023

Background

Early onset sporadic Alzheimer’s disease (AD) sometimes presents with non‐memory symptoms attributed to relatively greater neocortical than hippocampal tau neurofibrillary tangle (NFT) density. Posterior cortical atrophy (PCA) is a variant of AD presenting with visuospatial deficits and atrophy of the occipital cortex, yet the pathologic underpinning is poorly understood.

Method

We examined brains of 50 patients with early onset (age<65 y.), autopsy‐confirmed AD from the UCSD Alzheimer’s Disease Research Center, 12 of whom were clinically diagnosed with PCA. Immunohistochemistry for tau was performed in the hippocampus (HP), midfrontal cortex (MF), and occipital cortex (OC), and the density of NFTs was measured.

Result

PCA and non‐PCA patients did not significantly differ in age (63.35±4.59 y. at death) or sex (40% female). The APOE ε4 allele was much less frequent in PCA (p = 0.002). While the PCA group was less impaired on the MMSE (p = 0.01), they performed comparably on the CDR sum‐of‐boxes. The OC NFT density did not differ between the groups; however, the OC/HP (p = 0.04) and OC/MF (p = 0.008) ratios demonstrate that PCA cases had relatively greater OC pathology than non‐PCA patients. Across the groups, age at symptom onset was inversely associated with OC NFT density (p = 0.01) and the OC/HP NFT ratio (p = 0.008), such that earlier onset was associated with greater OC NFT burden. Visuospatial performance, measured by the Block Design test, was associated with the OC NFT density (p = 0.006), as well as the OC/HP (p = 0.007) and OC/MF NFT ratios (p = 0.03), with the effects remaining significant when restricting to non‐PCA participants. In contrast, memory performance measured by the Logical Memory Immediate Recall measure was only associated with HP NFT density (p = 0.02).

Conclusion

Despite differences in the predominance of early visuospatial symptoms, PCA and non‐PCA patients did not differ in OC tangle density, with some of the highest densities in non‐PCA patients. However, the degree of visuospatial impairment was associated with the OC/HP NFT ratio across both groups. Results suggest that greater memory impairment in the non‐PCA patients associated with a higher HP tangle density may moderate the predominance of visuospatial impairment so that they do not receive a formal PCA diagnosis.
Generative deep learning model‐based manifold construction for ATN biomarkers
Authors: Song Yeong‐Hun , Seong Joon‐Kyung
Published: December 2023

Background

Generative models have the potential to be beneficial in neuroimaging, as they can produce new data samples that closely resemble the ones they were trained on. This can assist in addressing the scarcity of brain scan data, which is a significant issue in neuroscience.

Method

In this study, we developed a one‐ring convolution‐based generative adversarial network (GAN) to generate ATN biomarkers, which operate on an icosahedron cortical mesh structure on a cortical surface. Data from the Alzheimer’s Disease Neuroimaging Initiative cohort was used in the study, including AV45, AV1451, and T1 magnetic resonance imaging (MRI) scans from 2283 subjects. The cortical thickness of all T1 MRI images was calculated using a Freesurfer pipeline and resampled into icosahedron subdivision level 3. AV45 and AV1451 scans were then converted into standard uptake value ratio (SUVR) and mapped to the cortical surface before being resampled into icosahedron subdivision level 3. For each modality, the proposed GAN was trained and evaluated using density and coverage metrics, which measure the fidelity and diversity of generated samples. Also, we validated the efficacy of the constructed ATN manifolds using the data augmentation scenario. Specifically, we evaluated the performance of tau stage classifiers using cortical thickness data with and without augmenting tau PET data from our manifolds.

Result

Our proposed GAN achieved high performance in density and coverage. Specifically, the density and coverage for the amyloid SUVR were 1.0 and 0.97, for the tau SUVR were 1.34 and 1.0, and for the cortical thickness were 1.66 and 0.98, respectively, showing high performance in generating realistic and diverse samples for all modalities. The effectiveness of our proposed GAN was further demonstrated to show improved performance in the Tau Braak stage classification experiment when using the generated data. When augmented with generated data, the classification accuracy was improved from 0.77 to 0.84 in terms of AUC scores.

Conclusion

Our proposed GAN achieved high performance in density and coverage, generating realistic and diverse samples for each ATN biomarker, and demonstrated improved performance in a Tau Braak stage classification experiment when using the generated data.