bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal associations between treated and untreated hearing loss and mild behavioral impairment in older adults without dementia
Authors: Gosselin Penny , Guan Dylan X. , Smith Eric E. , Ismail Zahinoor
Published: December 2023

Background

Hearing loss and mild behavioral impairment (MBI) are non‐cognitive markers of dementia that are cross‐sectionally linked to one another. Longitudinal approaches are necessary to further understand mechanisms underlying their association, which may inform interventions for hearing loss and MBI. This study investigated the relationship between hearing loss, with or without hearing aids (HAs), and MBI in dementia‐free older adults both cross‐sectionally and longitudinally.

Method

Data were analyzed from dementia‐free National Alzheimer’s Coordinating Center participants, aged ≥50, collected between 2005‐2022. Three self‐report questions were used to generate a three‐level categorical hearing status variable: No‐HL, Untreated‐HL (not wearing hearing aids), and Treated‐HL (regularly wearing hearing aids). MBI status was derived from the informant‐rated Neuropsychiatric Inventory Questionnaire using a published algorithm. At baseline (n = 7992), age‐, sex‐, education‐, and cognitive status‐adjusted logistic regression was used to examine the association between hearing status and presence of global and domain‐specific MBI. Cox proportional hazards models examined the effect of: 1) hearing status as exposure on rate of incident MBI (n = 6639); and 2) MBI status as exposure on rate of incident hearing loss (n = 7343).

Result

Cross‐sectionally, participants with Untreated‐HL (not wearing hearing aids) were more likely to exhibit global MBI (OR = 1.58) and individual MBI domains of social inappropriateness (OR = 2.08), affective dysregulation (OR = 1.64), and impulse dyscontrol (OR = 1.68), compared to those with No‐HL (Figure 1). Treated‐HL (regularly wearing hearing aids) did not differ from No‐HL for presence of global‐ or domain‐specific MBI. Longitudinally, older adults with Treated‐HL developed MBI at higher rates than No‐HL (HR = 1.42), and older adults with MBI at baseline developed Treated‐HL at higher rates than those without MBI (HR = 1.34) [Table 1].

Conclusion

Our cross‐sectional results indicate that HA use in dementia‐free hearing‐impaired older adults is associated with lower likelihood of having MBI. However, hearing loss requiring hearing aids was associated with incident MBI and vice versa. This bidirectional relationship may indicate a positive feedback loop between hearing loss and MBI, with Treated‐HL and MBI reflecting greater hearing loss severity and disease burden, increasing the rate of development of the complementary marker and of dementia.
Harmonization of amyloid and tau PET tracers in a multi‐center cohort from NIA Alzheimer’s disease research centers in the United States
Authors: Harrison Theresa M. , Landau Susan M. , Baker Suzanne L. , Lee JiaQie , Ward Tyler J. , Murphy Alice , Chadwick Trevor , Mormino Elizabeth C. , Johnson Sterling C , Rogalski Emily J , Koeppe Robert A. , Decarli Charles , Toga Arthur W. , Kukull Walter A. , Biber Sarah , Jack Clifford R. , Jagust William J.
Published: December 2023

Background

The Standardized Centralized Alzheimer’s & related dementias Neuroimaging (SCAN) project harmonizes processing of prospectively acquired PET and MRI scans from Alzheimer’s disease research centers (ADRCs) across the USA. SCAN data will be integrated with other ADRC data streams within the National Alzheimer’s Coordinating Center (NACC), including the Uniform Data Set which includes rich longitudinal demographic, cognitive, and neuropathological data, resulting in a large, potentially representative cohort. The project has sought to accommodate site‐to‐site variation in image acquisition while permitting harmonization of imaging data, necessitating new analytic approaches for different PET tracers and PET scans without MRIs.

Method

PET scans underwent preprocessing for quality control and smoothing to a uniform resolution. MRI‐free processing pipelines and positivity thresholds were developed for each beta‐amyloid (Aβ)‐PET tracer: [11C]PiB, [18F]florbetaben (FBB), [18F]florbetapir (FBP) and [18F]flutafuranol (NAV). A generic Aβ‐PET template was used for spatial normalization and cortical summary SUVRs were calculated in template space. Aβ‐positivity thresholds were determined by examining both MRI‐dependent thresholds transformed into MRI‐free units and a young control mean+2SD. Centiloid (CL) conversions were completed for each Aβ‐PET tracer. Tau‐PET tracers ([18F]flortaucipir (FTP) and [18F]MK‐6240) required tracer‐specific warping templates for best performance relative to gold‐standard MRI‐dependent processing. Demographic and clinical data were obtained from NACC.

Result

15 ADRCs have contributed data to SCAN as of January 2023. 477 participants had preprocessed, SCAN‐compliant (https://scan.naccdata.org/) Aβ‐PET scans and NACC data; 219 of these participants (46%) also had tau‐PET scans (Table 1). This cohort included 18% of individuals from underrepresented groups. Clinical diagnostic groups ranged from cognitively unimpaired to MCI and dementia (74% of whom had AD dementia). Using pooled Aβ‐PET data across 4 tracers in CLs, there were expected differences in Aβ burden by diagnosis group (Fig. 1) and positive associations with tau (Fig. 2).

Conclusion

SCAN has successfully harmonized PET data from more than a dozen US ADRCs yielding a large, clinically heterogeneous cohort of deeply phenotyped research participants. SCAN data will be compatible with ADNI data allowing for further pooling of data and greater statistical power to drive critical questions in AD and related dementias research.
To split or not to split: data‐driven components along the PPAOS‐PAA spectrum
Authors: Illán‐Gala Ignacio , Lorca‐Puls Diego L. , Miller Zachary , Rubio‐Guerra Sara , Santos‐Santos Miguel A , Lleó Alberto , Grinberg Lea T. , Spina Salvatore , Rankin Katherine P , Kramer Joel H. , Rabinovici Gil D. , Boxer Adam L , Rosen Howard J. , Perry David C. , Miller Bruce L. , Seeley William W. , Mandelli Maria Luisa , Tempini Maria Luisa Gorno
Published: December 2023

Background

It is unclear whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) represent the two ends of a clinical continuum or exist as distinct syndromic entities with specific pathologic/prognostic correlates. We aimed to characterize the main clinical features along the spectrum of progressive non‐fluent speech‐language disorders (nf‐SLD) and explore the existence of data‐driven symptom clusters with etiological/prognostic value.

Method

We included 98 participants presenting with progressive motor speech impairment and/or agrammatism, of which 43 had an autopsy‐confirmed neuropathological diagnosis. Speech pathologists rated motor speech features indicative of dysarthria and AOS. Quantitative measures of expressive/receptive agrammatism were obtained and compared with healthy controls. Baseline and longitudinal disease severity was assessed with the Clinical Dementia Rating sum‐of‐boxes (CDR‐SB). We explored the clustering tendency of the data to form robust symptom clusters and used principal component analysis to extract data‐driven clinical components. The longitudinal CDR‐SB change was estimated with linear mixed‐effects models.

Result

Ninety‐one participants fitted previously reported clinical profiles (69 AOS+agrammatism, 18 PPAOS and 4 PAA), while 7 remained unclassifiable and were characterized by nonfluent speech and dysarthria in the absence of apraxia of speech or agrammatism. None of the baseline clinical features discriminated between FTLD subgroups. The Hopkins statistic ruled out the existence of syndromic clusters in the whole sample. Three data‐driven components explained 71% of the variance ([i]severity‐agrammatism, [ii]AOS, and [iii]dysarthria). The component characterized by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy while the component characterized by severity‐agrammatism predicted a faster CDR‐SB increase.

Conclusion

Our results suggest that nf‐SLD represents a clinical continuum. Splitting this continuum into different clinical phenotypes based on its major clinical features does not improve clinical‐pathological correlations, stressing the need for new clinical and biological markers. The term nf‐SLD could be used to group together these speech‐language phenotypes strongly associated with FTLD.
Investigating the impact of hypertension with and without diabetes on progression to Alzheimer’s disease: A clinic‐pathological study
Authors: Ruthirakuhan Myuri , Swardfager Walter , Xiong Lisa Y. , Ottoy Julie , MacIntosh Bradley J. , Rabin Jennifer S. , Ramirez Joel , Herrmann Nathan , Keith Julia , Lanctôt Krista L. , Black Sandra E.
Published: December 2023

Background

Hypertension and diabetes have each been associated with an increased risk of progression to Alzheimer’s disease (AD) dementia. Here, we investigated their combined impact on progression from cognitively normal to clinically‐diagnosed AD.

Method

Cognitively normal individuals from the National Alzheimer’s Coordinating Center were identified as having neither hypertension nor diabetes (HTN‐/DM‐), hypertension without diabetes (HTN+/DM‐), or hypertension with diabetes (HTN+/DM+). The presence of HTN and DM were based on their diagnosis from recent medical history or medication use. This study investigated whether HTN+/DM‐ or HTN+/DM+ were predictors of progression to clinically‐diagnosed AD compared to HTN‐/DM‐. In a subgroup analysis with post‐mortem data, we investigated whether HTN+/DM‐, and HTN+/DM+ were predictors of progression to clinically diagnosed AD due to underlying AD‐ and/or vascular neuropathology.

Result

This study included N = 11074 cognitively normal individuals (mean age: 71.7 (9.0), MMSE: 28.9 (1.4), male: N = 3818 (34%)). Approximately 7% (N = 830) progressed to clinically‐diagnosed AD, and the average duration of follow‐up was 5.2 (3.6) years. Forty‐two percent (N = 4608) were HTN‐/DM‐, 45% (N = 5034) were HTN+/DM‐, and 13% (N = 1432) were HTN+/DM+. Both HTN+/DM‐ (hazard ratio (HR): 1.24 (1.17‐1.32), p<.001), and HTN+/DM+ (HR: 1.31 (1.19‐1.44), p<.001) were significant predictors of progression to clinically‐diagnosed AD. Subgroup analyses with post‐mortem data (N = 919) demonstrated that compared to HTN‐/DM‐, those with HTN+/DM‐ had a higher risk of progressing to clinically‐diagnosed AD with underlying cerebrovascular disease (CVD) neuropathology (HR: 1.54 (1.17‐2.03), p = .002), whereas those with HTN+/DB+ had a higher risk of progression to clinically‐diagnosed AD with underlying AD (HR: 2.10 (1.16‐3.79), p = .01) and cerebral amyloid angiopathy (CAA) neuropathology (HR: 1.52 (1.09‐2.12), p = .01).

Conclusion

These findings demonstrate that underlying CVD neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM‐, while both AD and CAA neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM+. This suggests that individuals with HTN+/DM‐ and HTN+/DM+ vary phenotypically and may warrant the need for different treatment strategies to reduce the future risk of AD.
Late‐life social activity and subsequent risk of dementia and mild cognitive impairment
Authors: Chen Yi , Grodstein Francine , Capuano Ana W. , Bennett David A. A , James Bryan D
Published: December 2023

Background

Previous research reported associations between more social engagement and better cognitive health. Social engagement is a multidimensional construct encompassing interrelated but distinct domains such as social activity, social network size, perceived social support, and loneliness. These domains are not equally amenable to interventions. We therefore focused on late‐life social activity, as a potentially modifiable facet of social engagement, and examined its relation to risks of dementia and MCI, independent of other aspects of social engagement, lifestyle, and health.

Method

In the Rush Memory and Aging Project (MAP), 1923 older adults without dementia at baseline were followed longitudinally, with annual clinical evaluation of dementia and MCI. The frequency of participation in six common social activities was assessed by a validated scale at baseline (mean = 2.6, range: 1‐4.3), as were size of social network, perceived social support, and perceived loneliness. A clinical diagnosis of MCI or dementia was rendered annually based on cognitive tests and diagnostic classification by a clinician. We used Cox proportional hazard models to quantify associations between social activity score and incident dementia or MCI. Primary models controlled for demographics; additional models included covariates for health, other social engagement indicators, and income. In secondary analyses, to consider reverse causality, we excluded participants who developed MCI or dementia within two years after baseline.

Result

During a mean follow‐up of 6.7 (std = 4.7) years, 545 (28%) participants developed dementia, and 695 (49% of those without MCI at baseline) developed MCI. Each one‐unit increment in social activity score was associated with a 37% reduction in dementia risk [HR = 0.63, 95% CI: 0.53‐0.74] after adjusting for age, sex, education, race/ethnicity, and marital status (Figure 1A). Social activity was also related to a lower risk of MCI [HR = 0.77, 95% CI: 0.66‐0.89] (Figure 1B). Results were not meaningfully different after adjusting for vascular disease burden, BMI, ADL disability, physical activity, depressive symtoms, social network size, social support, social isolation, and income. Excluding participants who developed MCI or dementia soon after baseline did not change the patterns.

Conclusion

Keeping socially active at older age is related to lower dementia risk, possibly informing strategies for developing preventive interventions.
Impact of self‐reported history of head injury on Alzheimer’s disease biomarker profiles
Authors: Dybing Kaitlyn M , Saykin Andrew J. , Risacher Shannon L
Published: December 2023

Background

Head injury (HI) as a risk factor for Alzheimer’s disease (AD) has been attracting increased attention thanks to the discovery that concussion is linked to earlier and more severe development of AD (1). HI is prevalent, and a better understanding of how it contributes to AD risk and prognosis is necessary (2). Previous cross‐sectional studies have provided evidence of differences in biomarker levels between individuals with a history of HI and those without (2); this study investigates the effects of a history of HI on longitudinal patterns of AD biomarkers to better understand how HI affects AD risk.

Method

Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, we examined longitudinal levels of amyloid β (Aβ), phosphorylated tau (p‐tau), and total tau (t‐tau) in the cerebrospinal fluid (CSF) of 100 individuals with a history of HI and 100 non‐HI controls demographically‐matched on age, sex, race, ethnicity, and years of education. We also analyzed longitudinal levels of blood plasma free plasma (FP) 42, total plasma (TP) 42, pTau181, and NFL.

Result

Individuals with a history of HI had lower CSF Aβ at baseline, lower plasma TP42 at a month 48 follow‐up visit, and lower plasma pTau181 at 72‐ and 96‐month follow‐up visits. There were no differences between the groups on CSF p‐tau or t‐tau levels or plasma FP42 or NFL at any time point.

Conclusion

Lower CSF and plasma amyloid in the HI group may indicate individuals with a history of HI have higher amyloid deposition, given the inverse correlation between CSF/plasma amyloid levels and amyloid deposition on PET (3). The unexpectedly lower plasma pTau in the HI group warrants further analysis. Some of our analyses may be underpowered, as underreporting of HI incidence in ADNI reduces the number of available HI participants. However, despite these limitations, we were able to find significant differences in some biomarkers in individuals with a history of HI. Future studies in expanded samples are needed.

1. Fleminger et al. (2003). Journal of Neurology, Neurosurgery & Psychiatry

2. Small et al. (2013). The American Journal of Geriatric Psychiatry

3. Fagan et al. (2006). Annals of Neurology
Enhanced arterial spin labeling in mild cognitive impairment phenotypes
Authors: Umfleet Laura Glass , Cohen Alexander D , Brett Benjamin L , Lancaster Melissa , Obarski Shawn , Mason Lilly , Franczak Malgorzata , Wang Yang
Published: December 2023

Background

Arterial spin labeling perfusion MRI is increasingly proving to be a promising tool for exploring neurovascular changes in neurodegenerative conditions. Using an advanced 3D pseudo‐continuous arterial spin labeling sequence with Hadamard‐encoded multiple post‐labeling delays (eASL), this study evaluated both cerebral blood flow (CBF) and arterial transit time (ATT) alterations in mild cognitive impairment (MCI) phenotypes.

Method

MCI patients (N = 19;Mage = 74.63±5.65) and controls (N = 20;Mage = 70.04±7.06) underwent a 3T MR scan with the eASL sequence. ATT and CBF were simultaneously measured. Voxel‐wise group comparisons of CBF and ATT were performed. Results were thresholded at a cluster‐size corrected p<0.001 (a<0.05). A region of interest (ROI) was defined as the overlap of clusters showing a significant difference in CBF and ATT between MCI and controls. Independent t‐tests between MCI phenotypes (amnestic, non‐amnestic) and controls on CBF and ATT ROIs were conducted. Pearson correlations of ROIs with measures of cognition, including executive functioning, were calculated. Correlations informed regression analysis.

Results

Voxelwise analyses (Figure1) demonstrated decreased CBF in MCI compared to controls in the default mode network, middle and superior frontal gyri, inferior parietal lobule, and temporal lobe. Increased ATT was seen in similar regions, with clusters centered in inferior and middle temporal lobe and visual cortex. T‐tests using created ROIs (as described above) revealed group differences between controls and MCI phenotypes in both CBF and ATT (ps≤.01); there was a non‐significant trend for higher ATT in naMCI versus aMCI. The highest correlational values emerged between CBF and ATT ROIs with a measure of executive functioning (TrailsB). IVs in regression analysis were age (step 1) and ATT and CBF overlapping ROI values (step 2, stepwise); TrailsB = DV . Across the entire cohort, CBF (R2 change = .239, p<.001), not ATT, was included in the model.

Conclusion

Advanced 3D pCASL with Hadamard encoded multiple PLDs (eASL) can be used to simultaneously measure CBF and ATT in MCI and controls. MCI patients showed different patterns of reduced CBF and prolonged ATT. While CBF and ATT values were significantly correlated with TrailsB, regression analysis revealed that CBF was a more robust predictor of TrailsB. Future research should examine eASL as a biomarker for MCI phenotypes.
Update of the “LIfestyle for BRAin health” (LIBRA) index: Results from an umbrella review and Delphi consensus study on modifiable dementia risk factors
Authors: Rosenau Colin , Köhler Sebastian , van Boxtel Martin P.J. , Deckers Kay
Published: December 2023

Background

Given the projected increase in the number of people with dementia and the lack of curative treatment, there is increasing attention to the contribution of modifiable risk and protective factors to dementia risk. In 2015, the “LIfestyle for BRAin health" (LIBRA) index was developed based on the results of a systematic literature review and Delphi expert study (Deckers et al., 2015). LIBRA consists of twelve modifiable risk factors for cognitive decline and dementia. Although this risk index has been well‐validated for cognitive decline and dementia risk in numerous population‐based cohorts and intervention studies, newly emerged risk factors might ask for an update (Deckers et al., 2019; Deckers et al., 2020).

Method

To update LIBRA, we conducted an umbrella review to assess all systematic reviews (SR) and meta‐analyses (MA) on modifiable dementia risk factors published between January 2015 and June 2021 in four databases (Pubmed, Embase, Web of Science, and PsychINFO). In parallel, a two‐round Delphi expert study was conducted. In the first round (May‐June 2022), eighteen dementia experts were asked to evaluate the factors currently included in LIBRA. Additionally, we asked to list new modifiable factors not previously included in LIBRA. In the second round (December 2022‐January 2023), the experts ranked the most important risk factors identified in the umbrella review and first Delphi round.

Result

The search returned 6,540 hits, of which 147 SR/MA were included in our umbrella review. Next to the existing LIBRA factors, new candidate risk factors that were consistently associated with increased risk for cognitive decline and dementia included: low social engagement, hearing impairment, vision impairment, atrial fibrillation, and anxiety. After triangulation of the results of the umbrella review and the first Delphi round, the experts identified hearing impairment, lifecourse inequalities, social contact, atrial fibrillation, and sleep as the most important new modifiable risk factors in the second Delphi round.

Conclusion

Several new modifiable risk factors for cognitive decline and dementia have been identified in this umbrella review and Delphi consensus study. These factors will be used for updating the existing LIBRA index, which will subsequently be externally validated in population‐based cohort studies.
Visit‐to‐Visit Glucose Variability and Global and Regional Brain Volumes: The Multi‐Ethnic Study of Atherosclerosis (MESA)
Authors: Schaich Christopher L. , Brown Elili R. , Bancks Michael P. , Nasrallah Ilya M. , Bryan R. Nick , Heckbert Susan R. , Luchsinger José A. , Hayden Kathleen M. , Mongraw‐Chaffin Morgana , Hughes Timothy M.
Published: December 2023

Background

Higher visit‐to‐visit fasting glucose variability (GV), indicating worse long‐term glycemic control, is associated with cognitive decline and incident dementia in adults with type 2 diabetes (T2D). We investigated the association of GV with brain volumes in a racially/ethnically diverse cohort of older adults with and without T2D.

Method

Fasting glucose was measured in MESA participants at six examinations from 2000‐2002 through 2016‐2018. Brain volumes including total gray matter (GM), white matter (WM), hippocampal, limbic, basal ganglia, and frontal and temporal lobe GM were measured by 3T MRI in 2017‐2021 (n = 1,429; 43% of surviving cohort). We calculated the standard deviation (SDG) and average real variability (ARV) of glucose across the six exams, and report standardized differences in brain volumes (95% CI) associated with log2‐normalized GV from multivariable linear regression adjusted for site, intracranial volume, age, sex, race/ethnicity, educational attainment, APOE ε4 status, cardiovascular risk factors, hypertension and lipid‐lowering medication use, mean glucose level during GV assessment, and T2D status

Result

Participants had mean age 73 (8) years; were 53% women, 42% White, 12% Chinese, 27% Black, and 19% Hispanic; and 24% had T2D. Two‐fold increments in SDG and ARV were associated with ‐0.06 (‐0.10, ‐0.02) and ‐0.05 (‐0.09, ‐0.01) lower SD units of adjusted total GM volume, respectively. Higher SDG and ARV were further associated with lower adjusted frontal lobe GM volume (‐0.09 [‐0.14, ‐0.04] and ‐0.07 [‐0.12, ‐0.02] SD units, respectively), but not with temporal lobe, hippocampal, limbic, basal ganglia, or WM volumes. Though not associated with GM volumes itself, T2D appeared to modify associations with regional volumes. For example, higher SDG and ARV were associated with lower limbic area volume (‐0.14 [‐0.23, ‐0.04] and ‐0.08 [‐0.17, 0.009] SD units, respectively) in participants with T2D, but not in T2D‐free participants (‐0.02 [‐0.09, 0.06] and ‐0.02 [‐0.09, 0.05] SD units, respectively). Associations were consistent across race/ethnicity.

Conclusion

Higher visit‐to‐visit GV over 16‐18 years is associated with a pattern of lower GM volume driven by frontal lobe volume, a key region for governing executive function. GV may have more involvement with GM volumes among individuals with T2D.
Easing the data sharing burden: perspectives and principles to successfully leverage AD data repositories, infrastructures and functionality
Authors: Sivakumaran Sudhir
Published: December 2023

Critical Path Institute (C‐Path) is a nonprofit organization that brings together patient groups, academic institutions, the pharmaceutical industry and regulatory agencies from around the world to improve public health. C‐Path provides the legal, scientific, and regulatory infrastructure to generate a unique neutral environment for medical product development, supported by more than a decade of experience in data standards development, platform development and hosting, patient‐level data privacy stewardship, data platform security, and controlled access methodology. The Critical Path for Alzheimer’s Disease (CPAD) is a pre‐competitive consortium that aims to promote, support, and manage a diverse source and format of data and facilitate knowledge sharing from the Alzheimer disease (AD) drug development community. The CPAD database currently contains 65 clinical trials and observational studies, with over 93,000 individual anonymized patient‐level records, with global access to many datasets through the C‐Path Online Data Repository (CODR). The unparalleled breadth, depth and wealth of data will enable us to discover yet‐to‐be identified unmet needs and unanswered questions. Further, CODR is interoperable with the Global Alzheimer’s Association Interactive Network (GAAIN), Vivli and other data platforms. The secure and neutral data sharing framework of CPAD has resulted in the development of several regulatory‐grade tools that help optimize drug development and accelerate bringing new therapies to patients in need. Sufficient case examples of successful data sharing are now available and should inform and encourage future data sharing initiatives.
Staging Neurodegeneration Across the AD Continuum
Authors: Moody Jason F , Dean Douglas C , Alexander Andrew L , Johnson Sterling C , Bendlin Barbara B
Published: December 2023

Background

While amyloid and tau staging are ubiquitous in Alzheimer’s disease (AD), there are no equivalent staging techniques for AD‐related neurodegeneration. Currently, neurodegeneration in AD is commonly assessed with structural MRI measures such as hippocampal volume and cortical thickness. However, recent work suggests that markers for microstructural neurodegeneration derived from diffusion MRI (DWI) may provide crucial additional information related to the onset and progression of AD. Neurite density index (NDI) and return to origin probability (RTOP) are two DWI metrics that have shown promise for characterizing these microstructural alterations.

To investigate the utility of DWI for staging neurodegeneration in AD, we implemented logistic regression to compare the abilities of NDI, RTOP, and hippocampal volume to predict AD dementia in 481 late‐middle‐aged participants on the AD continuum.

Methods

481 participants (383 cognitively unimpaired [CU], 68 Mild Cognitive Impairment [MCI], 30 AD) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged with T1‐weighted MRI and multi‐shell DWI. After delineating hippocampal volume, average NDI and RTOP values were extracted from the hippocampus and a whole brain white matter skeleton. All measures were fit to a logistic model with age, sex, and scanner as covariates.

Corresponding ROC curves were used to derive cutoff values for NDI and RTOP by maximizing the Youden Index.

Results

Box plots and ROC curves are provided in Figures 1‐2 and cutoff values for each DWI metric are provided in Table 1. NDI and RTOP outperformed hippocampal volume in predicting AD across brain regions. The best performing marker was WM NDI (AUC = 0.905), followed closely by WM RTOP (AUC = .878). Meanwhile, hippocampal RTOP (AUC = 0.861) slightly outperformed hippocampal NDI (AUC = 0.844).

Conclusion

Our work adds to a growing body of literature which suggests that neuroimaging markers of brain microstructure may capture unique signatures of AD progression. Furthermore, the fact that both DWI measures performed best in whole brain WM reinforces WM degeneration as a core feature of AD pathophysiology. Future work will incorporate CSF and PET measures of amyloid and tau to better characterize AD‐specific neurodegeneration.
A perspective on data sharing from potentially registrational trials
Authors: Sink Kaycee M. , Narburgh Lesley , Hu Nan , Tucker Katherine , Doody Rachelle S.
Published: December 2023

It is well recognized that sharing rich and rigorously collected clinical trial data with researchers who were not conducting the study has the potential to accelerate progress in Alzheimer’s disease.. Such data sharing can contribute to an understanding of pathophysiology, natural history, performance of outcome measures, and the profile of response to treatments, and can help researchers to design better studies and health authorities and payors to evaluate the benefits of therapies. The complexities involved in such data sharing include the need to keep up with evolving patient privacy laws, protecting participant anonymity, ensuring trial integrity, and balancing regulatory and publication requirements. In 2012 Roche/Genentech made a commitment to Banner Alzheimer’s Institute and the NIH to share baseline and longitudinal trial data from the Alzheimer’s Prevention Initiative Autosomal Dominant AD trial, a public‐private partnership. We will describe the mechanisms developed to share data from the API ADAD Trial (baseline data now available; longitudinal clinical, imaging, and biomarker data to follow) including methods employed to protect confidentiality and anonymity of participants, and the process for requesting and accessing baseline data. We will also offer learnings from our experiences in sharing data from other neurodegeneration trials.

The API ADAD trial was funded by NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. Florbetapir PET was partly supported by Avid and Lilly.
Baseline and Longitudinal Changes in Lateral Ventricle Volume Predict Cognitive Decline
Authors: Chen Gengsheng , Gordon Brian A. , Wang Qing , Schindler Suzanne E. , McKay Nicole S. , Liu Jingxia , Joseph‐Mathurin Nelly , Keefe Sarah J. , Aschenbrenner Andrew J. , Massoumzadeh Parinaz , Morris John C , Benzinger Tammie L.S.
Published: December 2023

Background

The use of biomarkers for early detection of Alzheimer disease (AD) is crucial for developing potential treatments. Previous research has linked structural alterations in specific brain regions to cognitive decline. Lateral ventricle volume can be estimated reliably from various modalities of brain imaging, but this has not been well studied as an AD biomarker. In this study, we tested the hypothesis that baseline and longitudinal changes in lateral ventricle volume as measured by MRI could predict changes in global cognitive composite scores.

Method

363 Participants enrolled in longitudinal studies at the Knight ADRC at Washington University in St. Louis were included. Magnetic resonance imaging (MRI) data was obtained through OASIS (www.oasis‐brains.org). Participants were required to have at least two cognitive assessments and MRI scans. Lateral ventricular volumes were extracted and corrected for head size using the FreeSurfer intracranial volume. A global cognitive composite score was calculated from the average z‐scores of 10 neuropsychological tests. A random coefficient model was used to calculate longitudinal change in lateral ventricular volumes, and to assess whether these measures predicted cognitive decline when adjusted for age, sex, APOE Ɛ4, and years of education. Spearman correlation was also used to evaluate the relationship between cognitive decline and baseline or longitudinal changes in lateral ventricle volumes.

Result

We found that baseline and longitudinal changes in lateral ventricle volume predicted the rate of change in global cognitive composite (Table 1 and 2, t = ‐4.82, p<0.0001 and t = ‐3.83, p = 0.0001). Additionally, there were significant correlations between baseline and longitudinal changes in lateral ventricle volume and the rate of change in global cognitive composite (Figure 1, R2 = 0.0657, p<0.0001; and R2 = 0.0412, p<0.0001).

Conclusion

Baseline and longitudinal changes in lateral ventricle volume predicted decline on a global cognitive composite. MRI scanners are widely available world‐wide. Baseline and longitudinal lateral ventricle volumes could potentially be used to stratify risk for cognitive decline for clinical trials.
Association between APOE‐ε4 allele and cognitive function is mediated by Alzheimer’s disease pathology: a population‐based autopsy study in an admixed sample
Authors: Paradela Regina Silva , Paes Vitor Ribeiro , Justo Alberto Fernando Oliveira , Leite Renata Elaine Paraizo , Pasquallucci Carlos Augusto , Grinberg Lea T. , Naslavsky Michel S , Zatz Mayana , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: December 2023

Background

Apolipoprotein E ε4 allele (APOE‐ε4) is the main genetic risk factor for dementia. APOE‐ε4 is also associated with Alzheimer’s disease (AD) pathology, cerebrovascular disease, and non‐AD neurodegenerative pathologies. Although APOE‐ε4 may influence cognitive impairment through these pathways, less evidence is available from diverse populations, considering that APOE genotype associations seem to vary by race. Therefore, we aimed to evaluate the pathways linking APOE‐ε4 to cognition through AD and non‐AD neuropathology in an autopsy study with an admixed sample.

Method

We used data from the Biobank for Aging Studies of the University of Sao Paulo Medical School. Participants were classified into APOE‐ε4 carriers (at least one ε4 allele) and non‐carriers. Cognitive function was evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the APOE‐ε4 association with cognition through direct and indirect pathways. Indirect pathways included the following mediators: AD‐type pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA‐binding protein 43 (TDP‐43). We used immunohistochemistry to detect AD pathology, CAA, LBD, and TDP‐43. AD pathology was scored using the Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for AD criteria for β‐amyloid plaque. Lacunar infarcts and hyaline arteriosclerosis were evaluated microscopically using hematoxylin and eosin‐stained. All analyses were adjusted for demographic and clinical cofounders.

Result

We included 648 participants (mean age 75±12 y, 52% women, 69% white, and 28% APOE‐ε4 carriers). The association between APOE‐ε4 and cognitive abilities was mediated by the burden of neurofibrillary tangles (β = 0.78, 95% CI = 0.39; 1.22, p<0.001) and β‐amyloid plaques (β = 0.87, 95% CI = 0.39; 1.40, p<0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP‐43 were not mediators in the pathway from APOE‐ε4 to cognitive function. Direct pathways remained significant in the presence of all mediators except TDP‐43 (p = 0.09) and β‐amyloid plaques (p = 0.07).

Conclusion

The influence of APOE‐ε4 on cognitive abilities was partially mediated by AD pathology. However, cerebrovascular lesions and non‐AD pathologies were not mediators in the pathway linking APOE‐ε4 to cognition.
Novel quantitative method for characterization of hippocampal sclerosis and its association with other neuropathologies and cognitive deficits
Authors: Sordo Lorena , Qian Tianchen , Nguyen Katelynn M. , Bukhari Syed A. , Woodworth Davis C. , Montine Thomas J. , Head Elizabeth , Corrada María M. M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: December 2023

Background

Hippocampal sclerosis of aging (HS) is characterized by neuronal loss and astrogliosis in subiculum and/or CA1 subfield of hippocampus. Using a novel quantitative approach, we studied the prevalence and localization of HS pathology in a well‐characterized oldest‐old cohort and examined its association with other neuropathologic changes and cognitive impairment.

Methods

We studied 409 consecutive autopsied participants of The 90+ Study with longitudinal assessments. In those with HS by traditional method (presence/absence), we used digitized hematoxylin and eosin and luxol fast blue hippocampal slides for further quantitative analysis. Using QuPath, we measured the length of each hippocampal subfield partitioned into three subregions (Figure1). We then calculated the proportion affected by HS for each subregion. Both traditional (presence/absence) and quantitative (subfield‐specific proportions) measures were used to study the relationship between HS and other neuropathologic changes and cognitive outcomes using regression models adjusted for sex, age at death, and education with all neuropathologic changes as covariates.

Results

HS was present in 11% of participants and was always focal, mostly affecting CA1 (89%), followed by subiculum (27%). Overlapping CA1/subiculum pathology was seen in 16% (Figure2). Left‐sided HS was more frequent (75%) than right‐sided (18%). Bilateral cases were the least frequent (7%). HS presence (traditional measure) was only associated with Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (OR = 3.45, p<0.001). Quantitative measures revealed that HS proportion in subiculum and CA1 was associated with arteriolosclerosis (t36 = 4.11, p = 0.001) and LATE (t35 = 2.98, p = 0.005). HS proportion in subiculum alone was inversely associated with microvascular lesions (t41 = ‐3.16, p = 0.003) (Table1). HS proportion in subiculum and CA1 was associated with dementia at death and impairment of memory, language, calculation, and orientation. HS proportion in subiculum was additionally associated with impaired executive function. HS traditional measure was only associated with impaired orientation (Table1).

Conclusion

Based on our novel quantitative analysis, HS pathology was always focal, mostly unilateral, and associated with dementia and impairment in major cognitive domains. We found associations between HS and vascular pathologies that were not detected using traditional measure. The associations of HS with dementia and impaired memory, language, and calculation, identified with our quantitative method, were not detected using traditional measure.
Sex‐specific effects of genetically predicted BMI and education on risk of AD
Authors: Andrews Shea J , Chao Michael J , Fulton‐Howard Brian , Pa Judy , Yaffe Kristine , Goate Alison
Published: December 2023

Background

Examining sex differences on the impact of modifiable risk factors in Alzheimer’s disease (AD) risk can help us better understand the mechanisms underlying sex differences in the prevalence and incidence of AD. Here, we used polygenic risk scores (PRS) and Mendelian randomization (MR) to investigate sex‐specific effects of sleep duration, insomnia, blood pressure, diabetes, alcohol intake, smoking, body mass index, high cholesterol, and education on AD risk.

Method

We obtained combined and sex‐stratified genome‐wide association study (GWAS) summary statistics for each risk factor from the UK Biobank and used them as the base dataset for constructing PRS and exposure datasets in the MR analysis. Linkage disequilibrium clumping was performed to identify independent genome‐wide significant single nucleotide polymorphisms (SNPs) across the sex‐combined, male‐specific, and female‐specific GWAS. The combined lead SNPs were then weighted by their strata‐specific effect sizes in the stratified PRS and MR analyses. PRS were constructed for each risk factor in participants from the Alzheimer’s Disease Genetics Consortium. Linear regression was used to investigate the association of each PRS with AD risk, adjusting for age, principal components, and cohort. MR was used to estimate sex‐stratified causal effects of each risk factor on AD. Sex differences in PRS associations and MR causal estimates were determined using Fisher’s Z score method.

Results

Association testing of the PRS with AD risk in sex stratified cohorts revealed that the BMI PRS was associated with differential effects in men and women (OR [95%CI]: males: 1.05 [1.00, 1.10] vs females: 0.96 [0.93, 0.99], p = 0.003). Furthermore, the university completion PRS was non‐significant in men but was associated with reduced risk in women (OR [95%CI]: males: 0.96 [0.92, 1.01] vs females: 0.92 [0.89, 0.96], p = 0.12). In the follow‐up MR analysis, university completion was also causally associated with reduced risk in women only (OR [95%CI]: males: 1.09 [0.77, 1.53] vs females: 0.55 [0.42, 0.72], p = 0.002) (Figure 1). No other risk factors showed evidence of sex‐differences.

Conclusion

Our study found sex‐specific effects of genetically predicted BMI and educational attainment on AD risk. These findings suggest the need for sex‐specific approaches to AD prevention and management.
TMS‐based measures of cortical excitability are related to distributed atrophy in early Alzheimer’s disease
Authors: Buss Stephanie S. , Zeng Victor , Manning Daniel , Touroutoglou Alexandra , Dickerson Brad C. , Press Daniel Z. , Shafi Mouhsin , Pascual‐Leone Alvaro , Fried Peter J.
Published: December 2023

Background

Alzheimer’s disease (AD) is associated with increased cortical excitability, including an elevated risk of seizures. Transcranial magnetic stimulation with electromyography (TMS‐EMG‐EEG) can be used to index intracortical excitability. Prior work has shown that TMS‐based excitability measures are altered in AD and are related to disease severity. However, it is not yet known how TMS‐EMG measures are related to neurodegeneration within brain regions affected by AD.

Method

TMS‐EMG was applied to left motor cortex (M1) in 22 participants with biomarker‐confirmed mild cognitive impairment due to AD (early AD, aged 70.5±8.4, 11 females). Single pulse TMS was preformed to measure resting motor threshold (RMT) and motor evoked potential amplitude (MEP Amplitude). Paired‐pulse TMS was preformed to measure short interval intracortical inhibition (SICI, GABA‐ergic) and intracortical facilitation (ICF, glutamatergic). In 5 participants, TMS‐evoked responses on EEG were also obtained during single‐pulse stimulation to M1 and the inferior parietal lobe (IPL), and the local mean field amplitude (LMFA) was computed from 15 to 40 msec after the TMS pulse. Structural MRI scans for each participant were processed using Freesurfer to obtain cortical thickness measurements within the distributed Alzheimer‐signature brain regions (AD‐signature atrophy). The primary analyses tested the relationship between each TMS measure and AD‐signature atrophy using separate linear models, controlling for age. For TMS‐EEG analysis, effect sizes were reported in lieu of p‐values given the small sample sizes.

Result

In early AD, SICI was related to AD‐signature atrophy (R2
adj = 0.40, B = ‐0.13, p = 0.018; Fig1), with less intracortical inhibition related to greater atrophy. RMT, MEP Amplitude, and ICF were not related to AD‐signature atrophy (p‐values>0.105). There was a large effect size of IPL LMFA on AD‐signature atrophy (R2
adj = 0.70), while the effect size of M1 was small (R2
adj = ‐0.19).

Conclusion

Decreased intracortical inhibition is related to increased AD‐signature atrophy in early AD. Decreased function of GABA‐A circuitry related to cortical atrophy may play a role in the development of cortical hyperexcitability in AD. Our preliminary results further suggests that TEPs from stimulation of IPL, a node of the default mode network and an area commonly showing AD pathology, may also be related to AD‐signature atrophy.
Sex‐specific associations of gene expression in brain with Alzheimer’s disease pathology and cognitive performance
Authors: Clifton Michelle , Seto Mabel , Buckley Rachel F. , Gifford Katherine A. , Jefferson Angela L. , De Jager Philip L , Bennett David A. A , Barnes Lisa L. , Wang Yanling , Schneider Julie A , Hohman Timothy J. , Dumitrescu Logan C
Published: December 2023

Background

Alzheimer’s disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized.

Methods

We leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05).

Results

Of the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2).

Conclusion

Our results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation.