bluuebunny/crossref_metadata_2025 huggingface dataset:
Belgian Carriers of Rare ABCA7 Mutations Present with Pronounced Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Authors: de Craen Elisabeth Henndrickx Van , Bossaerts Liene , Sieben Anne , Loos Caroline , Yperzeele Laetitia , Engelborghs Sebastiaan , De Deyn Peter Paul , Van Broeckhoven Christine
Published: December 2022

Background

ABCA7 is a major risk gene for Alzheimer’s disease (AD) and rare premature termination codon (PTC) and missense mutations are enriched in AD patients. In preliminary studies we obtained that ABCA7 PTC and missense mutation carriers present with a classic AD phenotype, but severe levels of cerebral amyloid angiopathy (CAA) were also found (table 1, figures 1‐2). We aim to delineate the clinicopathological phenotype of rare ABCA7 mutation carriers in Belgian CAA patients.

Methods

Genetic screening of ABCA7 in a Belgian CAA cohort (n = 83), with genotype‐phenotype comparison of the ABCA7 carriers using demographics and clinicopathology data.

Results

In 21.4% (18/84) of CAA patients a rare ABCA7 mutation was identified. Seven patients carried a PTC mutation, 10 a rare missense variant, and in one CAA patient we found a deletion. The mean onset age was 66.4±12.8 (range 47‐84) years, while the mean age at death was 68.0±10.3 (range 48‐92) years. In 87.5% (7/8) of patients a positive family history of disease was mentioned. Cognitive decline was present in 52.9% (9/17). Nine patients were diagnosed as probable CAA, and four as possible CAA. In six patients postmortem examination showed moderate‐to‐severe levels of CAA in all but one patient (83.3%, 5/6) and AD neuropathological hallmarks (100%, 6/6). Extensive levels of CAA were present in both the meningeal and capillary blood vessels, and moderate to high levels of CAA in the parenchymal blood vessels (Figure 3).

Conclusions

Our data suggests that rare ABCA7 mutations are frequently present in CAA patients. Carriers show signs of severe levels of CAA, as well as AD neuropathological hallmarks. The findings of this study have important implications for future research and clinical practice.
Machine learning‐enabled epileptiform spike detection stratifies patient subpopulations with Alzheimer’s disease
Authors: Pathmanathan Jay , Laberinto Kim , Robertson Hannah , Hanson Eric , Donoghue Jacob
Published: December 2022

Background

A subpopulation of patients with Alzheimer’s disease exhibit epileptiform activity and have more rapidly progressing disease. Manual identification of these pathological events is infeasible at scale and machine learning tools may establish epileptiform activity as an actionable biomarker for stratification and endpoints within clinical trials.

Methods

Routine EEGs from 90 subjects with AD and 39 subjects with MCI from the Beacon data repository were analyzed via the Beacon Platform harnessing an ML‐enabled interictal epileptiform discharge (IED) detection algorithm, and by expert visual inspection.

Results

IEDs were found in 17 of the 90 subjects with AD (19%), and 8 out of the 39 MCI subjects (20%). In subcategorization, 13% (9 / 71) of AD subjects without epilepsy had IEDs, while 42% (8/19) of AD subjects with epilepsy had IEDs. In the AD/no epilepsy subgroup there were 24 patients taking an Anti‐Seizure Medication (ASM), and 4% (1/24) had IEDs (versus 17% (8/47) of the AD without epilepsy group that were not on ASMs).

Conclusion

Machine learning augmented detection of IEDs allows for rapid, quantitative identification of individuals with subclinical epileptiform activity in patients with AD and MCI. These results demonstrate that AI‐detectable IEDs are seen in a sizable minority of AD patients without epilepsy and in MCI patients, and more commonly in AD patients with epilepsy. Ultimately, automated analysis of EEG data is a promising way to stratify patients and track disease progression while enriching clinical trials with subjects most likely to respond to next‐generation treatments.
MultiTEP‐based conjugated vaccines targeting various phosphorylated tau epitopes are immunogenic and effective in the PS19 mouse model
Authors: Zagorski Karen , King Olga , Hovakimyan Armine , Antonyan Tatevik , Chailyan Gor , Ghazaryan Manush , Petrushina Irina , Cribbs David H. , Davtyan Hayk , Blurton‐Jones Mathew , Ghochikyan Anahit , Agadjanyan Michael G
Published: December 2022

Background

Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and represents a promising immunotherapy target. In theory, targeting an appropriate B‐cell epitope in pathological tau could effectively reduce the pathology without affecting normal native tau. Hyperphosphorylation of tau is a well‐known feature of Alzheimer’s and other tauopathies, with many disease‐specific phosphorylation sites documented. Accordingly, we attached several disease‐related phosphorylated tau peptides to our universal vaccine platform, MultiTEP that is safe and extremely immunogenic in various disease models of AD, rabbits, and aged monkeys. We hypothesized that high immunogenicity of MultiTEP‐based vaccines, coupled with the selectivity of the immune responses, will allow the identification of pathological and protective phosphorylation sites, thus leading to the generation of vaccines, which would preferentially clear the toxic forms of tau without disrupting the normal brain homeostasis.

Method

A genetically engineered variant of MultiTEP was generated to enable chemoselective bioconjugation of synthetic peptides under mild aqueous conditions. MultiTEP‐based vaccines targeting p‐tau 202/205, p‐tau 396/404, p‐tau 422 were tested in the PS19 mouse model of AD and other tauopathies. Antibody specificity and titers were tested via ELISA. Brain total and phosphorylated soluble and insoluble tau were measured by ELISA and IHC.

Result

All three vaccines generated robust and selective immune responses specific to phosphorylated tau in mice. The generated antibodies selectively bound to the appropriate phosphorylated, but not non‐phosphorylated form of the same peptide. Importantly, these antibodies effectively reduce/cleared pathological tau in the brains of immunized mouse model of tauopathy. The MultiTEP immunogenicity was sufficient to generate robust immune responses after two immunizations, even without adjuvant.

Conclusion

MultiTEP‐based conjugated vaccines could be used to generate robust immune responses selective to multiple phosphorylation sites of tau. This, in conjunction with a previous report on MultiTEP‐based pE3Aβ vaccine, suggests that the methodology is universally applicable for various post‐translational modifications. Our technology can facilitate the identification of optimal therapeutic targets of p‐tau for generating an active immunotherapeutic strategy that can be used in conjunction with pE3Aβ vaccine. If successful, preventive vaccinations targeting disease‐related tau and/or Aβ molecules could at least delay AD and related neurodegenerative disorders.
Natural premature menopause relates to higher risk of mild cognitive impairment and Alzheimer’s disease and related dementias in APOE‐ε4 carriers only
Authors: Sundermann Erin E. , Saelzler Ursula G , Shadyab Aladdin H. , Banks Sarah J , Jacobs Emily Goard , Rapp Stephen R. , Wactawski‐Wende Jean , Casanova Ramon , Panizzon Matthew S.
Published: December 2022

Background

Overall risk of Alzheimer’s disease (AD) and APOE‐ε4‐related risk for AD is higher among women than men, but the sex‐specific biological underpinnings of these sex differences are unknown. Earlier age at menopause has been associated with higher risk of AD and related dementias (ADRD); however, it is unclear whether this relationship holds among naturally menopausal (versus surgically menopausal) women only or whether it is impacted by APOE‐ε4 genetic risk. We examined the association of natural premature (occurring ≤40 years of age) menopause with MCI and ADRD risk among older women and whether this relationship was moderated by APOE‐ε4 genotype.

Method

This study included 3,557 older women (age range: 65‐79 years at baseline; all White; 5.3% premature menopause; 25.5% APOE‐ε4 carriers) from the Women’s Health Initiative Memory Study (WHIMS) who experienced menopause spontaneously and not as a result of hysterectomy or bilateral oophorectomy. All participants had data on reproductive history, APOE genotype and longitudinal cognitive evaluations, and were cognitively unimpaired at baseline (follow‐up time: range = 0.92‐24.19, mean = 9.92 years). Incident MCI and ADRD were determined with a comprehensive neuropsychological battery and centrally adjudicated by a panel of specialists with expertise in dementia diagnosis. A set of Cox regression models was applied to determine whether premature menopause and its interaction with APOE‐ε4 carrier status was associated with risk of MCI or ADRD, adjusting for age, education, cardiovascular risk factors, parity, age at menarche, past contraceptive use and current or past hormone therapy use and the timing of initiation relative to menopause.

Result

The APOE‐ε4 X premature menopause interaction was significant (p = .04). Among APOE‐ε4 allele carriers, premature (vs. non‐premature) menopause was associated with an approximate two‐fold increased risk of MCI/ADRD (HR = 2.05, 95%CI: 1.22‐3.44). No such association was present among women without an APOE‐ε4 allele (HR = 1.16, 95%CI: 0.72‐1.86).

Conclusion

Natural premature vs non‐premature menopause was associated with two‐fold higher risk of MCI/ADRD but only among APOE‐ε4 carriers. Results suggest interactive effects of premature menopause and the APOE‐ε4 genotype. Future studies are needed to determine whether the menopause and APOE‐ε4 pathophysiological mechanisms of dyslipidemia, inflammation and brain metabolism deficiencies may explain this association.
Baseline regional Tau distribution predicts fast cognitive decline in subjects with mild cognitive impairment
Authors: Charil Arnaud , Devanarayan Viswanath , Murali Leema , Qi Xin , Krause Stephen , Sachdev Pallavi , Reyderman Larisa , Koyama Akihiko , Dhadda Shobha , Irizarry Michael C
Published: December 2022

Background

Neurofibrillary tangles represent a pathological hallmark of AD that spreads throughout the brain in a relatively stereotypical spatio‐temporal fashion along Braak stages. Understanding the impact of regional Tau distribution and spread on future cognitive decline would be highly valuable for targeted patient selection and treatment strategy in drug development.

Method

Regional flortaucipir (FTP) PET SUVR in 77 brain regions, and Braak stage regions I‐VI, were available from 638 ADNI subjects (89 AD, 117 MCI, 432 age‐matched normal controls). Baseline FTP data, processed at UC Berkeley, was partial volume corrected to reduce off‐target binding contamination. Braak stage II (i.e., hippocampus) was excluded from the analysis due to known off‐target binding in this region.

A machine‐learning (ML) approach via stochastic gradient boosting was applied to determine the characteristics of regional Tau distribution that uniquely reflect AD relative to control subjects. This signature was then applied to PET scans of an independent group of 117 MCI subjects to predict their 24‐month cognitive decline, as defined by an increase in the clinical dementia rating sum of boxes (CDR‐SB). MCI subjects predicted to have ‘control‐like’ Tau deposition signature were considered as slow cognitive decliners while those predicted to have ‘AD‐like’ signature were considered as fast decliners. Prediction performance was evaluated and the regions of Tau deposition indicative of faster cognitive decline were identified.

Result

MCI subjects predicted as fast cognitive decliners had odds ratio of 7.3 relative to those predicted as slow decliners (7.3‐fold greater odds of decline), with the median and 75th percentile increase in CDR‐SB of 1 and 3 respectively, compared to an increase of 0 and 0.5 among those predicted as slow decliners. Subjects with Tau deposition in Braak I (entorhinal cortex) and Braak III at baseline, and particularly in the amygdala, were predicted to be fast decliners. Further presence of Tau in parahippocampal, fusiform and precuneus regions at baseline were strongly associated with fast cognitive decline.

Conclusion

The nature of baseline regional Tau distribution in MCI subjects is a strong indicator of fast cognitive decline that can help inform targeted patient selection and treatment strategy in drug development.
Alternative Theory of AD Pathogenesis: Membrane Delimitation of the Histone Acetyltransferase Tip60/Kat5
Authors: Wiley Jesse C , Young Jessica E. , Jayadev Suman , Darvas Martin , Swerdlow Russell H , Wolfe Michael S. , Heath Laura M , Gockley Jake , Cary Gregory A. , Poehlman William L. , Ladiges Warren , Carter Gregory W , Bothwell Mark A , Greenwood Anna K , Mangravite Lara M
Published: December 2022

Background

For decades, mounting genetic and physiological data have pointed to the APP proteolysis as a seminal event in AD pathogenesis. This data has been viewed as supporting the amyloid hypothesis. However, growing data from multiple disciplines disputes that amyloid is a causal mechanism of neurodegeneration. Evidence suggests that FAD mutations are loss of function, inhibiting normal proteolytic processing of APP. APP extracellular and intracellular domains exhibit a broad array of binding interactions. Tip60 (a histone acetyltransferase, also known as Kat5) is an intracellular binding partner that supports the long‐standing speculation that APP functions as a signaling receptor. Recently, a conditional knockout (cKO) of Tip60 demonstrated neurodegenerative pathology and massive reactive gliosis, supporting a role for Tip60 in neurodegeneration. Reports that Tip60 is restricted from the nucleus in AD patient brains bolsters this idea.

Method

To assess the overlap of the cKO Tip60 model and human AD pathogenesis, we compared the dysregulated gene sets (DEGs) in the cKO Tip60 mouse and late‐onset AD postmortem brains. We break DEGs from mouse and human models into AD “biological domains” (BDs), and perform GSEA of GO enrichment within each BD. We then perform downstream analyses using network reconstruction applications and by examining the enriched BDs with pseudotime measures of disease progression in LOAD patients.

Result

We find significant overlap between DEGs in LOAD patients and the Tip60 cKO in multiple BDs, including, mitochondrial metabolism, immune response, structural stabilization, synaptic function, and endolysosomal trafficking. GSEA of LOAD and cKO Tip60 further implicates similar deficits in both models. The network analysis shows a convergence of gene dysregulation at core nodes, further implicating similar processes of dysregulation may impact particularly significant genes in human and mouse models. The pseudotime analysis shows that this dysfunction is an early signature of AD, suggesting Tip60 dysregulation may trigger early‐stage homeostatic destabilization.

Conclusion

We propose that aberrant APP proteolysis traps Tip60 at the membrane, preventing the nuclear localization of Tip60, and altering both positive and negative gene regulation that is necessary for neuronal and glial homeostasis, and hypothesize that this is an explanation for the genetic linkage of APP proteolytic processing and AD.
Apnea‐associated hypoxemia is linked to greater tau deposition in women with Alzheimer’s disease risk
Authors: Lui Kitty K , Shepherd Alyx L , Wang Xin , Bernier Rachel A , Bosompra Nana , DeYoung Pamela N , Malhotra Atul , Sundermann Erin E. , Banks Sarah J
Published: December 2022

Background

Obstructive sleep apnea (OSA) is characterized by recurrent pharyngeal airway collapse and drops in blood oxygen levels that lead to intermittent hypoxemia. OSA has been associated with Alzheimer’s disease (AD) pathology, including tau. AD is more prevalent in women, and women tend to have higher levels of tau compared to men. OSA is underdiagnosed, particularly in postmenopausal women where OSA risk is similar to men. We conducted a pilot study examining the relationship between OSA and tau using positron emission tomography (PET) in older women at higher risk for AD who participated in the Women Inflammation and Tau Study (WITS).

Method

10 older women (aged 71±3.3 years) were recruited to WITS, which required elevated genetic risk of AD and a Montreal Cognitive Assessment score suggestive of mild cognitive impairment (range 13‐20). A home sleep test was completed to derive the apnea‐hypopnea index (AHI), nadir and mean oxygen saturation (Osat), and proportion of time in bed (TIB) with oxygen saturation ≤88% (Osat≤88%). Participants also underwent MK‐6240 PET to determine tau deposition. Standardized uptake value ratio (SUVR) was computed in temporal meta‐region of interest (ROI) Braak Stages I, III‐IV, and V‐VI. Spearman correlation was used to analyze the associations between OSA characteristics and tau PET SUVR in the respective ROIs.

Result

In this initial sample from WITS, 40% had mild OSA (AHI≥5/h and AHI<15/h) and 40% had moderate OSA (AHI≥15/h and AHI<30/h). Greater proportion of TIB with Osat≤88% was associated with higher tau SUVR in temporal meta‐ROI (rho=0.69, p=0.03), Braak III‐IV (rho=0.70, p=0.03), and Braak V‐VI (rho=0.69, p=0.03). No significant relationships were observed between AHI and tau PET SUVR in the respective ROIs (all p>0.40).

Conclusion

In this small sample of women with elevated AD risk, OSA was evident in the majority. Additionally, we found positive relationships between proportion of TIB with Osat≤88% and tau deposition in temporal and neocortical regions. These findings suggests that OSA‐related intermittent hypoxemia could potentially contribute to the pathogenesis of tau; however, longitudinal studies are needed. Treatment of OSA may be a possible target to reduce or delay the impact of AD.
Peripheral inflammation and cognition in older adults with and without cognitive impairment
Authors: Wong Christina G. , Cross Chad L. , Kinney Jefferson W , Ritter Aaron , Caldwell Jessica ZK , Kramer Joel H.
Published: December 2022

Background

Understanding how different inflammatory markers relate to cognition is important for the development of therapeutic targets in Alzheimer’s disease (AD). However, many studies have relied on a single, broad measure of inflammation or a select handful of markers that have been identified in the AD literature. We examined a large set of plasma inflammatory markers that were statistically grouped via principal component analysis (PCA). Associations between inflammation component scores and cognition were examined.

Method

Participants included 41 cognitively normal (CN) and 64 cognitively impaired (CI; 47 mild cognitive impairment and 17 AD) older adults from the Center for Neurodegeneration and Translational Neuroscience. Composite scores for memory, executive functioning, processing speed, and language were created by averaging age‐adjusted z scores for two tests per domain. Plasma levels of inflammatory cytokines were measured using the Luminex platform and Biorad 48‐plex cytokine assay. Five markers with null values were excluded, and the remaining markers were included in a PCA. Relationships between the inflammation component scores and cognition were examined using linear regression models with inflammatory marker as the predictor and each cognitive composite separately as the dependent variable, with adjustment for education, sex, and clinical diagnosis (CN vs CI).

Result

The PCA produced a 7‐component solution that accounted for 75% of the variance. In the final models, Components 2 (β = 0.260, p = 0.020) and 4 (β = 0.235, p = 0.036) were positively associated with memory, Components 2 (β = 0.231, p = 0.052), 4 (β = 0.260, p = 0.031), and 6 (β = 0.280, p = 0.016) were positively associated with executive functioning, and Components 2 (β = 0.221, p = 0.032) and 4 (β = 0.283, p = 0.007) were positively associated with processing speed. Inflammatory components were not significantly related to language.

Conclusion

Higher levels of peripheral inflammatory cytokines were associated with better memory, executive functioning, and processing speed in older adults, even when accounting for clinical diagnosis. Acute elevations of certain inflammatory markers may be associated with a protective role in cognitive aging. Longitudinal research examining stability of cytokine levels and association with cognition in AD trajectories is needed.
Regulation of T helper 17 to regulatory T cell (Th17/Treg) as mediator of stress‐induced psychological impairment and cognitive deterioration
Authors: Pasinetti Giulio Maria , Yang Eun‐Jeong
Published: December 2022

Background

Chronic stress disrupts immune homeostasis while gut microbiota‐derived metabolites attenuate inflammation, thus promoting resilience to stress‐induced immune and behavioral abnormalities. There are both peripheral and brain region‐specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of cognitive deterioration in a mouse model of Alzheimer’s disease (AD) type cognitive deterioration

Methods

Chronic unpredictable stress was performed in wild‐type mice. Mice were treated with a combination of either prebiotics and probiotics (synbiotics) or vehicle. Mice were assessed for behavioral changes including mood and cognitive dysfunction. RNAseq was in performed in the gut and correlative analyses of behavior and inflammatory responses in the brain were conducted.

Results

Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic’s effect on the ileum’s inflammatory response to stress. Synbiotic treatment attenuated the stress‐induced immune and behavioral aberrations in both the ileum and the brain while in a gut‐immune co‐culture model, the synbiotic‐specific metabolites promoted anti‐inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic‐stress induced behavioral impairments while defining a putative mechanism of gut‐microbiota host interaction for modulating cognitive functions through modulationof of the peripheral and brain immune systems.

Conclusion

This study shows that a combination of probiotics and polyphenol‐rich prebiotics, a synbiotic, attenuates the chronic‐stress induced inflammatory responses in the ileum and cortical‐hippocampal regions promoting resilience to the consequent cognitive deterioration in male mice.
Consensus Automatic Speech Recognition (CASR) in Cognitive Testing
Authors: Herron Timothy J , Hall Kathleen , Sucich Gabriel , Blank Michael , Geraci Kristin , Baldo Juliana , Woods David L.
Published: December 2022

Background

Scoring verbal cognitive tests with automatic speech recognition (ASR) engines increases the efficiency of scoring and provides word timestamps that enable detailed temporal analyses of spoken responses. Here, we describe consensus ASR (CASR) procedures that incorporate multiple ASR engines to increase transcription and timing accuracy and generate CASR transcript confidence scores.

Method

Seven ASR engines produced automatic transcriptions of both speech database samples (GMU Speech Accent Archive and NUS Auditory English Lexicon Project) and verbal test responses of 41 subjects from the California Cognitive Assessment Battery (CCAB). A novel Recognizer Output Voting Error Reduction (ROVER) algorithm was used to mutually align the transcripts, and a Bayesian weighted voting algorithm produced the best CASR transcript, mean word timestamps, and consensus scores. Word error rates (WER) gauged CASR accuracy against either predetermined or manually corrected transcripts.

Result

Database sentence WERs from 1767 subjects ranged from a mean of 22% (Windows10 UWP) to 6% (Rev.ai) with CASR producing 5%, with no significant gender or age effects but better performance for native english speakers (Figure 1). In CCAB test responses, for limited word response tests CASR WERs ranged from 3% to less than 1% (Figure 2); for expansive word response tests CASR WERs ranged from 8% to 2% (Figure 3); and for discursive speech, CASR WERs ranged from 6% to 5%. Word start time ASR estimates for 594 database words in lists ranged in mean deviations from true times from 250ms std.dev. (Google) to 17ms std.dev. (Amazon) with CASR obtaining 14ms errors (Figure 4). Finally, consensus confidence scores from CCAB test responses, ranging from 0 to 1 (1 = complete agreement across ASR engines), show that CASR words with consensus scores above 0.8 and 0.9 are correct >99% and >99.8% of the time, respectively (Figure 5).

Conclusion

CASR produces transcripts for verbal test responses accurate enough for estimating scores in most limited word response tests. In large vocabulary response tests, CASR transcripts facilitate quick manual correction, and confidence values can identify transcript words needing manual correction. Patterns in CASR errors also indicate future substantial reductions to CASR WER on a per test basis.
Modeling retinal Alzheimer’s disease histopathology with human iPSC‐derived retinal organoids for mechanistic and DRUG DEVELOPMENT studies
Authors: Vergara M. Natalia , Vielle Anne , Li Helen T. , James Ethan , Johnson Noah R , Chial Heidi J , Potter Huntington
Published: December 2022

Background

The neuropathological features that characterize Alzheimer’s disease (AD), including the presence of beta‐amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of abnormally phosphorylated Tau proteins (pTau), are manifested not only in the brain but also in the retina, an extension of the central nervous system. This is likely to contribute to the visual manifestations of AD that can pose additional challenges to this vulnerable population. Moreover, due to its accessibility and the availability of non‐invasive imaging technologies, the retina is being investigated as a potential biomarker of AD progression. In this context, hiPSC‐derived retinal organoids offer new opportunities for AD modeling that present advantages for DRUG DEVELOPMENT applications. Retinal organoids mimic the histoarchitecture of the native retina, have a consistent cellular composition, and are optically clear. Moreover, 3D automated reporter quantification (3D‐ARQ) technologies have been established to facilitate quantitative assay design in these models without loss of their 3D structure. Thus, we set out to develop and characterize an hiPSC‐derived retinal organoid model of AD that can be applied to the evaluation of pathophysiological mechanisms and to the validation of potential therapeutic drugs.

Methods

Human iPSC‐derived retinal organoids were generated from three healthy control (HC) and two familial AD (fAD) donors using the Zhong et al. (2014) protocol. Organoid structure, cellular composition and AD histopathology were assessed at three and six months of differentiation by immunoblotting and immunofluorescence staining, including retinal cell type‐specific markers as well as Aβ, pathological pTau forms, and NIAD‐4 staining for amyloid plaques. We also developed a NIAD‐4 fluorescence‐based assay for amyloid quantification in intact organoids using 3D‐ARQ technology.

Results

We found similarities in the cellular composition of AD and HC retinal organoids, confirming the validity of the models. However, pathological Tau hyperphosphorylation and Aß deposits were significantly increased in AD retinal organoids compared to HCs. Finally, we developed proof of concept of a quantitative assay for amyloid plaque detection that is amenable to translational research applications.

Conclusions

Our AD retinal organoid models mimic critical aspects of the histopathology of the human AD retina and constitute valuable tools for the screening and validation of candidate molecules with therapeutic potential.
CSF Biomarkers of Amyloid and Tau Pathologies in Participants Enrolled in the Stanford Alzheimer’s Disease Research Center
Authors: Ramos Benitez Javier A. , Wilson Edward N. , Swarovski Michelle S. , Shahid Marian , Corso Nicole , Channappa Divya , Belnap Malia , Tian Lu , Kerchner Geoffrey A. , Sha Sharon , Henderson Victor , Longo Frank M. , Wyss‐Coray Tony , Poston Kathleen L , Mormino Elizabeth C. , Andreasson Katrin I.
Published: December 2022

Background

Heterogeneity in the clinical presentation of Alzheimer’s disease (AD) underscores the importance of biomarker‐defined diagnosis for use in medicine, research and clinical trials. Therefore, CSF measurement of amyloid and tau is an important tool in the diagnostic toolbox for inferring AD‐related brain pathologies. Because differences in preanalytical handling and in study population demographics render it difficult to apply a set of global concentration cut points for defining normal/abnormal for each analyte, it is critical that analyte cut points representing normal/abnormal be determined in a center‐specific manner.

Method

This is a cross‐sectional analysis of CSF collected from participants enrolled in the ongoing prospective cohort study of the Stanford Alzheimer’s Disease Research Center. Participants underwent lumbar puncture and cognitive evaluation to receive a diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or AD. The current study included cognitively normal adults (n=78), individuals with MCI (n=36), and individuals with AD (n=26). Core CSF AD biomarkers p‐tau181, total tau, Aβ42 and Aβ40 were measured (Lumipulse G1200 platform, Fujirebio US, Inc). Cutpoints identifying normal/abnormal amyloid and tau were generated using the Youden method and Amyloid+ was defined as abnormally low CSF Aβ42/Aβ40 while Tau+ was defined as abnormally elevated CSF p‐tau181 and/or total tau.

Result

Classification by amyloid and tau biomarkers revealed that in this population, 64.1% (n=50) CU were biomarker negative for tau or amyloid pathology. However, 28.2% (n=22) of the CU were Amyloid+, 5.1% (n=4) were Amyloid+ and Tau+, and 2.6% (n=2) were Tau+ alone. In the MCI diagnostic group, 33.3% (n=12) were Amyloid+ alone, while 30.6% (n=11) were both Amyloid+ and Tau+, and 5.6% (n=2) were Tau+ alone. 30.6% (n=11) were both Amyloid‐ and Tau‐. Within those receiving an AD diagnosis, 23.1% (n=6) had CSF biomarker evidence for being Amyloid+ only, 65.4% (n=17) were both Amyloid+ and Tau+, and 11.5% (n=3) participants had no biomarker evidence for Amyloid+ or Tau+.

Conclusion

These results highlight the heterogeneity underlying amyloid and tau pathology in clinically defined diagnostic groups. Biomarker‐defined diagnosis using center‐specific cut points will support accurate diagnosis, treatment, clinical research and enrollment in clinical trials.
Associations Between Mild Behavioral Impairment (MBI‐C) Affective Domains and Alzheimer’s Disease Neuroimaging Biomarkers in Older Adults
Authors: Mayblyum Danielle V. , Quiroz Yakeel T. , Langella Stephanie , Udeogu Onyinye J. , Jacobs Heidi I.L. , Rubinstein Zoe B. , Sperling Reisa A. , Johnson Keith A. , Blacker Deborah , Marshall Gad A , Gatchel Jennifer R
Published: December 2022

Background

Previous work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer’s disease (AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD.

Method

21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers.

Result

GDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p<0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants.

Conclusion

Preliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology.
Midlife and current physical activity is associated with functional brain connectivity in older age
Authors: Ai Meishan , Morris Timothy Peter , Thovinakere Nagashree , de la Colina Adrián Noriega , Tremblay‐Mercier Jennifer , Villeneuve Sylvia , Kramer Arthur , Geddes Maiya R. ,   the PREVENT‐AD Research Group
Published: December 2022

Background

Previous studies have shown a physically active lifestyle in both midlife and later life to benefit cognition and brain health in older age. However, exploring the influence of physical activity engagement on functional brain connectivity is needed to fully understand the neural mechanism underlying the effect of physical engagement. Additionally, in order to give lifestyle advice to different age groups, it is important to understand the unique contributions of physical activity at different life stages, which has rarely been examined.

Method

The current study investigated the effect of self‐reported midlife and current physical activity engagement on functional connectivity among 105 cognitively high functioning older adults (age = 66.6±4.1). Self‐reported midlife and current moderate‐to‐vigorous physical activity (MVPA) were recorded using the Lifetime Total Physical Activity Questionnaire. We included covariates in all analyses (i.e., age, sex, years of education, socioeconomic status, genetic risk of Alzheimer’s disease (i.e., APOE ε4 carrier status). Five regions of interest (ROIs) were selected based on previous literature on the relationship between exercise and brain health which included: prefrontal (i.e., bilateral superior frontal, middle frontal, and pars opercularis of the inferior frontal gyrus), and bilateral hippocampus.

Result

Results showed that people who were active in midlife had greater functional connectivity between middle frontal gyrus and superior parietal region, postcentral gyrus (Voxel p<0.005, Cluster p<0.05 FDR corrected; figure 1a) than people who were relatively inactive in midlife. This effect stayed the same after controlling for current MVPA time. Secondly, the results showed that people who were active currently have greater functional connectivity between hippocampus and frontal pole (Voxel p<0.005, Cluster p<0.05 FDR corrected; figure 1b). Currently active participants also showed greater functional connectivity between pars triangularis of the inferior frontal gyrus, and bilateral middle temporal region, and frontal pole (Voxel p<0.001, Cluster p<0.05 FDR corrected; figure1c) compared to currently inactive participants, which stayed consistent after controlling for midlife MVPA time.

Conclusion

As a conclusion, although midlife and current MVPA time were positively associated with each other, they both influence brain functional connectivity in later life independently. The results emphasize the importance of keeping a physically active lifestyle across midlife and into later life.
Associations between intergenerational transmission of AD, type 2 diabetes, and cognitive function among non‐Hispanic Black adults in midlife
Authors: Kraal A.Zarina , Palta Priya , Brickman Adam M. , Manly Jennifer J
Published: December 2022

Background

Type 2 diabetes (T2D) and parental history of Alzheimer’s disease (AD) are independent risk factors for late‐life cognitive impairment. The presence of T2D may strengthen the association of parental AD risk on cognition through pathways of vascular function, insulin signaling, and amyloid β/tau metabolism. Examining the independent and interactive association of parental AD risk and T2D on cognitive function, specifically in non‐Hispanic Black adults may advance our understanding of their contribution to the disproportionate rates of AD in this group. We hypothesize that parental AD risk and T2D would be independently associated with worse cognition and that the association between parental AD risk and cognition would be stronger in participants with T2D.

Method

Participants comprised non‐Hispanic Black adults (N = 331; 25.8% with T2D; Table 1) in the Offspring Study who are the adult children of participants in the Washington Heights Inwood Columbia Aging Project (WHICAP). AD risk was operationalized as parental memory performance residualized for age and education and assessed at their last WHICAP visit. Participant T2D was based on self‐reported physician diagnosis and cognition was assessed with measures of attention, language, and memory. Cognitive test scores were residualized for age and education (Table 1). Linear regression models quantified the independent associations and interaction of AD risk and T2D on offspring cognition.

Result

T2D was associated with lower language (B = ‐0.13, 95% CI: [‐0.55, ‐0.08]) and memory (B = ‐0.45, 95% CI: [‐0.72, ‐0.17]) scores, but AD risk was not associated with cognition in any domain. However, AD risk was associated with lower language scores among participants without T2D, but not in participants with T2D (B = ‐0.36, 95% CI [‐0.71, ‐0.02]; Figure 1). No interaction was observed for AD risk and T2D with memory and attention (Figure 2).

Conclusion

Our results suggest that among middle‐aged non‐Hispanic Black adults, AD risk is associated with lower language performance in individuals without T2D. The association between AD risk and cognition may be masked by exposure to risk factors, such as T2D.
Cognition in the Oldest Old Using the NIH Toolbox
Authors: Mather Molly A , Ho Emily , Karpouzian‐Rogers Tatiana , Rogalski Emily J. , Gershon Richard C. , Weintraub Sandra
Published: December 2022

Background

The percentage of cognitively intact older adults living into their 80s and beyond is growing rapidly. This age group is not only one of the fastest growing segments of the population, but it is also the group most susceptible to developing dementia. Effective detection of early cognitive decline is paramount but is complicated by a dearth of normative data for older adults above the age of 85. It is well‐established that crystallized cognition remains stable into older adulthood, whereas fluid cognition tends to decrease; however, it is unknown whether the same holds true for the oldest old. We use the comprehensive NIH Toolbox Cognition Battery (NIHTB‐CB) to assess differences in cognition.

Method

Participants (age range 65 to 94) were diagnosed as having normal cognition and were either 65–85 years old (N = 175, Mage
 = 73.9, SDage
 = 6.06) or 86+ (N = 98, Mage
 = 88.6, SDage
 = 2.39). Participants completed the NIHTB‐CB, which assesses fluid reasoning, executive functioning, processing speed, episodic memory, and crystallized language abilities. A series of univariate linear models regressed age with covariates (education, gender, race/ethnicity, site) on each NIHTB‐CB domain.

Result

Age was a significant predictor for all NIHTB‐CB fluid measures. The R2 for each fluid reason model ranged from 0.17 to 0.22, suggesting a medium effect size. Of the crystallized measures, Picture Vocabulary decreased with age, while oral reading ability remained constant. The effect for Picture Vocabulary appears to be at least partially driven by education levels, as more educated participants exhibited higher scores. For all statistically significant models, age remained a significant predictor after adjusting for demographic covariates and site. The fluid measure with the steepest decline was Picture Sequence Memory and Pattern Comparison, while the fluid measure with the least steep decline was Flanker.

Conclusion

As expected, fluid reasoning ability decreased with age in the oldest old. Contrary to theoretical expectations of stability across crystallized abilities, scores on one crystallized measure decreased with age. This study comprehensively characterizes the oldest old across multiple facets of cognition and adds to the extant literature regarding cognitive performance in the oldest old.
Influence of Socioeconomic Opportunity Disparities on Sex/Gender Inequalities in Cognitive Decline
Authors: Avila Justina F , Seblova Dominika , Turney Indira C , Schupf Nicole , Mayeux Richard , Brickman Adam M. , Manly Jennifer J
Published: December 2022

Background

State‐level socioeconomic opportunity disparities have been linked to health outcomes. We examined whether early‐life exposure to state‐level socioeconomic opportunity disparities between women and men influences the pattern of sex/gender inequalities in cognitive decline.

Method

Participants were 2,394 U.S.‐born non‐Latinx Black and non‐Latinx White women and men enrolled in the Washington Heights/Inwood Columbia Aging Project (WHICAP), who were dementia free at their baseline study visit. Age at first cognitive assessment ranged from 61‐101 and the average follow‐up time was 4.8 years. Cognitive outcomes were level and trajectory on memory and language scores. A socioeconomic opportunity disparity index (SODI) was created using census data on sex/gender disparities in labor force participation, occupational status, and educational attainment between the years 1900 to 1960 (birth year range for WHICAP participants). The SODI ranged from 0 to 1, with higher scores reflecting wider sex/gender disparities in socioeconomic opportunities. SODI values were linked to WHICAP individual data via birth year and state. Multiple‐group growth curve modeling was used to examine interactions between sex/gender and SODI on cognitive trajectories across racial groups. All models accounted for age, childhood SES, and state of birth, as well as differential study attrition due to death.

Result

Smaller disparities in state‐level opportunity were associated with 1) higher baseline cognitive test performance across groups and 2) slower memory and language decline for Black women and White women and men. Women demonstrated an advantage over men on cognitive measures and we expected women’s advantage to be more pronounced in states with lower opportunity disparities. This pattern held true for Black individuals with regards to memory and language level and for memory decline among White individuals. However, White women’s advantage over White men on baseline memory was more pronounced in states with higher opportunity disparities.

Conclusion

Being born in a state where socioeconomic opportunities were more equally distributed among women and men was positively linked to cognitive outcomes later in life. Our results suggest that this relationship varies across men and women depending on their race, contributing to different patterns of sex/gender inequalities in late‐life cognitive trajectories.
Effects of Eicosapentaenoic Acid Supplementation in obese Transgenic Mouse Model of Alzheimer’s Disease
Authors: Razafimanjato Fitia , Yavari Mahsa , Chavira Angela , Davis Mckenna , Ramalingam Latha , Harris Breanna N. , Zu Yujiao , Moustaid‐Moussa Naima
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive brain disease characterised by cerebral aggregation of amyloid beta (Aβ) plaques. Obesity is a chronic complex disease characterised by excessive fat accumulation, that is associated with systemic and adipose tissue inflammation, and may increase the risk for AD. Eicosapentaenoic acid (EPA) found in fish oil, is an omega‐3 polyunsaturated fatty acid with anti‐obesity and anti‐inflammatory properties. In this study, we propose that EPA supplementation will protect against AD‐associated metabolic dysfunctions in diet‐induced obese mice. We aim to determine the mechanisms mediating EPA effects in obesity‐related metabolic impairments in diet‐induced obese APPswePS1dE9 AD mouse model.

Method

Wild‐type (WT) and transgenic Alzheimer’s (TG) male and female mice were randomly assigned to either a low‐fat LF (10% kcal fat), a high‐fat (HF, 45% kcal fat), or a HF diet supplemented with 36 g/kg EPA (EPA) for 8 months. Body weights were measured weekly and tissues including adipose tissue were collected at the end of the intervention for analyses of genes involved in inflammation (TNF, fatty acid synthesis (ACACA), fatty acid oxidation (CPT1). Data were analysed by three‐way ANOVA using GraphPad Prism.

Result

Overall, TG females gained less weight in HF and EPA groups, compared to male mice (P = 0.0075 and P < 0.0001, respectively). Moreover, TNF was lower in EPA groups compared to HF groups. Significant main effects were observed for sex in TNF, ACACA, and CPT1 (P<0.0001, P=0.0008, and P<0.0001, respectively). Main effects for genotype were observed for ACACA and CPT1 expression (P=0.0497 and P=0.0318, respectively). Main effects for diet (LF vs HF) were observed for TNF, ACACA, and CPT1 (P=<0.0001, P=0.0004, and P=0.0040, respectively). Moreover, significant main effects of HF vs EPA were observed for ACACA (P=0.0497). Interactions in sex x diet (LF vs HF and HF vs EPA) were observed for TNF (P=0.0003 and P=0.0252, respectively), also in sex x diet (LF vs HF) interactions for CPT1 (P=0.0086).

Conclusion

Our findings showed that EPA counteracted both inflammation and obesity induced by HF diets, especially in female mice. Further analyses are ongoing to determine mechanisms underlying potential benefits of EPA in obesity‐associated AD.