bluuebunny/crossref_metadata_2025 huggingface dataset:
Residual reserve index modifies the effect of amyloid pathology on FDG metabolism: implications for efficiency and capacity in cognitive reserve
Authors: McKenzie Cathryn , Bucks Romola S , Weinborn Michael , Bourgeat Pierrick , Salvado Olivier , Gavett Brandon E
Published: December 2022

Background

Cognitive functioning may be protected against AD pathology via cognitive resilience (conferred by cognitive reserve) or brain resilience (conferred by brain reserve or maintenance). The residual approach to measuring cognitive reserve (i.e., using the residual reserve index) aims to capture cognitive resilience, but may be confounded by unmeasured brain factors representing brain resilience. We sought to distinguish between brain and cognitive resilience by comparing the interactions between the residual reserve index and amyloid, tau, and neurodegeneration (AT(N); Jack et al., 2018) biomarkers when predicting executive function. We hypothesized that the residual reserve index would moderate at least one path from an AT(N) biomarker to executive function (consistent with cognitive resilience), as opposed to moderating a path between two AT(N) biomarkers (suggestive of brain resilience).

Method

Participants were 332 older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). AT(N) biomarkers were measured as follows: amyloid = CSF Aβ42/Aβ40; tau = plasma p‐tau181; neurodegeneration = FDG metabolism in AD‐specific regions. AT(N) biomarkers were measured at consecutive time points and entered in a sequential mediation model testing the indirect effects from amyloid to executive function intercept and slope, via tau and/or FDG metabolism. The residual reserve index was entered as a moderator of paths between AT(N) biomarkers, and between AT(N) biomarkers and executive function.

Result

The only significant interaction was between the residual reserve index and amyloid when predicting FDG metabolism, such that the indirect effect of amyloid → FDG metabolism → executive function intercept and slope varied as a function of the residual reserve index. With lower amyloid pathology, a higher residual reserve index predicted better executive function via lower FDG metabolism. With higher amyloid pathology, a higher residual reserve index predicted better executive function via higher FDG metabolism.

Conclusion

Although the residual reserve index moderated a path between two AT(N) biomarkers, the net effect was consistent with cognitive rather than brain resilience. Our results suggest the residual reserve index captures variation in cognitive reserve; specifically, neural efficiency and neural capacity to upregulate metabolism to enhance cognitive resilience in the face of more severe amyloid pathology.
Social Determinants Influencing the Severity of Dementia on Screening: An Observational Study in the Indian Population
Authors: Kainth Tejasvi , Singh Gagandeep , Prasanna Prateek , Manjila Sunil , Rao Anitha
Published: December 2022

Background

With increased longevity and decreased fertility rate, the percentage of population over 65 years of age is growing in India. Literacy rates, family size, socioeconomic status, and comorbidities are rapidly changing due to the increased migration from rural to urban areas. Data‐driven studies are required to determine the influence of social factors and comorbidities on the distribution of Alzheimer’s disease and related dementias (ADRD) and neurological care resources. We demonstrate results from a feasibility study that uses state‐of‐the‐art AI, data analytics, and a HIPAA‐compliant Telehealth platform to screen patients over 65 years in India for ADRD.

Method

A primary care provider used a telemedicine platform, Artificial Intelligence (AI), and a standardized cognitive test to screen every consenting patient aged 65 years and older. The screening used an algorithm‐based intake tool, baseline Mini‐Mental Status Exam (MMSE), and clinical judgment of the primary care physician. We documented sociodemographic data and comorbidities: age, gender, education, living situation (family size), geographical location (urban/rural), the number and types of comorbidities.

Result

Nine patients (4 females, 5 males) over 65 years of age, consented and enrolled in this study. 55% (5 in 9 patients) had a bachelor’s degree or higher, 22% (2 in 9 patients) were high school graduates, 22% (2 in 9 patients) were 8th grade and below. 44% (4 in 9 patients) were from rural backgrounds, and 55% (5 in 9 patients) lived in urban backgrounds. 44% (4 in 9 patients) had one comorbidity, 11% (1 in 9 patients) had two comorbidities, 44% (4 in 9 patients) had three and more comorbidities. Out of four patients screened as mild dementia by AI (44%), three patients (75%) had two or more underlying comorbidities.

Conclusion

Our results demonstrate that medical comorbidities and social determinants may influence India’s ADRD severity scores and neurocognitive screening. We can use the results to address foreseeable gaps for ADRD screening and ensure equitable resource distribution via telemedicine in India. The data captured in this AI and telemedicine collaboration may provide the foundation for identifying new biomarkers and developing targeted treatments that work for ethnically diverse patients.
Dyadic retention in a phase 3 mild cognitive impairment clinical trial
Authors: Hakhu Navneet R , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

Exiting a study early (dropout) may bias treatment effect estimates, while dropout and missing visits reduces study power. Simply increasing planned sample sizes cannot remove bias due to non‐ignorable missingness (Fleming, 2011). Preventing missing data is best (National Research Council, 2010). Hence, quantifying associations with missingness may identify ways to improve retention. Alzheimer’s disease (AD) clinical trials require study participation by a participant and study partner. Previous research examined dyadic retention in AD dementia trials (Grill et al., 2013; Bernstein, Grill & Gillen, 2021), yet less is understood in mild cognitive impairment (MCI) trials. Here, we examined MCI trial dropout rates and missingness patterns by dyad type.

Method

We performed retrospective analyses of the Alzheimer’s Disease Cooperative Study phase 3 MCI trial of donepezil and vitamin E. Scheduled study visits occurred at baseline, month 3, and semi‐annually until month 36. Study completion included the progression to a possible or probable AD diagnosis or month 36 visit. Dropout was withdrawal of consent or lost‐to‐follow‐up. Deaths and study completions were censored. Dyad types were spousal, adult child, or other. We estimated Kaplan‐Meier‐based dropout rates and summarized frequencies of on‐study missing visit patterns by baseline dyad type and stratified by randomized treatment (placebo, donepezil, vitamin E).

Result

Figure 1 displays cumulative dropout rates by dyad type and treatment (panels A, B, C). Among 259 participants randomized to placebo, estimated study dropout rates were 24% for spousal, 16% for adult child, and 14% for other dyads. Table 1 summarizes on‐study missing visit patterns by dyad type and treatment; Figure 2 displays placebo data for specific patterns of missing data. While on study, 21% of spousal, 23% of adult child, and 27% of other dyads missed at least one scheduled visit, primarily monotonic missingness.

Conclusion

Dyad type may be associated with some types of missingness in MCI clinical trials. Implementing dyad‐type‐specific strategies that encourage staying on study and attending all scheduled visits may improve retention, thus reducing bias, in future MCI trials.
Diverse Ancestral Populations and the ADSP
Authors: Kunkle Brian W. ,   Alzheimer’s Disease Sequencing Project (ADSP)
Published: December 2022

Background

A major goal of the ADSP is to fully reveal the genetic architecture of AD/ADRD across diverse ancestral populations with the hope that new discoveries and the therapeutic or prevention strategies they enable will benefit all ancestral groups.

Method

While the project’s ‘Discovery Phase’ (2012‐2017) sequenced predominantly non‐Hispanic White individuals of European ancestry (NHW‐EA) [whole‐exome sequencing: N = 10,061; whole‐genome sequencing (WGS): 197 NHW‐EA and 351 Hispanic/Latino (HL) familial individuals], the ‘Discovery‐Extension Phase’ of the project added WGS on 1,183 NHW‐EA, 1,141 HL, and 1,070 non‐Hispanic Black individuals with African ancestry (NHB‐AA). The ADSP’s current phase, the Follow‐Up Study (FUS) (2018‐2023) has targeted existing ancestrally diverse and unique cohorts with clinical AD/ADRD data. Over 40,000 individuals have been ascertained and ∼32,000 sequenced to date (ancestry distribution: 9,192 NHB‐AA; 9,952 HL; 13,531 NHW‐EA, 4,600 East Asian, 2,760 Indian, 89 Amerindian).

Result

Despite relatively small sample sizes, important instances of unique AD/ADRD genetic variation have been identified in HL and NHB‐AA studies, including population‐specific rare/low‐frequency variants, and evidence of the importance of ancestral background in conferring risk for genetic factors such as APOE ε4. Power studies show ∼16,100 cases and ∼16,100 controls are needed per ancestry for discovery of risk/protective variants with minor allele frequency (MAF) of 0.5% and odds ratios (OR) of 2.0 at genome‐wide significance (P = 5×10−8). Using region‐based testing ∼10,000 cases and ∼10,000 controls are needed for finding variants with MAF = 0.005% and ORs = 1.4. To this end, the next phase of the ADSP, the “ADSP‐FUS 2.0: The Diverse Population Initiative” NIH_PAR‐21‐212 aims to ensure there are enough study participants to achieve statistical power for rare variant analysis in the largest US populations, with a particular focus on HL, NHB‐AA, and Asian populations. Initiatives such as the Asian cohort for Alzheimer’s disease (ACAD), focusing on increasing recruitment of Asians in AD/ADRD studies, are also in development.

Conclusion

These datasets, some of which will include data for assessing social and environmental influences of AD/ADRD, will be an invaluable resource for the AD research community and will enhance ongoing efforts for the identification of shared and novel genetic risk factors for AD/ADRD across populations.
Incentives to increase willingness to undergo research lumbar puncture
Authors: Witbracht Megan G. , Baumgartner Morgan , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

Alzheimer’s disease (AD) research increasingly relies on biomarker testing to understand longitudinal biological contributions to clinical disease progression. The collection of cerebrospinal fluid (CSF) through a lumbar puncture (LP) is an efficient method to obtain reliable AD biomarkers; however, most people are unwilling to participate in the procedure for research. This study aimed to understand what incentives could be offered to increase the propensity for people to consider a research LP.

Method

As part of a previous study testing an educational intervention to increase willingness to consider the research LP (Witbracht et al, 2020), we asked participants an open‐ended question about incentives that could be offered to change their mind about undergoing a research LP. One reviewer assessed a subset of responses to establish preliminary categories of independent themes. A second reviewer assessed these themes and then a consensus exercise was used to create final themes for coding. Two reviewers then coded all responses and discordant assignments were resolved by a third rater.

Result

Of 851 participants who enrolled in the study, 467 answered the open‐ended question. Among those who responded, 72.8% were female; 87.6% were white; 86.7% were non‐Hispanic. The mean age of respondents was 57.9 (15.2) years and the mean years of education was 18 (9.0). Responses deemed valid incentives were provided by 205 (44%) participants, while 121 participants (26%) indicated that nothing could be offered to make them more likely to consider the procedure and 30% provided a non‐incentive response. The top 3 themes identified accounted for 60% of the total coded incentives: financial compensation (n=69), diagnostic value (n=30), and more information (n=26). Other themes identified included assurance of no adverse events, post procedure care, performance by a qualified clinician, improved techniques, mitigated fear, first person testimonies of procedure, evidence of research value, providing logistical support, approval from personal doctor, anda guarantee of no biomarker disclosure.

Conclusion

Barriers to recruitment are significant for research involving LP. Participants in this study identified several feasible (and some infeasible) incentives that could increase willingness to consider a research LP.
Contribution of modifiable dementia risk factors to cognitive performance and subjective cognition in middle‐aged adults
Authors: Bransby Lisa , Rosenich Emily , Buckley Rachel F. , Yassi Nawaf , Maruff Paul , Pase Matthew P , Lim Yen Ying
Published: December 2022

Background

Characterization of the contribution of modifiable risk factors (MRF) to dementia generally consider MRFs individually, despite strong evidence that MRFs co‐occur. In a large group of middle‐aged adults, the prevalence and co‐occurrence of MRFs for dementia was determined, spanning five broad domains (mood, lifestyle behaviours (e.g., physical inactivity), cardiovascular health, cognitive/social engagement, and sleep). We then investigated relationships between MRFs, both individually and combined, to cognitive performance and subjective cognition.

Method

Middle‐aged adults (n = 1610), most (70%) with a family history of dementia, enrolled in the Healthy Brain Project, completed an extensive set of questionnaires about their physical and psychological health and lifestyle. Participants also completed the Cogstate Brief Battery (CBB), and the Cognitive Function Instrument (CFI), a measure of subjective cognition. Participants were classified according to the number of domains (mood, lifestyle behaviours, cardiovascular health, cognitive/social engagement, and sleep, ranging from 0‐5) in which they reported at least one MRF. Age, sex, education and ethnicity were adjusted for in analyses.

Result

Most participants (65%) reported at least one MRF in two or more domains (Fig 1A). Compared to participants reporting no MRFs, participants who reported at least one MRF in 3‐5 domains showed worse memory performance and reported greater subjective cognitive concerns, with magnitudes of differences moderate to large (d = 0.30‐0.93; Fig 1B). Participants who reported at least one MRF in five domains also showed worse attention than those reporting no MRFs (d = 0.58). When individual MRFs were considered simultaneously, MRFs in the mood (e.g., anxiety symptomatology) and cognitive/social engagement domains (e.g., leisure activities) were associated with worse attention and memory performance. Individual MRFs reflecting mood and sleep symptomatology were associated with greater subjective cognitive concerns.

Conclusion

In middle‐aged community dwelling adults, multidomain MRFs for dementia are highly prevalent and co‐occur, and are associated with poorer cognitive outcomes. This suggests that the presence of multiple MRFs as early as midlife may have negative neurological outcomes, however, this will need to be explored in future neuroimaging studies. These findings indicate that multidomain lifestyle prevention trials in middle‐aged adults may be useful to delay or prevent future cognitive impairment or dementia.
Translating network activity in an Alzheimer mouse model to human Alzheimer's disease mutation carriers
Authors: van Nifterick Anne M , van Heusden Fran C , Stam Cornelis J , Scheltens Philip , van Kesteren Ronald E. , Gouw Alida A
Published: December 2022

Background

Alzheimer’s disease (AD) mouse models allow for the identification of cellular and molecular processes underlying neuronal network imbalance. In order to interpret these processes in a disease context, we need to link network changes in AD animals to those in human patients. Brain oscillations reflect neuronal network (im)balance and offer a tool to translate findings from mice to men. In this preliminary study, we investigate and compare cortical and hippocampal oscillatory activity using magnetoencephalography (MEG) in human patients and longitudinal electrophysiology recordings in AD mice.

Methods

Source reconstructed resting state whole‐brain MEG of ten APP and PSEN1 mutation carriers and ten age‐ and gender‐matched control subjects were acquired. Carriers did not show objectively impaired cognitive functioning on any of the composite scores after extensive neuropsychological testing. Longitudinal local field potential recordings were obtained by implanted electrodes in APP/PS1 transgenic and wildtype controls from 3 until 10 months of age in different brain regions of the left hemisphere: hippocampus, prefrontal and parietal cortex. MEG analyses were constrained to similar brain regions. We estimated peak frequency, total (absolute broadband) and relative power across canonical frequency bands and compared these between human or mice mutation carriers and controls.

Results

Human APP and PSEN1 mutation carriers showed lower peak frequency in the hippocampus and lower relative alpha 2 power in the precuneus and frontal cortex compared to controls (Fig1.). APP/PS1 mice also showed specific network alterations compared to wildtype control mice, but these seem to have more faster oscillations instead.

Conclusion

In cognitively unimpaired human APP and PS1 mutation carriers we find oscillatory activity changes in the cortex and hippocampus, indicating network imbalance. However, opposite network changes are observed in the APP/PS1 AD mouse model compared to human mutation carriers using spectral measures. Future studies should explore other measures of network imbalance to identify potential cross‐species mechanistic links of early stage AD.
Best combination of CSF biomarkers for predicting cognitive decline and clinical progression: A multi‐cohort study
Authors: Salvadó Gemma , Larsson Victoria , Cody Karly Alex , Cullen Nicholas , Jonaitis Erin M. , Stomrud Erik , Kollmorgen Gwendlyn , Wild Norbert , Palmqvist Sebastian , Janelidze Shorena , Mattsson‐Carlgren Niklas , Zetterberg Henrik , Blennow Kaj , Johnson Sterling C. , Ossenkoppele Rik , Hansson Oskar
Published: December 2022

Background

Amyloid‐β (Aβ) and tau markers have very good prognostic value for Alzheimer’s disease (AD); however, novel neurodegeneration and glial‐related cerebrospinal fluid (CSF) biomarkers may help further improve prognosis. Using multiple CSF biomarkers from a single multi‐panel, we explored the combination of biomarkers that best predicts cognitive decline and clinical progression in three separate cohorts with relevance for clinical practice and trials.

Method

In this study, we included 1,991 participants (cognitively unimpaired [CU], n=1,462; mild cognitive impairment [MCI], n=529) from three separate cohorts (BioFINDER‐1, BioFINDER‐2 and Wisconsin’s: Wisconsin Registry for Alzheimer’s Prevention [WRAP] & Wisconsin Alzheimer’s Disease Research Center [WADRC]; Table 1) with longitudinal cognitive and clinical measurements. CSF was measured in all participants using the NeuroToolKit panel (a panel of automated Elecsys® and robust prototype immunoassays, Roche Diagnostics International Ltd) for biomarkers of AD pathology (p‐tau/Aβ42 ratio), neurodegeneration (neurofilament light chain [NfL], neurogranin, and α‐synuclein), and glial function (sTREM2, GFAP, YKL‐40, IL‐6, and S100b). Linear mixed models and generalized linear mixed models were used in each cohort to identify biomarker combinations most predictive of clinical progression (to Alzheimer’s dementia or all‐cause dementia) or cognitive decline (Preclinical Alzheimer’s cognitive composite [PACC] for CU and Mini‐Mental State Examination [MMSE] for MCI). Best performing models were compared to single‐predictor (p‐tau/Aβ42) models using Akaike information criterion (AIC) and areas under the curve (AUC), respectively.

Result

Only p‐tau/Aβ42 ratio was selected as predictor in the parsimonious models for predicting conversion to Alzheimer’s dementia in all cohorts and conversion to all‐cause dementia in the Wisconsin’s cohort (Table 2, Figure 1). In the other two cohorts, model performance was significantly improved by the addition of NfL and neurogranin (BioFINDER‐1) and NfL alone (BioFINDER‐2). For predicting cognitive decline, parsimonious models included p‐tau/Aβ42 ratio alone (MMSE in BioFINDER‐1 and PACC in the other cohorts) or together with NfL (rest) as predictors.

Conclusion

The CSF p‐tau/Aβ42 ratio is sufficient for prediction of AD progression, showing very high accuracy in three separate cohorts. The addition of NfL to p‐tau/Aβ42 can be applied to a clinical setting to further improve the prediction of all‐cause dementia and cognitive decline.
Medial temporal lobe subregional atrophy patterns in early‐ and late‐onset amnestic Alzheimer’s disease
Authors: Wuestefeld Anika , Wutt Hmon , Berron David , Baumeister Hannah , Binette Alexa Pichet , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , van Westen Danielle , Hansson Oskar , Wisse Laura EM
Published: December 2022

Background

The medial temporal lobe (MTL) is hypothesized to be relatively spared in early‐onset compared to late‐onset Alzheimer’s disease (AD). However, detailed examination of MTL subfields comparing amnestic early‐ and late‐onset AD is lacking. We investigate MTL subfield atrophy patterns in individuals with amnestic early‐ and late‐onset cognitive impairment (EOCI and LOCI).

Methods

Cognitively impaired (mild cognitive impairment and dementia) adults from the BioFINDER‐2 study with memory impairment (>1.5SD age‐ and education‐specific norms), amyloid‐beta (Aβ+ based on CSF Aβ42/40), and tau positivity were included (Table 1). [18F]RO948‐PET standardized uptake value ratios (SUVRs) were calculated for the MTL, and tau‐PET positivity was determined from a temporal meta‐ROI. EOCI individuals were <65 years, LOCI >70 years of age. Self‐reported age‐of‐onset matched with EO/LO status. Two reference groups of Aβ‐ cognitively unimpaired (CU) which were age‐matched to EOCI/LOCI were included. Hippocampal subfield volumes and thickness of entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex were obtained using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted MRI. We focused particularly on BA35, region with earliest tau accumulation. Episodic memory was determined (errors on delayed word‐list recall).

Results

Compared to CU, LOCI showed widespread atrophy across all MTL subfields, while the atrophy pattern in EOCI was slightly more restrictive (Fig. 1). Compared to EOCI, LOCI showed more severe atrophy in hippocampal subfields and entorhinal cortex.

There was no difference between EOCI and LOCI for MTL tau‐PET SUVR (Fig. 2).

Zooming in on BA35, there was a trend for an association between MTL tau‐PET SUVR and BA35 atrophy in LOCI. This association was stronger for EOCI but non‐significant, likely due to limited power (Fig. 2C). In both groups, smaller BA35 was associated with worse episodic memory (Fig. 3A). In LOCI, higher MTL tau‐PET SUVR was associated with worse episodic memory (Fig. 3B).

Conclusion

The findings suggest that MTL tau‐PET uptake and atrophy is present in both amnestic LOCI/EOCI and is related to the observed memory impairment in these groups. The MTL atrophy pattern is more extensive in LOCI, which may be due to longer presence of tau pathology and/or the involvement of comorbid pathologies.
A synergistic association of diabetes and AD biomarkers on cognitive decline in persons without dementia?
Authors: van Gils Veerle , Jansen Willemijn J. , Hort Jakub , Martinez‐Lage Pablo , Ramakers Inez H.G.B. , Rouaud Olivier , Zetterberg Henrik , Dalsgaard Søren , Verhey Frans R.J. , Visser Pieter Jelle , Vos Stephanie J. B. , Consortium EMIF‐AD MBD , Consortium EPAD
Published: December 2022

Background

To improve prognostic procedures, we aimed to explore whether diabetes mellitus and Alzheimer’s disease (AD) biomarkers are synergistically associated with cognitive decline in persons without dementia.

Method

We included 1.737 persons with normal cognition (NC) and 634 with mild cognitive impairment (MCI) from 8 European memory clinic and aging cohorts as part of the PRIME project. We examined cognitive decline in MMSE (raw scores), memory (delayed recall), attention, executive functioning, and language domains (Z‐scores). AD biomarkers included CSF amyloid‐beta42 (data‐driven cut‐offs) or amyloid PET (center‐specific cut‐offs) as measure of amyloid positivity, CSF p‐tau as measure of tau tangle positivity and CSF t‐tau as measure of neurodegeneration (both center‐specific cut‐offs). We performed generalized linear mixed models with random intercepts and slopes, all adjusted for demographics.

Result

Mean age was 65.9 (SD=8.9) years, 54% were women, and diabetes was diagnosed in 7% of NC and 12% of MCI. Mean follow‐up time was 1.8 years (range 0.5‐8).

In NC, we found decline in memory and attention in persons with both diabetes and t‐tau positivity. This was not shown in persons with only diabetes or only t‐tau positivity (Figure 1). We also found this interaction between diabetes and p‐tau on attention decline (Table 1). When stratifying for amyloid status, we found that this was only significant in amyloid negative individuals (memory t‐tau: p=0.005, attention p‐tau: p=0.033, attention t‐tau: p=0.039). A higher baseline language performance was found in persons with both diabetes and p‐tau or t‐tau positivity (p=0.011; p=0.034) compared to those with only diabetes or tau positivity. We found steeper decline in language in persons with both diabetes and amyloid positivity, compared to other groups (Figure 2). A similar synergism with diabetes was found for p‐tau. No interaction was found for executive functioning.

In persons with MCI with both diabetes and t‐tau positivity, we found higher baseline MMSE scores (p=0.041) compared to other groups. Diabetes was not associated with cognitive decline in any domain in MCI.

Conclusion

Diabetes may affect non‐AD‐related decline in memory and attention as well as AD‐related decline in language at an early clinical stage. This may help improve prognostic procedures.
Five pathophysiological Alzheimer’s disease subtypes detected with unsupervised clustering of CSF proteomics
Authors: Tijms Betty M. , Wesenhagen Kirsten E. J. , Teunissen Charlotte E. , Scheltens Philip , Birkeland Even , Berven Frode , Visser Pieter Jelle
Published: December 2022

Background

We previously identified three CSF proteomic Alzheimer’s disease (AD) subtypes: one with increased amyloid metabolism and aberrant neuronal plasticity, one with innate immune activation and one with blood‐brain barrier dysfunction. We studied their replicability in another cohort, and whether increasing the number of proteins (from 556 to 1059) would enable detecting more subtypes.

Method

We selected 419 AD individuals with abnormal CSF abeta42 and 187 controls (normal cognition and normal AD biomarkers) from Alzheimer center Amsterdam studies. With 16‐plex TMT‐MS we detected 3987 proteins in CSF, of which we clustered 1059 proteins with complete observations that were associated with AD (all p<.05). Subtypes were compared on all 2906 proteins with at least 10 observations per subgroups. Potential upstream drivers of molecular subtypes were identified with ENRICHR.

Result

We found 5 subtypes with distinct protein profiles, of which three subtypes were highly concordant with our previously observed subtypes (figure1: subtype 1a, 2a and 2b) and two were new (1b and 1c). Compared to controls, subtype 1a, 1b and 1c had high levels of neuronal plasticity proteins, and subtype 2a and 2b had low levels of plasticity proteins. Thirty‐one proteins were increased in all subtypes (figure 2). Subtype 1a individuals (n=137, 32%) also showed increased amyloid processing. Their 827 proteins associated with REST and SUZ12 as potential upstream drivers. Subtype 1b individuals (n=124, 30%) also showed increased levels of inflammation proteins. Their 988 proteins converged on SOX2 as potential upstream driver. Subtype 1c individuals (n=24,6%), also showed proteasome dysfunction. Their 517 proteins were associated with TAF1 and MYC as potential upstream drivers. Subtype 2a individuals (n=78, 19%) showed increased levels of 469 proteins, of which 45% is expressed by the choroid plexus. These converged on NFE2L2. Subtype 2b individuals (n=56, 13%) showed high levels of 649 proteins that associated with blood‐brain barrier (BBB) leakage. These proteins converged on ERG1 and ESR1 as potential upstream drivers.

Conclusion

In this new dataset we replicated three AD subtypes, and detected two new subtypes. Subtypes differed on plasticity proteins, immune activation, choroid plexus function and BBB function. Each AD subtypes may require a different treatment.
A multimodal pilot study of default mode network (DMN) connectivity across the lifespan in healthy volunteers using functional imaging, CSF, and plasma Alzheimer's disease biomarkers
Authors: Shapiro Noah L , Galler Jake A , Trombetta Bianca A. , LaCasse Kathryn , Ramirez Christopher E. , Riley Misha M. , Williams Victoria J. , Kivisäkk Pia , Salat David H , Rashid Barnaly , Arnold Steven E.
Published: December 2022

Background

Normal aging is associated with decreased functional connectivity (FC) in the brain’s default mode network (DMN). Additionally, cerebral burden of both amyloid‐β (Aβ) and tau proteins further contribute to decreased DMN FC in the course of the normal aging process (Wales and Leung, 2021). However, the current literature is sparse and unclear as to the independent actions of Aβand tau on FC of DMN, with tau being associated with general hypoconnectivity (Wales and Leung, 2021). The current pilot study examines resting state fMRI (rsfMRI) data in conjunction with Alzheimer’s Amyloid/Tau/Neurodegeneration (ATN) biofluid biomarkers in healthy individuals, using the isthmus cingulate of the retrosplenial cortex as seed for FC analysis of the DMN.

Method

rsfMRI scans are collected in the LifeSPAN Biobanking project [ongoing]. Scans are preprocessed utilizing standard FreeSurfer pipeline. Standard parcellations are assigned using the Desikan‐Killiany atlas. In initial analyses, isthmus cingulate served as the seed for DMN analysis using the FSFAST processing stream within FreeSurfer. ATN biomarkers are obtained from cerebrospinal fluid (CSF) and the following biomarker ratios were computed: Aβ42/Aβ40 (Aβ ratio) and phosphorylated tau‐181 (pTau181) / total Tau (tTau) (pTau181/tTau ratio).

Result

In the initial 14 participants (aged 26‐82 years) [Table 1], General Linear Models (GLMs), adjusted for age, were utilized to evaluate the associations between DMN FC and the following AD biomarkers: Aβ40, Aβ42, Aβ ratio, tTau, pTau181, and pTau181/tTau ratio [Table 2; Figure 1]. After correcting for multiple comparisons (p<0.05), significant association between tTau, and the FC between the DMN and the right inferior temporal region was observed [Table 3].

Conclusion

The pilot analysis indicates at least tTau has an association with DMN FC, but sample size precludes conclusion or interpretation. Preliminary data obtained in this exploratory analysis provides a framework for examining the effect of AD biomarkers on the DMN and other functional networks. Future research will incorporate synaptic, inflammatory and other markers into similar statistical models and report preliminary associations.

Reference

Wales R, Leung H‐C. The Effects of Amyloid and Tau on Functional Network Connectivity in Older Populations. Brain. 2021;142(8):2483‐2491. doi:10.1093/brain/awz162
Novel peptide‐driven global proteomics platform to identify unique peptide profiles linked to Alzheimer’s disease
Authors: Saxena Satya , Devanarayan Viswanath , Ye Yuanqing , Reyderman Larisa , Koyama Akihiko , Sachdev Pallavi
Published: December 2022

Background

There is a growing need for new biomarker signature(s) to further improve the predictive values of currently used markers for Alzheimer’s disease (AD) staging, monitoring, and prognostic prediction of disease progression. Most AD biomarker discovery studies have not focused on peptide level alterations despite unquestionable importance of abnormal proteolysis in AD. Here we present a peptide‐focused unbiased global proteomics platform to identify unique peptide profiles associated with amyloid pathology in cognitively impaired subjects.

Method

We used the mass spectrometry (MS) data from a recently published multi‐cohort study (PRIDE archive PXD016278) using cerebrospinal fluid (CSF) from cognitively impaired AD (classified based on t‐tau > 400 ng/l, Aβ1–42 <550 ng/l and Aβ1–42/Aβ1–40 ratio <0.065) and non‐AD control participants. Data from the Sweden cohort was used for “discovery” and Magdeburg and Kiel cohort for “validation”. RAW MS files were analyzed using a novel platform integrating a de novo‐based workflow with comprehensive project‐specific hybrid spectral libraries to enable the identification of non‐tryptic and microbial peptides missed in traditional proteomics workflows. Raw intensities were quantile normalized and log transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, at 20% false discovery rate.

Result

1199 peptides identified as significant for amyloid positivity in discovery cohort were confirmed in an independent validation cohort. Most of the confirmed peptides demonstrate strong separation of amyloid (+) and amyloid (‐) subjects; 270 out of 1199 peptides had area under receiver operating characteristic curve (ROC‐AUC) over 90%, and 975 peptides had ROC‐AUC over 80%. Interestingly, 64.4% of CSF proteins identified as significant for amyloid positivity were altered only at the peptide‐level, including recently reported markers of AD progression such as VGF and PTPRN, underscoring the importance of tracking peptide‐based alterations in biomarker discovery.

Conclusion

Our unbiased peptide‐focused global proteomics platform has yielded a unique profile of over 1000 novel peptide signatures linked to amyloid pathology. Further evaluation is ongoing to study the pathways and interactions associated with these unique peptide profiles, and their potential utility for disease staging, monitoring, and progression.
Normative data for the Digit Symbol Substitution Test for diverse Hispanic/Latino adults: Results from the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Paredes Alejandra Morlett , Tarraf Wassim , Gonzalez Kevin A , Stickel Ariana M , Graves Lisa V. , Salmon David P. , Kaur Sonya , Gallo Linda C , Isasi Carmen R , Lipton Richard B. , Lamar Melissa , Goodman Zachary T , Zeng Donglin , Garcia Tanya P , González Hector M
Published: December 2022

Background

Neuropsychological assessment plays an important role in identifying mild cognitive impairment and dementia; demographically appropriate norms are essential for interpreting test performance and maximizing diagnostic accuracy. Limited availability of normative data for cognitive tests administered to older Hispanic/Latino adults can lead to diagnostic error. Executive functioning and information processing speed are crucial elements of neuropsychological assessment. To meet the needs of the Hispanic/Latino population, we investigated the associations of age, education, ethnic background, gender, and language on the Digit Symbol Substitution (DSS) test – a subtest of the WAIS‐R – and to provide demographically adjusted norms for a diverse group of Hispanics/Latinos.

Method

The target population for the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA; 2015–2018) included individuals from Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American backgrounds (n = 6,172). Average age was 63.4±8.3 years, 54.5% were female, and mean education was 11.0±4.6 years. The DSS was administered as part of a larger cognitive protocol in participants’ preferred language (English or Spanish). Lower scores on the DSS are associated with slower processing speed. Demographic adjusted DSS scores, and percentile cut‐points were created using survey‐adjusted regression and quantile regression models.

Result

In covaried regression models, each year increase in age was associated with B = ‐0.54 (p<0.001) units decrease in DSS scores, and each additional year of education with B = 1.42 (p<0.001) units increase in performance. Males had, on average, lower DSS scores than females (B = ‐2.41; p<0.001), and individuals with English as their preferred language performed better than those preferring Spanish (B = 6.18; p<0.001). DSS performance varied significantly by Hispanic/Latino background with, predominantly, Mexicans scoring highest and Dominicans lowest on the DSS.

Conclusion

While other norms for Hispanic/Latino populations exist, results from this study represent the largest and only norms for Hispanic/Latinos living in the US. Representative DSS test norms for diverse groups of US‐based Hispanics/Latinos will advance cognitive assessment and the accuracy of neurocognitive disorder diagnosis in this country. We have developed an online dashboard to facilitate potential clinical use and interpretation (https://solincalab.shinyapps.io/DSST/)
Disentangling selective vulnerability underlying sleep disfunction in neurodegenerative diseases: differential gene expression in neuromodulatory subcortical system in Alzheimer’s disease vs. Progressive supranuclear palsy vs. controls
Authors: Satpati Abhijit , Pereira Felipe Luiz , Mladinov Mihovil , Seeley William W. , Spina Salvatore , Neylan Thomas C. , Walsh Christine M , Grinberg Lea Tenenholz
Published: December 2022

Background

Sleep‐wake disturbance precedes the prodromal stage of Alzheimer’s disease (AD) and is characterized by excessive daytime sleepiness and sundowning. In contrast, hyper‐insomnia is seen in progressive supranuclear palsy (PSP), a pure 4‐repeat tauopathy. The wake‐promoting histaminergic (HA) neurons of the tuberomamillary nucleus (TMN) together with the orexinergic (OX) neurons of the lateral hypothalamic area (LHA) modulate the sleep‐wake cycle. Previously, we reported wake‐promoting nucleus (WPNs) are selectively vulnerable to AD‐tau toxicity than PSP, and neuronal loss in TMN is specific to AD. In the present study, we investigated changes in RNA expression in the TMN and LHA to understand the selective vulnerability of WPNs in AD at the molecular level.

Method

LHA and TMN were dissected from serial histological sections from the postmortem brains of AD, PSP, and healthy control (HC) subjects. 50ng total RNA was extracted using RNeasy Micro Kit, and RNA integrity was accessed using Nanodrop. Cases with RIN > 5 were included for RNA sequencing. The nCounter Neuropathology panel and nSolver software (NanoString Technologies) was employed to obtain and analyze the data.

Result

Molecular profiling of TMN in AD demonstrated 13 upregulated genes associated with angiogenesis, apoptosis, chromatin modification, disease‐association, and transcription factor, and 12 genes in PSP. The proto‐oncogene RELA, RNA binding protein FUS and oligodendrocyte specific NKX6‐2 genes were upregulated in AD and PSP. Further, in the LHA, we identified 17 differentially expressed genes associated with circadian rhythm, inflammatory cytokines, apoptosis, autophagy, and angiogenesis in AD over HC and 72 genes in PSP over HC. Both IL4 and CRY2 genes demonstrated downregulation in the AD and PSP.

Conclusion

Differential gene expression in the WPNs revealed a significant upregulation of genes associated with pro‐inflammatory cytokines, activated microglia, apoptosis, oxidative stress, and autophagy in AD over PSP. The neuromodulatory subcortical system shows different vulnerability patterns in AD vs. PSP making it an excellent candidate to interrogate the molecular bases of vulnerability.
Potential Savings in Caregiver Time and Societal Costs Associated with Slowing Disease Progression over 36 months in Patients with Early Alzheimer’s Disease: Findings from GERAS‐US
Authors: Chandler Julie , Ye Wenyu , Johnston Joseph , Mi Xiaojuan , Doty Erin
Published: December 2022

Background

Alzheimer’s disease (AD) is associated with significant costs that increase with disease progression. These analyses describe the relationship between cognitive decline and measures of caregiver time and societal costs and estimate the impact of slowing disease progression over 36 months.

Methods

Amyloid positive patients with mild cognitive impairment (MCI) and mild AD dementia (MILD) from the GERAS‐US study1 were included. Assessments included: Mini Mental State Examination (MMSE‐ cognition); Resource Utilization in Dementia (RUD‐ caregiver time, societal costs). The generalized linear model (GLM) with normal distribution was performed for caregiver time and with log link and gamma distribution for total societal cost. The associated outcome savings over 36 months were calculated based on least squares mean change (LSMC) in MMSE and coefficient of MMSE change from baseline to month 36.

Results

Table 1 shows baseline characteristics of 617 patients (300 MCI, 317 MILD, 47.3% male) with a mean (SD) age of 71.0 (7.8) years. MILD vs. MCI patients had greater cognitive impairment, higher caregiver time, and higher monthly societal cost. Over 36 months, MILD patients had significantly greater disease progression compared to MCI (MMSE LSMC 4.1 vs. 2.1). A 2.1‐point worsening in MMSE over 36 months for MCI was associated with an increase of 35.7 hours in total caregiver time and an increase of $8,084 per patient in total societal costs (Table 3). Delaying progression by 20% ‐30% could lead to a savings 7.2 to 10.7 hours for caregiver time and $1,675 to $2,502 in total societal costs. For MILD, a 4.1‐point worsening in MMSE was associated with an increase of 77.3 hours in total caregiver time and $12,807 per patient in total societal costs. Delaying progression by 20%‐30% could save 15.5 to 23.2 hours in caregiver time and $2,665 to $ 3,978 in total societal cost.

Conclusion

Caregiver time and total societal costs are higher in MILD than in MCI; caregiver time increases over 3 years for both MCI and Mild. Treatments that slow cognitive decline have the potential to keep patients in earlier disease stages longer with a resulting savings in caregiver time and societal cost. 1J Alzheimers Dis. 2019;72(1):279‐292
Hippocampal volume mediates the association between depression and cognitive function differently by sex
Authors: Ortega Nancy E , Aslanyan Vahan , Pa Judy
Published: December 2022

Background

Sex differences are prominent features of both depression and Alzheimer’s disease, with women showing an increased lifetime risk relative to men. However, the neural mechanisms that explain sex differences in the relationship between depression and cognition are poorly understood. The goal of this study was to evaluate whether smaller brain volumes mediate the relationship between higher depression symptom severity and poorer cognition, and whether this association differed by sex.

Method

UK Biobank participants were included in the sample based on availability of demographic variables, mental health assessments, structural MRI scans, and four cognitive measures (Fluid Intelligence, Numeric Function, Pairs Matching, and Symbol Digit Substitution). Depression symptom severity was evaluated using the Patient Health Questionnaire (PHQ‐9). The indirect effect of depression symptom severity on cognition via hippocampal volumes was evaluated using causal mediation analyses. Models were adjusted for age, sex, APOE‐e4 status, and Townsend Deprivation Index, a measure of material deprivation (Fig.1). A priori sex‐stratified models evaluated sex differences. Exploratory analyses assessed the indirect effect of depressive symptom severity on cognition with amygdalar and total brain volumes as separate mediators. The significance of indirect effects was evaluated using bootstrapping procedures.

Result

The study sample consisted of 39,692 middle‐aged and older adults (53% women, mean age±SD = 64.1±7.6 years, 28% APOE‐e4 carriers). Hippocampal and amygdalar volumes mediated the effect of depression symptom severity on cognition, for Fluid Intelligence, Numeric Function, and Symbol Digit Substitution, but not Pairs Matching. Total brain volume mediated the effect of depression symptom severity on Symbol Digit Substitution performance (Fig.1, Table1). In sex‐stratified analyses, the effect of depression symptom severity on Fluid Intelligence, Numeric Function, and Symbol Digit Substitution was mediated by hippocampal and amygdalar volumes in women. In men, the effect of depression symptom severity on Symbol Digit Substitution was mediated by total brain volume (Table2).

Conclusion

Depression symptom severity influences cognition via hippocampal and amygdalar volumes in women, while in men, total brain volume mediated the relationship with cognition. These data suggest sex‐specific neural pathways for the relationship between depression and cognition.
Race, Gender, and Late‐life Productive Activities and Dementia in the Health, Aging, and Body Composition Study
Authors: Rooks Ronica Nicole
Published: December 2022

Background

Scholars have not addressed if productive activities, like working and volunteering, can mitigate Black vs. White racial disparities in incident dementia among older adults. We hypothesized: working vs. not, and volunteering vs. not, will reduce dementia risk and decrease racial disparities in the Health, Aging, and Body Composition (Health ABC) study.

Method

Health ABC is a 17‐year epidemiologic, prospective cohort study developed by the National Institute on Aging, including community‐dwelling, well‐functioning, Black (42%) and White, men and women (52%), aged 70‐79 in 1997‐98 (n = 3,069 at baseline). Full sample and gender‐stratified logistic regression model incident dementia risk among older adults with adjustments for socio‐demographics (e.g., race, age, education, family income, and site) and Apolipoprotein E genotype (APOE).

Result

In a full sample, unadjusted model, working vs. not (Yr1) was significantly related to 22% lower odds of dementia (OR = 0.78, p0.05) and volunteering vs. not (Yr1) was borderline‐significantly related to 16% lower odds of dementia (OR = 0.84, p = 0.059). In respective socio‐demographic and full model adjustments, working and volunteering were not significantly related to dementia. Black vs. White older adults had 31% (OR = 1.31, p0.05) and 29% (OR = 1.29, p0.05) higher odds of dementia in working and volunteering models with socio‐demographic adjustments, respectively. Race was not significant after APOE adjustment. Among older men, no significant relationships existed between dementia with work or race in any models. Similarly, no significant relationships existed between dementia with volunteering or race in any men’s models. Among older women, in the unadjusted model, working vs. not (Yr1) was significantly related to 30% lower odds of dementia (OR = 0.70, p0.05), but it was not significant in other models. Similarly, in an unadjusted model for women, volunteering vs. not (Yr1) was significantly related to 24% lower odds of dementia (OR = 0.76, p0.05), but it was not significant in other models. Black vs. White women had 35% (OR = 1.35, p0.05) and 32% (OR = 1.32, p = 0.052) higher odds of dementia in working and volunteering models with socio‐demographic adjustments, respectively, but race was not significant after APOE adjustment.

Conclusion

This research provides insight about productive activities as possible contextual interventions to reduce racial disparities in incident dementia among older women.