bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood phosphorylated tau 181 predicts early, preclinical brain amyloid deposition
Authors: McGrath Emer R. , Beiser Alexa S. , Yang Qiong , Ghosh Saptaparni , DeCarli Charles S. , Himali Jayandra J. , O’Donnell Adrienne , Satizabal Claudia L. , Johnson Keith A. , Tracy Russell P. , Seshadri Sudha
Published: December 2021

Background

Plasma phospho‐tau181 is a promising new biomarker for Alzheimer’s disease (AD) with greater specificity than t‐tau and greater convenience compared to cerebrospinal fluid or neuroimaging biomarkers. However, its association with regional brain cortical amyloid and tau deposition is not well characterized. We evaluated 1) the association between plasma p‐tau181 levels and regional cortical amyloid and tau deposition and 2), determinants of circulating phospho‐tau181 levels.

Method

Plasma p‐tau181 levels were measured in 52 [48% women, mean age 64.4 (SD 5.5)yr] cognitively normal Framingham Heart Study Offspring cohort participants at examination cycle nine (2011‐2014) who subsequently underwent 11C‐Pittsburgh Compound‐B (PiB)‐PET and/or 18F‐Flortaucipir (FTP)‐PET scans. We related phospho‐tau181 levels to PiB‐PET (composite of frontal, lateral temporal and parietal and retrosplenial cortices [FLR], as well as individual cortical regions) and FTP‐PET (entorhinal, inferior temporal and precuneus regions). Additionally, we compared p‐tau181 with plasma neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) in predicting brain amyloid deposition.

Result

The mean time from plasma biomarker measurement to brain‐PET was 6.8 (SD 0.6)yr. On linear regression analysis adjusted for age, sex and time to PET, log p‐tau181 was associated with increased FLR (SE, 1.24±0.30, p<0.0001), precuneus (1.35±0.30, p<0.001), superofrontal (1.10±0.31, p=0.001), superotemporal (1.24±0.30, p<0.001) and insular amyloid deposition (1.17±0.31, p<0.001). Plasma p‐tau181 was not associated with tau‐PET deposition in the entorhinal (‐0.31±0.63, p=0.63), inferotemporal (‐0.19±0.64, p=0.77) or precuneus (‐0.05±0.64, p=0.94) regions, n=21 with available tau‐PET. Log NFL (1.30±0.49, p=0.01) and GFAP (1.46±0.39, p<0.0001) showed univariate associations with FLR amyloid deposition. On multivariable analysis adjusting for age, sex, apoE4 allele, AD polygenic risk score and all three biomarkers, p‐tau181 (0.92±0.31, p=0.005) and GFAP (0.92±0.41, p=0.03), but not NFL (0.25±0.51) remained associated with FLR amyloid deposition. Total cholesterol was the only vascular risk factor associated with circulating p‐tau181 levels (‐0.004±0.001, p=0.01).

Conclusion

Elevated plasma phospho‐tau181 is associated with preclinical cortical amyloid (but not tau) deposition in a relatively young, cognitively normal sample. Circulating levels of p‐tau181 appear to be independent of vascular risk factors, highlighting the potential of phospho‐tau181 as a robust and generalizable blood‐based biomarker for AD dementia in a community‐based setting. Additional studies replicating our findings are warranted.
CSF amyloid, tau, and neurodegeneration biomarkers are associated with longitudinal cognitive decline in preclinical AD
Authors: Cody Karly Alex , Betthauser Tobey J. , Hulle Carol A. , Koscik Rebecca L. , Jonaitis Erin M. , Clark Lindsay R. , Chin Nathaniel A. , Okonkwo Ozioma C. , Bendlin Barbara B. , Asthana Sanjay , Suridjan Ivonne , Kollmorgen Gwendlyn , Zetterberg Henrik , Carlsson Cynthia M. , Blennow Kaj , Johnson Sterling C.
Published: December 2021

Background

This work examined heterogeneity in cognitive trajectories between amyloid(A) and tau(T) cerebrospinal fluid (CSF) stratified biomarker groups in late‐middle‐aged, initially cognitively unimpaired individuals. Additionally, candidate biomarkers of neurodegeneration were investigated for potential added value in predicting cognitive decline.

Method

Individuals (N=535) recruited from Wisconsin Alzheimer’s Disease Research Center (n=301) and Wisconsin Registry for Alzheimer’s Prevention (n=234) underwent a lumbar puncture and serial (1 to 9) cognitive assessments (Table 1). CSF biomarkers were measured using the exploratory Roche NeuroToolKit assays (Roche Diagnostics International Ltd). Four biomarker groups (A‐T‐, A‐T+, A+T‐ and A+T+) were established based on combinations of CSF Aβ42/40 and p‐tau biomarker positivity, where (A) and (T) positivity was determined as CSF Aβ42/40≤0.046 and CSF p‐tau≥24.8 pg/mL. Decline on a Preclinical Alzheimer’s Cognitive Composite (PACC‐3) was investigated using linear mixed effects models (including subject‐specific random intercepts and age‐related slopes) adjusting for sex, education, cohort, and the number of prior exposures to the cognitive battery. In primary analyses, the predictors of interest included the biomarker group and its interaction with age to investigate whether longitudinal PACC‐3 trajectories differed between biomarker groups. Secondary models added one of the following biomarkers for neurodegeneration and its interaction with age: neurofilament light chain (NfL), neurogranin, or alpha‐synuclein. Models were compared against the primary model using the Akaike information criterion and log likelihood ratio tests.

Result

The results from the primary model indicated a significant biomarker group×time interaction (P<.001, Figure 2). Tukey‐adjusted pairwise comparisons indicated that the A+ groups (A+T‐ and A+T+) had significantly different PACC‐3 trajectories compared with the A‐T‐ group (P<.0001, Figure 2). Comparison of the simple age‐related slopes suggest that the A+T+ group was declining approximately 3.6 times faster compared with those without elevated biomarkers. Higher NfL, but not neurogranin or alpha‐synuclein, was associated with PACC‐3 decline after accounting for AT(+/‐) status (Table 2).

Conclusion

In this preclinical sample, cognitive decline was evident in A+ groups. Secondary analyses suggest that NfL may contribute additional value to the AT(neurodegeneration) framework in explaining cognitive decline before the onset of dementia.
Interaction of obstructive sleep apnea severity and amyloid burden on novel plasma biomarkers of tau and neurofilament light protein in community‐dwelling cognitively normal older‐adults
Authors: Bubu Omonigho Michael M. , Umasabor‐Bubu Ogie Queen , Williams Ellita T. , Turner Arlener D. , Williams Natasha , Jean‐Louis Girardin A. , Osorio Ricardo
Published: December 2021

Background

Recent evidence suggest that plasma Tau and neurofilament light (NfL) have high potential as markers of neurodegeneration in Alzheimer disease (AD). Obstructive sleep apnea (OSA) severity increases AD risk and is associated with well‐validated markers of AD pathology in cognitively normal older‐adults. We determined the independent and combined effects of OSA severity and amyloid burden on plasma levels of Tau, and NfL, in community‐dwelling cognitively normal older‐adults.

Method

Cross‐sectional analysis of baseline data from 70 community‐dwelling cognitively normal older‐adults, selected from ongoing NYU prospective longitudinal studies on memory, sleep and aging. CSF‐Aβ42 (measured using ELISA) quantified amyloid burden. OSA severity was defined using AHI4%. Levels of plasma Tau and NfL were determined using single molecule array (SIMOA) technology ultra‐sensitive assays. Associations of OSA severity and plasma Tau and NfL were assessed using Pearson correlation analysis. The interactive associations of OSA severity and CSF‐Aβ42 levels on plasma Tau and NfL was assessed using generalized linear models. Analyses were adjusted for age, sex, BMI, education and APOE4.

Result

Of the 70 participants, 42 (60%) were women. Mean (SD) age was 68.7 (7.1) years. Mean (SD) AHI was 11.4/hr. (13.7) {29 (40%) had AHI <5, 20 (25%) had AHI: 5 to ≤ 15, 11 had AHI: 15 to ≤30 and 10 had AHI >30}. Independent of CSF‐Aβ42, OSA severity was not associated with plasma Tau (r=.11, p‐value=.38), or plasma NfL (r=.05, p‐value=.67). The interactive associations of OSA severity and CSF‐Aβ42 levels on plasma Tau (β =0.042; 95% CI, 0.013 to 0.070) and NfL (β = 0.055; 95% CI, 0.022 to 0.089) were significant, P < .05 for all. The analysis was not powered for generating dichotomized strata specific (i.e. OSA+/Aβ+, OSA+/Aβ‐, OSA‐/Aβ+ and OSA‐/Aβ‐) estimates.

Conclusion

In this sample of cognitively normal older‐adults, OSA severity was not associated with plasma levels of Tau and NfL. However, β estimates of the interactive associations of OSA severity and CSF‐Aβ42 levels suggest that their combined effect is associated with higher plasma levels of Tau or NfL. Larger cohorts are necessary to delineate mechanisms and examine for OSA/Aβ strata‐specific estimates.
Pilot study of genome‐wide differences in DNA methylation among older adults with normal cognition and mild cognitive impairment, with and without neuropsychiatric symptoms
Authors: Vyas Chirag M. , Gatchel Jennifer R. , Sadreyev Ruslan I. , Kang Jae Hee , Mischoulon David , Reynolds Charles F. , Chang Grace , Manson JoAnn E. , DeVivo Immaculata , Blacker Deborah , Okereke Olivia I
Published: December 2021

Background

Genome‐wide DNA methylation assay (DNAm) reflects epigenetic aging and differences in gene expression, and may help to elucidate the role of systemic aging in cognitive decline. Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and may increase the risk of progression to dementia. However, few investigations have addressed whether genome‐wide differences in DNA methylation underlie presentations of NPS in MCI.

Method

We included 45 older participants (mean age=70 years) from a depression prevention ancillary study (VITAL‐DEP) to the VITamin D and OmegA‐3 TriaL. We defined 3 groups: cognitively normal (CN; n=20); amnestic MCI (aMCI; n=16); non‐amnestic MCI (naMCI; n=9). Genomic DNA was extracted from leukocytes; DNA methylation was assayed using Illumina MethylationEPIC (Methyl850K chip). DNAm age metrics were computed using Horvath methods; genome‐wide differential methylation was examined among the 866,836 CpG sites in MethylationEPIC. Annotations were performed using Gene Ontology (GO) databases and tools.

Result

The sample was balanced by age and sex across cognitive groups (CN and MCI). Participants with MCI had higher DNAmAge compared to those with CN [median (interquartile range): 66.4 (63.5‐71.1) vs. 65.3 (63.4‐69.2)]. Comparing MCI vs. CN, there were 48 CpG sites at p<1x10‐4, but not genome‐wide‐significant, suggesting possible differential methylation in novel genes. For example, over‐representation analysis revealed genes associated with dysregulation of the tight junction (ACTR3, TUBA4A, JUN) and one‐carbon folate pathways (DPYD, GART), suggesting blood‐brain barrier dysfunction and metabolic dysregulation. Comparing MCI with vs. without NPS, there were 49 CpG sites at p<1x10‐4, but not genome‐wide significant. Top hits in GO suggested involvement of negative regulation of neuron projection development (KANK1, RAP1GAP2), activation of protein kinase C activity (PARD3, F2R), regulation of blood coagulation (STXBP5, F2R), and glycosaminoglycan degradation (HSPG2, HGSNAT). Functional annotations suggested involvement of important cellular pathways (e.g., serotonergic synapse, alpha‐linolenic metabolism, calcium signaling). Further, several identified genes had prior reports as summarized in the AlzGene database (e.g., PPP1R10, HSPG2).

Conclusion

Genome‐wide differential methylation in DNAm analysis suggested potential genomic variations in MCI vs. CN and in NPS among patients with MCI. If confirmed, such genomic biomarkers could inform development of targets in prevention studies.
Development of small‐molecule tau‐SH3 interaction inhibitors that prevent amyloid‐β toxicity
Authors: Roth Jonathan R , Rush Travis , Pugh Derian A , Dean Hunter B , Cochran J. Nicholas , Thompson Samantha J , Aldaher Adam R , Mesina Jacob S , Ruiz Pedro , Pathak Vibha , Wu Mousheng , Bostwick J Robert , Suto Mark J , Augelli‐Szafran Corinne E , Roberson Erik D.
Published: December 2021

Background

Alzheimer’s disease (AD) is the leading cause of dementia and lacks disease‐modifying treatments. Tau‐based therapies are attractive and Tau reduction prevents amyloid‐induced dysfunction in preclinical AD models. Tau reduction also prevents amyloid‐independent dysfunction in diverse disease contexts, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau’s interaction with SH3 domain containing proteins likely underlie mechanisms of amyloid‐induced dysfunction, so we targeted their interaction as a therapeutic strategy.

Method

We previously designed a peptide Tau‐SH3 interaction inhibitor based on the region of Tau that binds FynSH3, and determined that it prevented amyloid‐induced dysfunction in primary neurons. We next completed a high‐throughput screen to identify compounds that inhibit Tau‐Fyn interaction. Here, we studied a top hit from that screen, generated and characterized a series of daughter compounds, and tested whether the compounds prevented amyloid‐induced dysfunction in primary neurons.

Result

The hit compound, SR31627, prevented amyloid‐β toxicity in primary neurons. The medicinal chemistry program resulted in lead compound SR42667, which had five‐fold improved potency and improved drug‐like properties. We found that SR42667 binds Tau, is cell‐permeable, and prevents amyloid‐induced dysfunction.

Conclusion

We demonstrate that Tau‐SH3 interactions can be targeted using small molecule inhibitors and that these inhibitors have efficacy for blocking amyloid‐induced dysfunction.
The relationship between subjective hearing impairment and mild behavioral impairment – A study of older adults without dementia in the COMPASS‐ND Study
Authors: Guan Dylan X. , Gosselin Penny , Chen Hung‐Yu , Pichora‐Fuller M. Kathleen , Phillips Natalie , Smith Eric E. , Ismail Zahinoor
Published: December 2021

Background

Hearing loss and mild behavioral impairment (MBI) are both early warning signs of cognitive decline and dementia in older adults and have been recommended for use as non‐cognitive markers of dementia. To date, few studies have directly investigated the relationship between these two markers.

Method

Baseline data from 219 non‐demented participants (10 cognitively normal; CN, 48 subjective cognitive decline; SCD, 161 mild cognitive impairment; MCI) in the COMPASS‐ND study (February 2020 release) were analyzed. Hearing impairment was measured in three ways: with a 10‐item self‐report measure using the Hearing Handicap Inventory for the Elderly – Screening Version (HHIE‐S), with a speech and noise test using the Canadian Digit Triplet Test (CDTT), and with screening audiometry using 2 discrete input levels at 2000 Hz to generate 6 hearing loss categories. Global and domain‐specific MBI burden was approximated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) with a published algorithm. Multivariable linear regressions were conducted to examine the association between the three hearing impairment measures and global MBI burden, adjusting for sex, age, education, hearing aid use, and Montreal Cognitive Assessment (MoCA) score or diagnosis. Multivariable logistic regressions were used to investigate whether the hearing variables could predict MBI domains.

Result

Half of all participants showed MBI symptoms (Figure 1). Greater self‐reported hearing impairment measured by the HHIE‐S was significantly associated with greater global MBI burden and the presence of apathy and affective dysregulation when controlling for global cognition or diagnosis (Table 1). These associations remained significant in analyses restricted to MCI alone. Performance on CDTT and screening audiometry, were not associated with global or domain‐specific MBI burden.

Conclusion

The HHIE‐S, which was designed to capture the emotional and social aspects of hearing loss, was positively related to global MBI burden and more specifically to apathy and affect. Unlike audiometry and speech and noise measures, self‐reported measures of hearing impairment can be influenced by age, sex, other comorbidities, and social factors. Our findings underscore that value of self‐report measures of hearing impairment as distinct from audiometry and speech and noise measures in their association with behavioral impairment and as non‐cognitive markers of dementia.
Digital mobility outcomes to assess habitual physical activity in people with cognitive impairment: A systematic review
Authors: Ardle Ríona Mc , Jabbar Khalid Abdul , Din Silvia Del , Kerse Ngaire , Rochester Lynn , Callisaya Michele L
Published: December 2021

Background

Maintaining habitual physical activity (HPA) is essential for people with dementia and mild cognitive impairment (MCI) to remain functionally independent. Therefore, physical activity interventions may complement care services and promote wellbeing and independence in this population. The advent of digital technology, such as wearable technology and ambient sensors, has enhanced our ability to objectively and reliably measure HPA in a cognitively‐impaired population. Digital technology can continuously and remotely capture a range of digital mobility outcomes important to independence, such as volume (i.e. amount of HPA), intensity (i.e. rate/magnitude of HPA), pattern (i.e. distribution of HPA over time) and variability (i.e. how regular or dynamic HPA is) of HPA. In order to inform clinical interventions and public health strategies for dementia, appropriate HPA outcomes must be quantified. The key aim of this review is to identify the digital tools and HPA outcomes used in community‐dwellers with dementia and mild cognitive impairment, and describe the volumes, intensities, pattern and variability of physical activity in this population.

Method

2975 article titles were systematically reviewed. Following title search, 266 abstracts were selected for abstract review. Seventy‐five articles are currently undergoing full text review.

Result

This review will report (1). digital technology used to assess HPA (e.g. accelerometers, infra‐red sensors), (2). the range of digital outcomes reported (e.g. steps per day, average ambulatory bout length), (3). key findings relating to the quantification of volume, intensity, pattern and variability of HPA in people with dementia and MCI, drawing comparisons to healthy older adults were applicable.

Conclusion

Findings from this review will be informative to future selection of digital mobility tools and outcomes to quantify HPA in people with dementia and MCI. The literature will be synthesized to identify the current state of research and identify gaps for future investigation. Recommendations will be made for the development of protocols to continuously and remotely assess HPA in people with cognitive impairment, and for identifying the most appropriate digital mobility outcomes to serve as clinical or interventional endpoints to monitor change in HPA in this population.
The roles atherosclerotic cardiovascular disease risk and depression on cognitive outcomes in Mexican Americans and non‐Hispanic whites
Authors: Marcela Marcela Davila , Large Stephanie E , Hope Michael , Hall James R , O'Bryant Sid , Johnson Leigh Ann
Published: December 2021

Background

Mexican Americans (MA) experience cognitive decline at younger ages and have higher rates of cardiovascular disease (CVD) than Non‐Hispanic whites (NHW). Persons who are depressed are more likely to have one or more risk factors for cardiovascular disease. The purpose of this study was to examine the impact of depression and Atherosclerotic Cardiovascular Disease (ASCVD) on cognitive function in MA and NHW.

Method

Data was collected from the Health and Aging Brain Study: Health Disparities (HABS‐HD) study. A total of 1094 participants who were classified as normal controls were stratified into 4 groups: no depression and low risk ASCVD (N= 684), no depression and high risk ASCVD (N= 222), depression and low risk ASCVD (N=140), and depression and high risk ASCVD (N=48). Depressive symptoms were assessed via Geriatric Depression Scale (GDS). ASCVD risk was calculated using a risk calculator. One‐way ANOVAs were conducted to examine differences in cognitive performance based on ASCVD risk and depression.

Result

The results showed that depressed NHW and MA males with a low ASCVD risk had significantly lower mean scores on Trail Making Test A than the non‐depressed with low ASCVD risk group (p < 0.006), (p < 0.017). Depressed MA males with high ASCVD risk had significantly lower mean scores on the MMSE than the non‐depressed low ASCVD risk group (p < 0.00). Depressed NHW females with low ASCVD risk had significantly lower mean scores on delayed memory than the non‐depressed low ASCVD risk group (p < 0.008). Depressed MA females with a high ASCVD risk demonstrated significantly lower mean scores on the COWA and SEVLT Trials 1‐5 and the non‐depressed low ASCVD risk group (p < 0.002), (p < 0.046).

Conclusion

The results of this study indicated that depression and risk of ASCVD can impact cognitive functioning in different ways. In men depression impacted scores on Trails A. In MA women comorbid depression and high risk for ASCVD affect scores on the COWA and SEVLT. These findings support that medical comorbidities influence cognitive function. Future research directions include exploring the relationships between other CVD risk factors and depression.
Neurocognitive effects of immune checkpoint inhibitors: A literature review
Authors: Mostafa Neveen , Raji Mukaila
Published: December 2021

Background

Immune checkpoint inhibitors (ICI) are novel but rapidly growing class of cancer treatments. They have pleotropic effects on several cancer‐specific targets that underlie their therapeutic properties. These targets include programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways. ICI have been approved in treatment guidelines of several cancers like melanoma and lung cancers and are being routinely used in clinical practice due to its proven efficacy.

The mechanism of ICI primarily targets the immune system, which also serves important roles in the structure and function of the central and peripheral nervous system. The reported associated adverse effects are essentially immune mediated due to T‐cell activity upregulation that causes disrupted immune tolerance. The same mechanism leading to cancer death might be driving the neurocognitive sequalae. Several specific neurological adverse events were described due to the role of inflammatory pathways in mediating behavioral and cognitive functions.

ICI have clear proven responses, leading to increase in the overall survival such that patients are now living longer with its side effects. Thus, it is essential to understand and assess the long‐term side effects and quality of life outcome among the growing population of cancer survivors previously treated with ICI.

Method

This review discusses the reported cognitive changes associated with immune checkpoint inhibitors. We employed a systematic search of literature in PubMed database, up to November 2020, mentioning neurological and cognitive side effects in patients treated with ICIs. Eligible studies included clinical trials, observational studies and case reports

Result

The clinical spectrum of neurological disorders is highly heterogeneous. Most of the reported neurological adverse events consist of non‐specific symptoms such as headache and fatigue, with the more functionally devastating ones being myasthenia gravis, demyelinating polyradiculopathy, meningitis and limbic encephalitis. Cognitive decline and memory problems were infrequently reported in the reviewed studies.

Conclusion

Although few clinical studies have targeted ICI immunotherapy for associated neurological sequelae, it appears that cognitive decline is not a common adverse effect for ICI. However, over time and with longer use of ICI, there will be a need for more rigorous studies to explore possible long‐term neurological complications.
Sleep efficiency is associated with amyloid burden, cerebral blood flow, and cognition in healthy older adults
Authors: Fenton Laura E , Albrecht Daniel S , Isenberg Lisette , Aslanyan Vahan , Stradford Joy , Monreal Teresa , Pa Judy
Published: December 2021

Background

Prior work has identified associations between sleep quality and amyloid‐beta (Aβ). However, how sleep efficiency relates to Aβ, cerebral blood flow (CBF), and cognition are not well understood. The objective of this study was to evaluate these relationships and the modifying role of APOE4 status.

Method

Objective sleep efficiency, Aβ, CBF, and cognitive performance on neuropsychological assessments (MoCA, Flanker, CVLT, and Complex Figure) were examined in a sample of 52 non‐demented, older adults (age=66.5+6.82, 67% female, 27% APOE4 carriers). Sleep efficiency, defined as the percentage of time asleep within a given sleep period, was objectively measured using the GENEActiv tri‐axis accelerometer for an average of 30.25 days. Aβ was measured in vivo using positron emission tomography and the F‐18 florbetaben tracer to calculate composite SUVR scores. Global gray matter CBF was quantified using a pseudo‐continuous arterial spin labeling MRI scan. All analyses were adjusted for age, sex, and education (for cognitive measures).

Result

Overall, higher sleep efficiency was associated with lower Aβ burden (p=.04), higher CBF (p=.03), higher MoCA scores (p=.05) and a trend for better Complex Figure Test recall (p=.07). There was a significant moderating effect of APOE4 status on the association between sleep and Aβ, such that poorer sleep efficiency was associated with higher Aβ burden in APOE4 carriers only (p=.01). APOE4 moderation was not observed for CBF. When stratified by high and low sleep efficiency levels (median split), APOE4 carrier status predicted Aβ burden only in individuals with low sleep efficiency (p =.02). Additionally, sleep efficiency predicted performance on long delay free recall of the CVLT and Complex Figure Test (p=.01) in the low sleep efficiency group only. No association between sleep efficiency and Flanker were observed.

Conclusion

These results provide evidence that sleep efficiency is associated with brain health and cognition, and suggest a modifying effect of APOE4 on the relationship between sleep and amyloid. Mechanistic evidence from animal models and human studies suggests that impaired slow wave activity during NREM sleep may disrupt dynamic fluid oscillations important for amyloid clearance and brain blood flow. Future work is needed to understand the causal and temporal relationships between these processes.
The impact of COVID‐19 on the well‐being and cognition of older adults living in the United States and Latin America
Authors: Babulal Ganesh M , Torres Valeria L , Acosta Daisy M , Aguero Cinthya , Aguilar‐Navarro Sara Gloria , Amariglio Rebecca E , Ussui Juliana Aya , Baena Ana Y , Bocanegra Yamile , Brucki Sonia MD , Bustin Julian , Cabrera Diego , Custodio Nilton , Diaz Monica M , Duque Lissette , Franco Idalid , Gatchel Jennifer R , Garza‐Naveda Ana Paola , Gonzalez‐Lara Mariana , Gutiérrez Lidia Antonia , Guzman‐Velez Edmarie , Hanseeuw Bernard J , Jiménez‐Velazquez Ivonne Z , Leon Tomas , Llibre‐Guerra Jorge J , Marquine Maria J , Martinez Jairo E , Medina Luis D , Miranda‐Castillo Claudia , Morlett Alejandra , Munera Diana , Nuñez‐Herrera Alberto , de Oliveira Maira Okada , Cancel Santiago Palmer , Pardilla‐Delgado Enmanuelle , Perales Jaime , Pluim Celina F , Ramirez‐Gomez Liliana A , Rentz Dorene , Rivera‐Fernandez Claudia , Rosselli Monica , Serrano Cecilia , Suing María Jose , Slachevsky Andrea , Soto Marcio , Sperling Reisa A , Torrente Fernando , Thumala Daniela , Vannini Patrizia , Vila‐Castelar Clara , Escalante Tatiana Mirella Yanez , Quiroz Yakeel T
Published: December 2021

Background

In the COVID‐19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic’s impact on the well‐being and cognition of older adults within and outside of the United States (US).

Method

1,747 (646 White, 991 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and 14 Latin American countries completed an online survey regarding well‐being and cognition during the pandemic. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups, and Latinos living in the US and Latin America.

Result

Mean age was 66·5 (SD = 7·70) years and mean education was 15·4 (SD = 2·76) years. We found no differences in the pandemic’s overall impact across US ethnoracial groups. Compared to Whites, Latinos reported greater economic impact (p < ·001, ηp2 = .031); while Blacks reported experiencing discrimination more often (p < ·001, ηp2 = .050). Blacks and Latinos reported more positive coping (p < ·001, ηp2 = 040). Latin American Latinos reported greater pandemic impact (p < ·001, ηp2 =.013 ), more positive coping (p =·006, ηp2 =.008 ), and less discrimination than US Latinos (p < ·001, ηp2 = .013 ).

Conclusion

The COVID‐19 pandemic has differentially impacted the well‐being of older ethnically diverse individuals in the US and Latin America. Future studies should examine how mediators like income and coping skills modify the pandemic’s impact.
Reduced amyloid and greater neuropsychological testing exclusion in the A4 study in individuals that self‐identify as non‐Hispanic Asian
Authors: Jin Meghan , Kennedy Gabriel , Deters Kacie D , Trelle Alexandra N , Donohue Michael C , Sperling Reisa A , Mormino Elizabeth C
Published: December 2021

Background

The prevalence of amyloid positivity among diverse groups of clinically asymptomatic older individuals is underexplored, especially in the context of prevention trials of Alzheimer’s disease (AD). We sought to determine whether rates of amyloid‐positivity differ in non‐Hispanic Asian individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) study as compared to non‐Hispanic White individuals.

Methods

We compared cross‐sectional amyloid PET data for 169 self‐identified non‐Hispanic Asian (NHA) and 3843 non‐Hispanic White (NHW) from the A4 Study, controlling for age, sex, education, and APOE genotype (number of E4 and E2 alleles). We additionally examined neuropsychologic eligibility data for the 111 NHA and 1910 NHW that did not meet study criteria to advance to the PET visit ("PET‐screenfail"). Finally, Japanese language was used as a proxy variable to account for potential site differences (Tokyo versus North American recruitment sites; 99/169 NHA with PET and 57/111 NHA in the PET screenfail group indicated Japanese as their primary language).

Results

Individuals that self‐identify as NHA show lower levels of amyloid compared to NHW, both when treating amyloid dichotomously or continuously (see Figure, and Table). Overall, NHA are more likely to screenfail before the PET visit compared to NHW (40% versus 31%; X2=7.8, df = 1, p‐value = 0.0052). NHA that screenfail before the PET visit have lower MMSE (p<0.0001) and Logical Memory delayed recall (p<0.0001) scores than the NHW screenfail group. All results remained similar when additionally controlling for language as a proxy for site.

Conclusions

Self‐identified NHA individuals show reduced amyloid‐positivity in a large‐scale prevention trial of AD, similar to our previous report in non‐Hispanic Blacks. Recruitment strategies and eligibility requirements deserve more attention, as increased exclusion due to scores on the MMSE and Logical Memory likely reflect inadequacy in these measurements across diverse populations. These findings highlight bias within PET datasets and gaps in knowledge related to key AD biomarkers in diverse individuals.
Pre‐pivotal clinical study of β‐amyloid in the ocular lens by Sapphire II‐aftobetin eye scan: Correlation with amyloid PET imaging in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD)
Authors: Goldstein Lee E. , Wilke Susanne , Goodman Ira J. , Nilan Dennis , Sadowsky Carl H.
Published: December 2021

Background

We identified AD‐associated Aβ pathology in ocular lenses from patients with neuropathologically‐confirmed AD but not non‐AD neurodegenerative diseases or normal aging (Goldstein et al., Lancet, 2003). We reported identical early‐onset Aβ lens pathology in Down syndrome (Moncaster et al., 2010). In Framingham Eye Study participants, we found that AD phenotypes are expressed years‐to‐decade+ earlier in lens than brain and identified a new GWAS‐significant AD risk gene (CTNND2, δ‐catenin) that modulates Aβ expression in lens and brain (Jun et al., 2012). This research spurred development of a novel drug‐device eye scanner (Sapphire II‐Aftobetin system) that combines a topically‐applied Aβ‐binding fluorescent ligand (Aftobetin) with a purpose‐designed fluorescence laser eye scanner (FLES). Sapphire II detects lens Aβ with high reliability, sensitivity, specificity, and SNR. Clinical testing showed that Sapphire II distinguishes subjects with probable AD from normal controls (Kerbage et al., Front Neurol, 2013; Am J Alz Dis Dement, 2015). This study evaluated Sapphire II compared to amyloid PET scans in subjects with MCI or early AD.

Method

48 participants: 28 MCI, 16 mild AD, 4 normal controls (NC); age range: 60‐85 years. MCI and AD subjects underwent cognitive testing and amyloid PET scans (Florbetapir, Amyvid). The Sapphire II system detects a highly‐specific fluorescent lifetime decay spectroscopic signature associated with bound Aftobetin‐Aβ complexes in the lens. Each scan requires <1 sec. Multiple scans can be acquired in a single sitting.

Result

43 subjects have been evaluated to date. No serious adverse events have been reported. Subject correlation with amyloid PET yielded 75% specificity, 100% sensitivity, 95% accuracy, 94% PPV, and 100% NPV. To date, there has been no subject in which Sapphire II was negative and amyloid‐PET was positive. Of the 39 Sapphire II‐positive subjects, 26 were amyloid‐PET positive. Evaluation of individual PET scans and cognitive testing suggest that lens amyloid burden assessed by Sapphire II eye scan is more sensitive than amyloid PET compared to clinical criteria.

Conclusion

The Sapphire II‐Aftobetin drug‐device combination platform provides a safe, sensitive, and convenient screening tool for rapid non‐invasive evaluation of AD‐associated β‐amyloid (Aβ) burden in subjects with MCI and mild AD.
Self‐reported and informant‐reported depressive symptoms are independent and divergent predictors of new onset dementia in older adults
Authors: Rehman Tanaeem , McGirr Alexander , Ismail Zahinoor
Published: December 2021

Background

Depressive symptoms in older adults are important predictors of incident dementia. Symptoms can be assessed in several ways, including self‐reported or informant‐reported measures. It is unclear whether one is superior in predicting dementia onset or how to interpret discordant reports. Here, in a large sample of non‐dementia older adults for whom depressive symptoms were assessed via both self‐report and informant‐report, we test independent and divergent prognostic utility for dementia.

Method

Data from 10,684 non‐dementia subjects from the National Alzheimer’s Coordinating Centre were analysed. This included individuals with normal cognition (NC; CDR=0) and Mild Cognitive Impairment (MCI; CDR=0.5). Geriatric Depression Scale‐15 (GDS) was used for self‐report and the Neuropsychiatric Inventory Questionnaire depression item (NPI‐Q‐D) was used for informant‐report. Cox regression and Kaplan Meier (KM) survival analyses were used to explore the measures as independent predictors of dementia, and the putative interaction between them. Outcome was defined as change to CDR≥1 at follow‐up. The cox model was adjusted for age, sex, and education. CDR category was included to determine applicability of findings across cognitive categories. GDS‐15 and NPI‐Q‐D scores were added as continuous predictors. For the KM analysis, depressive symptoms were dichotomized as GDS+/GDS‐ and NPI‐Q‐D+/NPI‐Q‐D‐ using cut‐off scores of ≥5 for GDS‐15 and ≥2 for NPI‐Q‐Depression.

Result

GDS (HR: 1.096; CI: 1.070–1.122) and NPI‐Q‐D (HR: 1.428; CI: 1.291–1.580) independently predicted dementia, with a significant interaction between them (p<0.000) even after controlling for CDR. KM analyses showed that in the self‐reported non‐depressed group (GDS‐), there was a significant difference in the hazard of incident dementia based on the informant report. The discordant group i.e., GDS‐/NPI‐Q‐D+ progressed to dementia significantly faster (9.6yrs; SD=0.292) compared to the GDS‐/NPIQ‐D‐ group (12.0yrs; SD=0.055) (p<0.000; Log‐rank test). No significant difference was found based on informant reports in the GDS+ group (p=0.114).

Conclusion

Self‐reported and informant‐reported depressive symptoms are not duplicative, and independently predict dementia risk across cognitive categories. Informant report is particularly important when self‐report is negative, to detect individuals with compromised insight at higher risk for progression. Discordance of self‐informant reports require greater clinical and research consideration in NC and MCI populations.
Clinical profile of an Alzheimer´s disease cohort in the Peruvian population
Authors: Cornejo‐Olivas Mario R , Mena Pedro Ramon , Illanes‐Manrique Maryenela , Adams Larry D. , Marca Victoria , Isasi Rosario , Castro‐Suarez Sheila , Beecham Gary W. , Mejía Koni Katerin , Vance Jeffery M. , Manrique‐Enciso Carla , Cuccaro Michael L. , Meza‐Vega Maria , Pericak‐Vance Margaret A.
Published: December 2021

Background

Among older Peruvians (over 65‐years) the prevalence of dementia is 7%, with 56% meeting clinical criteria for Alzheimer Disease (AD). Peruvians, are an admixed population with approximately 80% Amerindian ancestral background. We have ascertained a cohort of Alzheimer Disease (AD) cases and cognitively intact controls for genetic studies.

Method

All participants have been recruited since 2019 using community outreach ascertainment strategies and hospital‐based recruitment from Lima, Peru. Cases were assessed by neurologist following NINDS/ADRDA criteria; and completed a comprehensive neurocognitive, neuropsychiatric and functional assessments. Controls were screened using MMSE, Clock drawing test and Pfeffer functional activities questionnaire. IRBs approvals from the participating Peruvian institutions and University of Miami were obtained for this study.

Result

A total of 102 AD cases (4 familial cases) and 152 controls were recruited since 2019 to December 2020. For AD cases: age at examination were 76.5±9.09, age at onset were 72.15±8.82, and 63.7% were female, average of 9.9±4.9 year of education. For controls: age at examination were 73.13±6.54, 62.5% were female, average of 11.62±4.41 year of education. Among cases diagnosis was classified as: 62.8% possible AD (two cases screened for Cerebrospinal fluid Abeta42 and tau protein levels) and 37.2% probable AD. Clinical and cognitive assessment profile for cases: MMSE average score was 17.2± 4.9 and Addenbrook’s Cognitive Examination average score was 38.5± 21.7 with memory loss predominance. Based on NPI the most frequent neuropsychiatric symptoms were irritability (51%), delusions (46%) and apathy (45%). Severity of dementia were assessed by CDR (CDR=3 for 33.9%, CDR=2 for 32.3%, CDR=1 for 24.2% and CDR=0.5 for 9.7%). Depressive symptoms were assessed with Geriatric Depression Scale with an average of 4.4±3.5 .

Conclusion

The clinical features of the AD cohort in the Peruvian population are consistent with previous reports. There is a tendency of a higher level of education in the control . Among the Peruvian AD cohort, the main neuropsychiatric symptoms are irritability, delusions and apathy consistent with the predominance of moderate to severe dementia. Reference: Marca V. et al. Dissecting the role of Amerindian genetic ancestry and ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population, Neurobiology of Aging, 2020.
Plasma transcript profiling identifies significant differentially expressed genes and expression of quantitative trait loci in African Americans
Authors: Carrasquillo Minerva M. , Jin Jianli , Reddy Joseph S. , Crook Julia E. , Lincoln Sarah J. , Ho Charlotte C.G. , Malphrus Kimberly G. , Nguyen Thuy , Greig‐Custo Maria T. , Lucas John A. , Graff‐Radford Neill R. , Ertekin‐Taner Nilufer
Published: December 2021

Background

African Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being ∼2X higher in this population compared to non‐Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing primarily on the identification of genetic risk factors and novel plasma biomarkers.

Method

Utilizing plasma samples from FCA3DS AD cases (n=158) and cognitively unimpaired elderly controls (n=272), we have performed differential gene expression (DEG) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom NanoString® panel that we have designed to measure transcript levels in plasma of genes relevant to AD. Transcript counts were determined using the NanoString® nCounter system, following manufacturer’s protocols. Transcript counts from 43 of the 50 customs assays passed pre‐established quality control thresholds and were utilized for the DEG and eQTL analyses. Our published FCA3DS whole exome sequence (WES) data was utilized for the eQTL analyses. Linear mixed models adjusted for relevant biological and technical covariates were implemented with the lme4 package in R software (v3.6.2) for the DEG and eQTL analyses.

Result

An association with higher plasma CLU in controls compared to AD remained significant after Bonferroni correction for the 43 transcripts tested. The eQTL analysis revealed significant association (FDR q‐value<0.05) with 105 WES variants in cis with 22 of 43 genes tested, including variants in genes previously associated with AD risk in AA.

Conclusion

The results from this AA plasma eQTL analysis revealed ABCA7 variants that are significantly associated with lower plasma ABCA7 transcript levels. One of the significant plasma ABCA7 eQTLs was previously shown by our group to be associated with increased AD risk in AA, suggesting that this may be a functional eQTL underlying the risk of AD in AA. The association of higher levels of CLU transcript in plasma from controls compared to AD is in line with results published by others which showed that higher baseline concentration of clusterin protein in plasma was associated with slower rates of brain atrophy. These results support plasma transcripts as novel endophenotypes in AD biomarker studies.
Reduced longitudinal change in 18F‐flortaucipir PET is associated with clinical phenotype in atypical Alzheimer’s disease
Authors: Phillips Jeffrey S , Nitchie Frederick J. , Da Re Fulvio , Olm Christopher A , Cook Philip , McMillan Corey T , Irwin David J. , Gee James C. , Dubroff Jacob G. , Grossman Murray , Nasrallah Ilya M.
Published: December 2021

Background

Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer’s disease (AD) have noted reduced increases or frank decreases in tau signal. It is unclear whether these reductions reflect measurement/processing error or biological changes in advanced neurodegeneration.

Method

We assessed regional and interindividual variation in rates of longitudinal change on 18F‐flortaucipir PET imaging in 24 amyloid‐β+ patients with atypical, early‐onset amnestic or non‐amnestic AD and 117 amyloid‐β+ participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.

Result

In atypical AD, 18F‐flortaucipir uptake appeared to slow or decline over time in areas with high baseline signal and older individuals with greater cognitive impairment. In secondary analyses, these effects were not explained by regression to the mean or atrophy. Among ADNI participants, longitudinal change was reduced in early Braak stage regions relative to late‐stage neocortical areas, demonstrating partial generalization of findings from atypical AD.

Conclusion

Results suggested that radioligand uptake may plateau or decline in advanced neurodegeneration. Further research is warranted to investigate whether results generalize to other tau‐binding radioligands and to typical, later‐onset AD.
MIND and Mediterranean diet association with Alzheimer’s disease pathology
Authors: Agarwal Puja , Wang Yamin , Aggarwal Neelum T , Cherian Laurel J , James Bryan D , Dhana Klodian , Leurgans Sue E , Bennett David A , Schneider Julie A
Published: December 2021

Background

Healthy dietary patterns, primarily Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND), and Mediterranean diet (MedDiet) are related to slower cognitive decline and reduced risk for Alzheimer’s dementia. However, it is unknown if these diets and its primary food groups are associated with Alzheimer’s disease (AD) pathology in postmortem brains.

Method

The study was conducted in 459 deceased participants (age at death (91.0±6.3 years), 73% female, 20% with APO‐ε4 allele) of the Rush Memory and Aging Project (a clinicopathologic longitudinal cohort) with completed neuropathological evaluations, dietary data, and without mild cognitive impairment or dementia at first dietary assessments. Mean diet scores were obtained from a validated food frequency questionnaire administered annually over follow‐up years (6.8 ± 3.9 years). Multiple brain regions were assessed for percent cortical area occupied by amyloid‐beta and density of cortical phosphorylated tau (p‐tau) tangles. A global AD pathology score was computed, summarizing three pathologies (neuritic and diffuse plaques and neurofibrillary tangles) based on modified Bielschowsky silver‐staining. Linear regression models adjusted for age, sex, education, APO‐ε4 status, and total calories were used. We also assessed diet interaction with age, sex, education, and APO‐ε4 status. Diet was evaluated as continuous and in tertiles.

Result

Healthy diet scores were associated with lower global AD pathology (MIND:β=‐0.028,p=0.02; MedDiet:β=‐0.011,p=0.006) and less amyloid load (MIND:β=‐0.077,p=0.04; MedDiet:β=‐0.040,p=0.001). However, when stratified by APO‐ε4 status, this association was significant only in non‐carriers, and diet was also associated with lower p‐tau tangles. Overall, higher fish (p trend=0.007) and green leafy vegetable (p trend=0.014) intakes were associated with less global AD pathology. Sweets and pastries intake was related to higher amyloid load (β=0.021,p=0.009). Those in the highest tertile of legumes/beans (β=‐0.032,p=0.03), and surprisingly, butter intake had fewer p‐tau tangles (β=‐0.030,p=0.04) compared to the lowest tertile group.

Conclusion

Both the MIND and Mediterranean diets are associated with less AD pathology, primarily amyloid plaques. Dietary components, including green leafy vegetables, fish, legumes, butter, and sweets, were also related to AD pathology. These relationships were more significant in those without an APOE‐ε4 allele. Further studies with larger numbers should be explored in those with and without APOE‐ ε4 genotypes.