bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropsychiatric and behavioral markers of dementia risk
Authors: Ismail Zahinoor
Published: January 2025

A critical need exists to find simpler approaches for early detection of Alzheimer disease (AD) and related dementias. These approaches must increase access to preventative interventions and treatments, both pharmacological and non‐pharmacological, for people in preclinical and prodromal stages of disease. This need has been amplified by the emergence of disease modifying therapies (DMTs), which require biological confirmation of amyloid‐ß positivity. Confirmation methods include positron emission tomography (PET) tracers, lumbar puncture for cerebrospinal fluid analysis, and phlebotomy for blood assays. However, given the expense, invasiveness, and lack of availability to all, these methods are not suitable for larger scale screening or case detection. Finding higher‐risk persons, enriched for biomarker positivity, can help with case detection. Digital biomarkers, delivered at scale, may have a role. Conventionally, the at‐risk group is identified based on cognitive symptoms. An underappreciated approach to help with detection of AD is to incorporate neuropsychiatric symptoms (NPS) into screening or assessment. Historically, specificity has been a limitation, with NPS manifesting due to other, non‐AD aetiologies. More recently, the construct of Mild Behavioral Impairment (MBI) has been developed to improve specificity for AD detection and prognostication when using NPS. MBI leverages risk associated with later‐life emergent and persistent NPS to improve specificity. For example, in persons with Subjective Cognitive Decline or with Mild Cognitive Impairment, stratifying by MBI status selects a subgroup with higher rates of incident cognitive decline and dementia. Even more advantageous has been the utility of MBI to predict MCI and dementia in cognitively unimpaired participants, for whom cognitive symptoms cannot easily be used to detect risk. More recently, evidence has emerged supporting the role of MBI for detection of persons with elevated AD biomarker levels, with greater specificity than NPS not meeting MBI criteria. These findings extend the epidemiological data and highlight MBI as a potential tool for sample enrichment. With MBI validated for digital delivery, there is potential to improve screening and case detection at scale. In this session, we will review the MBI construct, the role of MBI in dementia prognostication, and the most current data linking MBI to amyloid, tau, and neurodegeneration.
The association of APOE with Alzheimer’s Disease in four Hispanic cohorts
Authors: Tosto Giuseppe , Barber Robert , Phillips Nicole , O'Bryant Sid E.
Published: January 2025

Background

The long‐term goal of Health & Aging Brain Study – Health Disparities (HABS‐HD) is to establish population‐specific informed precision medicine for novel treatment and prevention strategies as has been done in other fields. Genomic studies are integral to these efforts and contribute vital data regarding genetic ancestry of the HABS‐HD participants, as well as whole genome sequence data, genome‐wide genotype (Illumina Global Screening array version 3.0) and epigenetic data (Illumina EPIC DNA methylation array).

Method

We evaluated the association of APOE with Alzheimer’s Disease and Related Dementia (ADRD) in four different Hispanic populations: Mexicans in the Mexican Health and Aging Study (MHAS), Caribbean Hispanics in the Washington Heights Inwood Aging project (WHICAP) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA), Peruvians in the Genetics of Alzheimer’s disease In Peruvian Populations (GAPP) and Mexican Americans from The Health & Aging Brain among Latino Elders (HABLE) and the Texas Alzheimer’s Research and Care Consortium (TARCC). Analyses were adjusted for age (≥60 years old), sex, and education. Global ancestry proportions, Native Americans (NAA), European (EUR), African (AFR) were estimated with ADMIXTURE software using the Human Genome Diversity Project as the reference panel. Specific secondary analyses of genetic ancestry were conducted using the same models.

Result

The genetic ancestral composition was significantly different across cohorts. Peruvians and Mexicans showed a predominant NAA ancestry, Caribbean‐Hispanics appeared to have a major contribution of European and African ancestry, and Mexican‐Americans exhibited similar proportions of both European and Native ancestries. We observed a significant association with the ε4 allele dosage in all the cohorts. The strongest association between APOE‐ε4 and risk for ADRD was observed in the Peruvian population (OR = 6.05, 95%CI = 3.01‐12.40). The genetic effect of at least one copy of the ε4 allele on ADRD risk was very similar in WHICAP+EFIGA, HABLE/TARCC and MHAS (OR = 2.52, 95%CI = 2.22‐2.85, OR = 2.86, 95%CI = 1.94‐4.22, OR = 2.76, 95%CI = 1.52‐5.02, respectively). Overall, random‐effect metanalysis estimated the ε4 OR for ADRD at 2.56 (95%CI = 2.26‐2.87).

Conclusion

To our knowledge, this is the largest collection of Hispanic participants phenotyped for ADRD. Our results showed a differential risk for ADRD from the APOE‐ε4 allele across populations with admixed genetic ancestry.
Nuclear HMGB1 Loss in the Aging Brain Triggers cGAS‐STING Pathway and Neuroinflammation that Contributes to Senescence and Cognitive Decline in Tauopathies
Authors: Gaikwad Sagar , Haque Md Anzarul , Samples Madison , Xavier Rhea , Jerez Cynthia , Al‐Shaebi Fadhl , Kayed Rakez
Published: January 2025

Background

Aging, tau pathology, and chronic inflammation in the brain play crucial roles in neuroinflammation, synaptic loss, neurodegeneration, and cognitive decline in tauopathies, such as Alzheimer’s disease. However, the molecular mechanisms that trigger aberrant chronic inflammatory signaling in tauopathies are poorly understood.

Method

We utilized brain tissues from tauopathy patients and the tauopathy mouse models. Our study involved immunofluorescence microscopy and biochemical assays to investigate the role of nuclear HMGB1 in DNA damage, brain inflammation, senescence, and cognitive dysfunction. We evaluated impact of HMGB1 knockdown on tau pathology (including phospho‐tau, tau oligomers, and neurofibrillary tangles), senescence, inflammation, synaptic and postsynaptic proteins, as well as cognitive functions using the Y‐maze and novel‐object recognition tests.

Result

Here, we show that nuclear high mobility group box 1 (HMGB1) protein is reduced in the brains of human tauopathy patients and mouse models of tauopathies. Knockdown of nuclear HMGB1 using AAV‐based shRNA resulted in increased DNA‐damage and activation of the cyclic GMP–AMP synthase stimulator of interferon genesis (cGAS–STING) signaling pathway in the brain of hTau tauopathy mice. The activation of cGAS–STING upon HMGB1 knockdown induced inflammatory phenotypes of senescent cells and promoted neuroinflammation, tau pathology, synaptic loss, and cognitive decline in hTau mice. Further investigations in human tauopathy brains revealed that HMGB1 loss enhances DNA damage, and cytosolic DNA release, activating cGAS signaling and bystander inflammation.

Conclusion

Our findings demonstrate that during tauopathies, the loss of nuclear HMGB1 leads to DNA‐damage and triggers activation of the cGAS–STING pathway, contributing to aging‐related inflammation, tau pathology and synaptic loss in the brain, and ultimately leading to cognitive decline.
Evaluate the Efficacy of the Axl inhibitor Bemcentinib in the 5xFAD mouse model of Alzheimer’s Disease
Authors: Chen Guyin , Ozturk Gizem , Porta Sílvia , Lee Virginia M.‐Y.
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of phosphorylated tau neurofibrillary tangles and extracellular deposits of amyloid beta plaques (Aβ) in the brain. Microglia cells have been proposed to be involved in amyloid plaque formation since activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis.

Method

We aim to evaluate if the pharmacological inhibition of the myeloid/microglial receptor tyrosine kinase AXL, with bemcentinib (BGB) could be used as a novel therapeutic approach for AD. The objective is to evaluate the efficacy of the BGB inhibiting Axl activity in the brain of the 5xFAD mouse model, which recapitulates pathological hallmarks of AD, including Aβ plaques formation and overactive microglia. We evaluated target engagement and performed an efficacy study in 5xFAD and WT mice orally dosed with BGB and Vehicle (Veh) as control. Mice were dosed twice a day for 1 week. Mice were anesthetized to collect CSF and plasma and perfused to obtain their brains.

Result

In the present work, we have used the pharmacological Axl inhibitor BGB, to evaluate the therapeutic potential of targeting Axl signaling in 5xFAD mice. We have evaluated the effect of Axl inhibition measuring changes in total Axl levels and its soluble fragment (sAxl) across the hippocampus, plasma, and CSF of 5xFAD mice and WT mice. As expected, we found a significant upregulation of Aβ plaques and microglia in 5xFAD mice, and interestingly, a concomitant upregulation of Axl levels in the hippocampus of 5xFAD mice. We observed, although not statistically significant, a trend of increasing levels of sAxl in CSF and plasma of mice receiving BGB. Unfortunately, no significant effect of BGB drug was detected in 5xFAD mice when Aβ‐plaque burden and Iba1 immunoreactivity was measured after the treatment.

Conclusion

Overall, the preliminary findings do not show a significant effect of Axl inhibitor BGB in the brain. The reduced BBB penetrance of the drug could be a potential explanation for lack of significant changes in Axl levels and microglia activation. Further studies of increasing dosing time and cohort size could potentially improve the outcome.
Spatial proteome profiling for distinguishing tangle‐bearing neurons and their microenvironments from healthy neurons in Alzheimer’s disease brains
Authors: Dehkordi Shiva Kazempour , Orr Timothy C. , Bodamer Ryan H , Hudson Hannah R. , Sun Victoria , Keene C Dirk , Zare Habil , Orr Miranda E.
Published: January 2025

Background

An important hallmark of Alzheimer’s Disease (AD) is the presence of neurofibrillary tangles (NFTs) composed of phosphorylated tau, which are commonly assessed using AT8 immunostains. Identifying additional markers to characterize the spectrum of NFT pathology is crucial for advancing our understanding and diagnosis of AD. This study introduces new potential markers to differentiate between tangles and healthy neurons.

Method

Postmortem human AD brains were analyzed using GeoMx (NanoString, Inc) digital spatial profiling. The analysis focused on specific regions of interest (ROIs) in the hippocampal CA1 and entorhinal cortex (EC) region of the brain, chosen for their presence or absence of AT8. We measured the levels of 85 proteins associated with neuropathology, inflammation, and autophagy across these ROIs. Differentially expressed (DE) proteins in NFTs versus healthy neurons were identified. The top 10 DE candidate proteins were used to construct an eigengene, a weighted average expression of proteins, to summarize biological signatures. We also trained a classifier using a non‐linear support vector machine to distinguish NFTs from healthy neurons, which is validated on an independent unlabeled dataset.

Result

Tau phosphorylation at four specific epitopes, S199, S214, S396, and S404 were significantly elevated in tangle‐bearing neurons in both CA1 and EC (Fig. 1a‐b). Other top DE proteins, including P62, Neprilysin, Ubiquitin, and PSEN1, were also highlighted. Specifically, an eigengene combining these proteins exhibited distinct clusters separating AT8‐positive and negative cells (Fig. 1c). Our classification models using these markers as well as phosphorylated tau proteins showed significant concordance with AT8‐based labels, suggesting their potential as alternative diagnostic tools (Fig. 1d). Validating the association of each of these markers with tangles across the adult lifespan and with AD progression informs on the time course of their upregulation in relation to tau phosphorylation.

Conclusion

This study identifies alternative markers, particularly phospho‐tau epitopes S214, S396, S404, and other proteins including P62, Neprilysin, and Ubiquitin for tangle‐bearing neurons. These markers are promising to improve AD diagnosis and fill gaps in knowledge regarding molecular pathogenesis of NFTs, paving the way for possibly earlier and more accurate detection and intervention strategies
Comparing driving behaviors and physiological features of older adult drivers with and without elevated amyloid burden
Authors: Kumar Anu M , Murphy Yi Lu , Maher Amanda Cook , Persad Carol C , Flynn Emma , Bross Jordan R , Koeppe Robert A. , Giordani Bruno
Published: January 2025

Background

Identifying markers for increased risk of cognitive change and early Alzheimer’s disease (AD) is key to enhancing the effectiveness of treatments. Changes in instrumental activities of daily living, including the complex task of driving, may serve as potential markers to identify older adults at risk of cognitive decline. This study evaluates driving behaviors and associated physiological signals in older adults with and without elevated brain amyloid burden.

Method

Video and physiological data from 21 amyloid positive and 21 amyloid negative consensus diagnosed cognitively normal participants over the age of 65 who participated in the University of Michigan’s Driving and Physiological Responses study were analyzed. Amyloid positivity was determined based on the PET centiloid scale. All drivers completed the same fixed course route. Road‐ and driver‐view videos of each participant were annotated to mark 40 key road events and driving behaviors, such as right turns and looking at the rear‐view mirror. Heart rate (HR) and electrodermal activity (EDA) data collected through an Empatica E4 watch were analyzed for each road/driving event (e.g., average HR during freeway entrance). Independent sample t‐tests with α’s = 0.05 were used to look for differences between amyloid positive and negative groups.

Result

HR responses to intersections without signs and freeway entrance ramps were consistently higher among amyloid positive drivers compared to amyloid negative drivers (p’s<0.05). Furthermore, amyloid positive drivers showed a pattern of lower EDA responses to freeway exit ramps than amyloid negative drivers (p<0.05).

Conclusion

Cognitively normal amyloid positive older drivers demonstrated consistently higher HR and lower EDA in key driving situations compared to their amyloid negative peers. Findings suggest physiological responses of older drivers under different driving conditions may represent markers for identifying those individuals at higher risk of future cognitive decline. These results can be used to build an accurate and generalizable Machine Learning‐based AD diagnostic tool to detect early‐stage AD in drivers.
Do Alzheimer Disease genetic loci influence the risk of Age‐Related Macular Degeneration?
Authors: Moore Noel C. , Song Yeunjoo E. , Lynn Audrey , Miskimen Kristy L. , Wang Weihuan , Laux Renee A. , Fuzzell Sarada L. , Hochstetler Sherri D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Nittala Muneeswar Gupta , Sadda SriniVas R , Stambolian Dwight , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: January 2025

Background

Alzheimer’s Disease (AD) and Age‐Related Macular Degeneration (AMD) are two age related neurodegenerative diseases that share multiple characteristics, including deposition of amyloid beta. In AD, amyloid plaque accumulation contributes to neurological dysfunction, while in AMD amyloid is a component of the hallmark retinal drusen complexes that lead to degeneration of central vision. Both diseases have significant and opposite risk due to the APOE e4 and e2 alleles. Investigation into other potential genetic similarities between the two diseases is warranted.

Methods

Variants from the recent AMD meta‐analysis (Fritsche et al., 2016) and AD meta‐analysis (Bellenguez et al., 2022) were utilized to generate genetic risk scores (GRS) in an Amish founder population. 1293 individuals (1120 controls and 173 cases) were included in the AD analysis and 654 individuals were included in the AMD analysis (334 controls and 320 cases). AMD‐only and AD‐only GRSs were applied separately to both AMD and AD. We then combined both the AMD and AD variants into a single GRS applied to each disease. We subsequently removed AD SNPs sequentially from the GRS to identify any AD variants that might improve the association with AMD.

Results

As expected, the AD‐only GRS successfully predicted AD (p = 0.01). However, the AMD‐only GRS was less successful in predicting AMD (p = 0.145). The combined AD/AMD GRS was more successful in predicting AMD (p = 0.12) than the AMD‐only GRS, while AD prediction decreased in performance (p = 0.67) compared to the AD‐only GRS. The sequential analysis identified thirteen AD variants that improved the AMD‐only GRS when combined with the AMD variants (p = 0.06).

Conclusions

While the AD‐only GRS was most successful in predicting AD, the AD/AMD GRS outperformed the AMD‐only GRS in predicting AMD. These results suggest that several AD loci in addition to APOE may also influence AMD.
Sex‐specific genetic regulation of proteomics in cerebrospinal fluid uncovers genetic causes for sex differences in neurodegeneration
Authors: Sung Yun Ju , Wang Lihua , Western Daniel , Timsina Jigyasha , Gorijala Priyanka , Ruiz Agustin , Pastor Pau , Chen Han , Cruchaga Carlos
Published: January 2025

Background

Clear sex differences exist in AD and PD. Several studies examined genetic regulations for AD phenotypes and gene expression data in a sex‐specific manner, identifying some differences between males and females. In contrasts, although proteins are final effectors of most physiological pathways and important drug targets, sex‐specific regulations for proteins remain vastly understudied. This study therefore aims to investigate sex‐specific genetic regulation of proteomics in neurologically relevant cerebrospinal fluid (CSF).

Method

We recently identified 3,885 protein quantitative loci (pQTL) for 1,883 proteins, many of which were unique to CSF, demonstrating genetic regulation specific to the CSF proteome. Here, we performed a sex‐stratified pQTL (in 1,640 males and 1,713 females, separately) with >7000 proteins (SomaScan7K) on ∼13 million TOPMED imputed autosomal variants. pQTL considered significant at P<5 × 10‐8 (in cis) and P<3.45 × 10‐11 (in trans) in either sex. We subsequently examined shared genetic regulation using colocalization with neurodegeneration and psychiatric diseases.

Result

We identified 3,179 significant pQTLs (1,210 cis and 1,969 trans) in either sex in 726 genetic loci for 1,794 proteins. While 69.4% of pQTLs had similar regulation in both sexes, 21.1% (173 female‐specific; 220 male‐specific) were significant only in one sex. For example, pQTL for IST1 at rs71709684 (MAF = 0.047) on chr16 was female‐specific, significant only in females (β = 0.43, P = 4.40 × 10‐8 in females vs β = ‐0.02, P = 7.89 × 10‐1 in males). In addition, 8.5% (47 female‐biased; 97 male‐biased) were significant in both, but with different magnitudes. The PD locus LRRK2 on chr12 regulated several proteins (GRN, GPNMB, ITGB2), enriched in microglia, in males only. As the most pleiotropic region, the APOE region on chr19, the strongest AD locus, sex‐specifically regulated multiple proteins relevant to AD (PPP3R1, YWHAZ, PPP3CA, amyloidosis‐related NRXN2, VSNL1, and dementia‐related TIMM8A), enriched in neurons. The female‐specific pQTL of PLOD3 on chr17 colocalized with alcoholism, testosterone levels, and sex hormone‐binding globulin (SHBG). The male‐specific pQTL of NRXN2 on chr19 colocalized with AD, along with SHBG and telomere length.

Conclusion

By performing sex‐stratified pQTL, we uncovered distinctive sex‐specific genetic regulation of CSF proteome. Our findings complement sex‐aware eQTL from GTEx and provide insights on dissecting the underlying biological causes and mechanisms contributing to sex differences in neurodegeneration.
DCTclock metrics differentiate between amnestic and vascular mild cognitive impairment
Authors: Haas Brendan , Jannati Ali , Showalter John , Bates David , Tobyne Sean , Pascual‐Leone Alvaro
Published: January 2025

Background

Amnestic and vascular dementia are two common types of dementia. Currently, diagnosing and differentiating between these two conditions requires comprehensive neuropsychological testing, neuroimaging studies, and cerebrospinal fluid analysis. Identifying these conditions at early stages, i.e., mild cognitive impairment (MCI), is crucial for maximizing the therapeutic benefits of pharmacological agents or lifestyle modifications. Here we evaluated the utility of metrics derived from the DCTclock, a brief ML‐enabled digital cognitive assessment, in differentiating between amnestic and vascular MCI.

Method

We analyzed DCTclock tests from N = 215 participants (age 48‐90, 126 females, education = 6‐20 yrs) including patients at Lahey Hospital and Medical Center and participants in the Framingham Heart Study, for whom a diagnosis of vascular (n = 46) or amnestic (n = 169) MCI was available. Mann‐Whitney U Tests were used to compare the distributions for 78 features derived from the DCTclock performance. Random forest models with recursive feature elimination and 5‐fold cross‐validation were used to differentiate between the two MCI subtypes.

Result

16 DCTclock features returned p‐values below the 0.05 threshold for statistical significance, and one feature reached the Bonferroni‐corrected threshold of 6.4e‐4. The features showing the largest difference between the two populations were the total time to complete the copy clock (p = 4.2e‐4), drawing process efficiency on the copy clock (p = 1.7e‐3), and average latency on the copy clock (p = 3.7e‐3). 13 of the 16 top features were derived from the copy clock test. A random forest model using only 6 features (figure below) returned an accuracy of 77.9%.

Conclusion

Metrics derived from the process of DCTclock performance, especially those obtained during the copy clock condition, showed utility for differentiating between vascular and amnestic MCI. Comparing cognitive phenotypes at the early stage of MCI is arguably a more difficult task than comparing those phenotypes among individuals who have progressed to dementia and thus exhibit more pronounced signs of cognitive impairment. More data from individuals with such cognitive profiles are needed for building robust ML models that can differentiate among MCI subtypes with higher accuracy.
Therapeutic approach in an Alzheimer’s Disease rat model through GDNF overexpression by an astrocyte‐selective adeno‐associated virus
Authors: Escobedo Ana Abril Vidal , Peralta Facundo , Reggiani Paula Cecilia , Pardo Joaquín
Published: January 2025

Background

Sporadic Alzheimer’s disease (sAD) is the most common form of dementia, characterized by a progressive decline in cognitive function and, cortical and hippocampal atrophy. Our objective is to develop neuroprotective therapies that promote the homeostatic and modulatory properties of astrocytes, and enhance their protective functions. Glial‐derived neurotrophic factor (GDNF) has emerged as a promising factor for its ability to promote neuronal survival and function. However, the therapeutic potential of GDNF in AD remains uncertain. Consequently, we explored it in the sAD model induced by intracerebroventricular (icv) streptozotocin (STZ) in rats.

Method

We produced serotype 9 bicistronic adeno‐associated viruses (AAV), expressing GDNF and GFP (control), driven by the gfaABC1D promoter, targeting astrocytes expressing glial fibrillary acidic protein (GFAP). AAVs were characterized using RT‐qPCR and immunohistochemistry (IHC). For therapeutic approach, young male rats were divided into 4 groups: SHAM, STZ, GFP, and GDNF. On Experimental Day (ED) ‐28, animals received bilateral intrahippocampal injections of artificial cerebrospinal fluid (aCSF) (SHAM and STZ groups) or AAV‐GFP/GDNF (GFP and GDNF groups). On ED 0, animals received bilateral icv injections of aCSF (SHAM group) or STZ (3mg/kg) (STZ, GFP, and GDNF groups). Between ED +17/+26, behavioral tests were conducted to evaluate species‐typical behavior, object recognition memory, and spatial memory.

Result

AAV‐GDNF and AAV‐GFP were generated, and the overexpression of transgenes was confirmed by RT‐qPCR and IHC. In the therapeutic approach, animals belonging to STZ and GFP groups showed significant deterioration in all assessed behaviors. GDNF overexpression prevented cognitive impairment in treated animals, as they showed no significant differences compared to the SHAM group in the analysed parameters. Additionally, AAV‐GDNF treatment promoted an increase in branching and length of processes in the analysed astrocytes

Conclusion

We investigated an innovative therapeutic method specifically focused on hippocampal astrocytes. This allowed us to overexpress GDNF, generating protective actions that mitigated behavioral and cognitive alterations in our sAD animals. Furthermore, by acting on the brain’s astrocyte population, promoting an increase in their complexity, we could potentially have a positive effect on maintaining cerebral homeostasis.
Sleep Duration and Cognitive Performance in Middle‐Aged and Older Adults: What is the Role of Depression?
Authors: Young Vanessa M. , Bernal Rebecca , Baril Andree‐Ann , Zeynoun Joy , Wiedner Crystal , Beiser Alexa S , Pase Matthew P. , Himali Jayandra J. , Seshadri Sudha
Published: January 2025

Background

Recent research has highlighted the importance of sleep on cognitive processes. However, conflicting evidence exists regarding optimal sleep duration and the impact of other co‐occurring conditions, such as depression. A diagnosis of depression in mid‐life may increase the risk of developing dementia. We examined the association between self‐reported sleep duration and cognition and whether depression status modified this relationship.

Method

Dementia‐and‐stroke‐free participants 45 years and older from the Framingham Heart Study Third‐Generation, Omni 2, and New Off‐spring Cohorts were included (n = 1,853; age 49.8[SD 9.2] years; 42.69% male; Table 1). Neuropsychological testing assessed verbal learning and memory abilities, abstract reasoning skills, processing speed and visuospatial memory. Depression was defined as having CES‐D ≥16 or being under pharmacological treatment (n = 448; 32%). Multivariable linear regression models examined the association between sleep duration categories (≤6h; >6‐<9h [reference]; ≥9h), individual cognitive tasks and global cognition, adjusting for age, sex, education and time between sleep and cognitive assessments. A second model included further adjustment for vascular risk factors and APOE4 status.

Result

Long sleep duration (≥9h) was associated with worse global cognition (β±SE: ‐0.24±0.07; p<0.001) compared to average sleep duration. In cognitive domain‐specific tasks, long sleep was associated with worse verbal learning and memory abilities (‐1.50±0.60, p = 0.013), visuospatial memory (‐1.74±0.42, p<0.001), and processing speed (‐0.08±0.03, p = 0.014), but not with abstract reasoning skills (‐0.06±0.28, p = 0.838). Depression status significantly modified the association (global cognition int. p = 0.015; visual int. p = 0.006; and processing speed int. p = 0.038), where long sleep duration was associated with global cognition (‐0.34±0.11; p = 0.003), visuospatial memory (‐2.16±0.68; p = 0.002), and processing speed (‐0.14±0.05; p = 0.011) in those with depression. Long sleep duration was also associated with visuospatial memory in those without depression (‐1.27±0.55, p = 0.022) (Table 3). Short sleep duration (≤6h) was not associated with cognition (Table 2) and did not interact with depression status (Table 3).

Conclusion

Long sleep duration was associated with worse cognition particularly among adults with depression, underscoring the complex sleep‐mood‐cognition interplay. Further research should explore the longitudinal impacts and causal mechanisms of suboptimal sleep. These findings may inform public health promotion of optimal sleep to maintain cognitive health among persons with depression.
Mild Behavioral Impairment is associated with incident cognitive decline among dementia‐free, racially diverse older adults: Data from the African Americans Fighting Alzheimer’s in Midlife (AA‐FAIM) study
Authors: Fischer Barbara L. , Van Hulle Carol A. , Norton Derek L. , Wyman Mary F. , Ennis Gilda E. , Zuelsdorff Megan L. , Lambrou Nikolaus H , Bouges Shenikqua , Gooding Diane Carol , Gleason Carey E.
Published: January 2025

Background

Mild behavioral impairment (MBI) is associated with all‐cause dementia. Little is known about MBI’s effects on cognitive function among individuals in earlier disease stages, particularly in racially diverse samples. We examined relationships between MBI and cognitive decline in a richly characterized sample of white and African American (AA) older‐middle aged adults. AA participants were enrolled in African Americans Fighting Alzheimer’s in Midlife (AA‐FAIM), an ancillary study of the Wisconsin Disease Research Center’s (WADRC) Clinical Core.

Method

Analytic sample included participants without dementia, with ≥1 study visits and measures of cognitive/clinical function. A baseline MBI rating (present/absent) was derived using study partners’ report of neuropsychiatric symptoms at two consecutive visits, (i.e., two consecutive positive MBI scores = MBI present). Cognitive outcomes included measures of speed, mental flexibility and memory.

Result

Table 1 provides characteristics by MBI status for white (N = 450), AA (N = 100), and other underrepresented group (URG) (N = 34) participants. In the full sample, baseline MBI significantly moderated cognitive trajectory on Trails B, though not on any other tasks. Participants with MBI displayed worse trajectory of decline on Trails B relative to those without MBI (Figure 1). Additionally, MBI at baseline significantly predicted progression to cognitive impairment CDR >0 (HR est: 2.84; HR 95% CI: 1.68 — 4.81; p = 0.0001) (Figure 2). Stratified analysis in a smaller AA subgroup showed a similar pattern but was not significant.

Conclusion

MBI associated with more adverse cognitive trajectory and predicted incident cognitive decline in older, middle aged participants without dementia. Our findings highlight the importance of identifying MBI as a possible target for intervention in early disease stages. A fifth of our sample (21.5%) identified as Black/URG. Still, ongoing work in inclusive cohorts is needed to better understand MBI in under‐represented groups.
Diminished awareness, rather than hyperawareness, is more indicative for the progression along the Alzheimer’s clinical continuum, already in the subjective cognitive decline.
Authors: Incesoy Enise I , Düzel Emrah ,   DELCODE study group
Published: January 2025

Background

Anosognosia is a frequent phenomenon in Alzheimer’s dementia. Both heightened and decreased awareness of cognitive decline (AoCD) have been observed in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Despite some studies, the association between altered awareness and clinical conversion remained unclear. This study investigates the impact of AoCD on the conversion to incidental MCI (iMCI) and dementia within clinical high‐risk groups in the DELCODE study.

Method

Annually collected longitudinal data from 405 SCD and 163 MCI participants (4.33 ±1.99 years) were used. Awareness was assessed using two scores: AoCDinf (discrepancy between participant and informant reports from the SCD‐Interview) and AoCDobj (discrepancy between participant‐report and dichotomized objective test scores). Participants were categorized into hyperaware (AoCD > 0), N‐aware (AoCD = 0), and unaware (AoCD < 0) groups. Cox proportional hazard regression models predicted the effect of awareness group on progression to iMCI and dementia. Analyses were adjusted for age, sex, education, MMSE, and diagnostic group.

Results

a. MCI conversion: 109 (27%) SCD participants converted to iMCI (2.90±1.76 years). Non‐converters demonstrated more heightened initial awareness for both scores, even after adjusting for covariates (only for AoCDobj: F[5, 397] = 28.29, β = 0.224, p<.0001). Hyperawareness in SCD was associated with reduced risk of progression to MCI compared with diminished awareness (Hazard Ratio (HR)inf = 0.57, 95% CI: 0.34‐0.98, p = .04; HRobj = 0.25, 95% CI: 0.15‐0.42, p<.0001). b. Dementia conversion: 78 (14%) SCD+MCI participants converted to dementia (3±1.95 years). Converters exhibited significantly lower initial awareness in both scores, even after adjusting for covariates (Fobj[5, 562] = 47.79, β = 0.231, p<.0001; Finf[5, 534] = 17.63, β = 0.132, p<.01). Unawareness in the nondemented clinical group was associated with higher risk of progression to dementia compared with hyperawareness (HRinf = 2.26, 95% CI: 1.23‐4.15, p = .009; HRobj = 3.35, 95% CI: 1.40‐8.03, p = .007).

Conclusion

Unawareness of cognitive decline is related to a decreased risk of conversion to dementia in the clinical population. Specifically, in SCD, diminished awareness, rather than hyperawareness, is more indicative of progression to MCI. Informant reports and minor cognitive deficits in SCD provide valuable insights, emphasizing their importance in clinical settings and pharmacological trials.
Digitizing the Trails Making Test for Automatic Detection of Cognitive Impairment: Validity and Reliability
Authors: Toro‐Serey Claudio , Higgins Connor , Banks Russell , Jannati Ali , Tobyne Sean , Showalter John , Pascual‐Leone Alvaro
Published: January 2025

Background

The Trail Making Test (TMT) is one of the tests most commonly included in neuropsychological batteries to assess executive functions. A digitized version of TMT would provide objective measurements of time to complete (TTC) and total number of errors (TE) with minimal training, and eventually enable process metrics including detailed evaluation of drawing behavior. Here we evaluated the test‐retest reliability and validity of a new digital TMT Part B (dTMT‐B).

Method

We examined cognitively unimpaired participants from two clinical trials: DCT216 (N = 182, age mean±SD = 64.8±7.5; 60% female; years of education mean±SD = 14.4±2.5; 20% Hispanic; 3‐5 weeks between tests) and Bio‐Hermes‐001 (N = 342, age mean±SD = 70.5±6.4; 63% female; years of education mean[IQR] = 16[14‐23]; 6% Hispanic). For both TTC and TE, reliability was assessed via intraclass correlation coefficients (ICC 3, k) in DCT216. Internal consistency was evaluated using Cronbach’s alpha. We assessed validity by combining visit 1 of DCT216 and Bio‐Hermes‐001 and performing a multiple linear regression predicting TTC using predictors for study, age, sex, education, ethnicity, and interactions between study and each demographic. Specifically, we calculated the coefficients for age (key demographic in paper‐based TMT) and for demographic performance across both studies.

Result

ICCs showed great reliability for TTC (0.87, 95% CI = 0.83 ‐ 0.90, p < 0.0001) and good reliability for TE (0.65, 95% CI = 0.53 ‐ 0.74, p < 0.0001). Cronbach’s alpha showed good internal consistency across these metrics as well (0.68). For validity, we found the expected significant main effect of age (T = 7.48, p < 0.001) and no significant interactions (p > 0.05), suggesting similar trends with paper‐based TMT‐B and consistent TTC values across studies.

Conclusion

dTMT‐B is a valid and reliable digital implementation of the commonly used, paper‐based TMT Part B.
Expanded bile acid annotations linked to diet and AD biomarkers
Authors: Mohanty Ipsita , Caraballo‐Rodriguez Andres Mauricio , Zemlin Jasmine , Labus Jennifer S , Dorrestein Pieter , Kaddurah‐Daouk Rima F. ,   Alzheimer’s Gut Microbiome Project Consortium (AGMP)
Published: January 2025

Background

Bile acids (BA) are steroids regulating nutrient absorption, energy metabolism, and mitochondrial function, and serve as important signaling molecules with a role in the gut‐brain axis. The composition of BAs in humans changes with diet type and health status, which is well documented with a few known bile acids. In this study, we leveraged a new BA‐specific spectral library curated in the Dorrestein lab at UCSD to expand the pool of detected BAs in Alzheimer‐related LC‐MS/MS datasets and provide links to dietary profiles and AD markers.

Method

Fecal untargeted metabolomics (LC‐MS/MS) data from the ADRC cohort was analyzed using GNPS‐based molecular networking. Spectral matching and annotation were performed using the BA‐specific spectral library which consists of 21,549 BA spectra, with many previously undiscovered candidates. We obtained spectral matches to 113 BAs with 108 matches to new candidate BAs from our library. Further, using the score for delayed recall of Benson figure (UDSBENTD), peak areas of the BAs were plotted with the amyloid status. For diet readout, spectral match to a food database (“global foodomics”) was performed, and correlation with BAs was obtained by joint‐RPCA analysis.

Result

The joint‐RPCA analysis yielded many di‐, tri‐, and tetrahydroxylated BAs among the top 20 features guiding the separation in the ADRC samples (Figure 1a). From diet, meat, fish, and fruits were among the top features, with meat and fish vectors pointing in the opposite direction as grapes, onions, and lettuce. Peak area‐based levels of a candidate tetrahydroxylated BA, which was among the top 20 features, changed with the amyloid status measured with the UDSBENTD (Figure 1b). The spectral count of vegetables and dairy also increased in amyloid‐positive samples. However, the spectral counts related to meat and poultry products did not change significantly with amyloid status, implying a potential vegetable‐based diet impacting the change in some BA levels.

Conclusion

Previously unknown BAs are correlated to diet and AD markers in the ADRC cohort. This study highlights the importance of expanding our metabolite annotations, in this case with BAs, and performing integrative analysis with diet to aid our understanding of AD progression.
Longitudinal Neuropsychiatric Symptom Trajectories in Frontotemporal Dementia: From Presymptomatic to Symptomatic Conversion
Authors: Lee Hyunwoo , Scott Imogene M , Chatterjee Atri , MacKenzie Ian R , Lapid Maria I. , Huey Edward D. , Tartaglia Maria Carmela , Kantarci Kejal , Rankin Katherine P. , Rosen Howard J. , Boeve Brad F. , Boxer Adam L. , Hsiung Ging‐Yuek Robin ,   the ALLFTD Consortium
Published: January 2025

Background

Frontotemporal dementia (FTD) presents with heterogeneous neuropsychiatric symptoms (NPS). These symptoms often begin prior to the onset of FTD, and progress throughout the prodromal stages of FTD. Particularly, familial FTD due to autosomal dominant genetic mutations might display mutation‐specific NPS profiles. We hypothesized distinct NPS trajectories for chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule‐associated protein tau (MAPT) mutation carriers during their transition from presymptomatic to symptomatic stages of FTD.

Method

In this study, we analyzed N = 1662 participants from the ARTFL‐LEFFTDS Longitudinal FTLD (ALLFTD) Study, with 342 C9orf72, 148 GRN, 168 MAPT mutation carriers, and 1004 noncarriers. We used the CDR plus NACC FTLD global scores to define the conversion status, and stratified participants into four stages of progression: 1) Presymptomatic (CDR = 0 throughout the follow‐up), 2) Early conversion (began with CDR = 0, then increased to 0.5), 3) Advanced conversion (began with CDR = 0.5, then increased to 1.0 or above), and 4) Symptomatic (CDR>1.0 throughout). Over up to seven visits, the Neuropsychiatric Inventory Questionnaire (NPI‐Q) assessed changes in NPS. We analyzed total NPI‐Q score trajectories using a generalized linear mixed‐effects model, adjusting for age and baseline NPI‐Q scores.

Result

Our findings showed similar NPS trajectories among carriers and noncarriers during presymptomatic stages. However, in the early conversion stage, C9orf72 and GRN carriers exhibited significantly higher NPI‐Q score increases compared to MAPT carriers, primarily in the psychosis and hyperactivity domains. In the advanced and symptomatic stages, the rate of increase in NPS was not significantly different across groups.

Conclusion

This study suggests that people with familial FTD, particularly those predicted to have underlying TDP‐43 pathology, may experience more severe neuropsychiatric symptoms like psychosis or hyperactivity as they progress from presymptomatic to prodromal phases. This trajectory appears distinct from those with tau pathology or sporadic FTD. Further studies are warranted to understand these unique progression patterns and their implications for FTD management.
Inclusion and attrition in the community‐based cohort of functional decline of elderly with cognitive complaint of the Geroscience Center for Brain Health and Metabolism
Authors: Parrao Teresa , Saguez Rodrigo , Thumala Daniela , Lillo Patricia , Demanet Michele , Amieva Helene , Martínez‐Pernía David , Zitko Pedro , Cerda Mauricio , Muniz‐Terrera Graciela , Slachevsky Andrea
Published: January 2025

Background

Cognitive complaints (CC) refer to a reported experience of cognitive decline and are recognized as a potential precursor to future functional decline and progression to dementia. Identifying individuals with CC may be a valuable opportunity for preventive measures, early detection, and intervention strategies to address dementia risk. However, the characteristics of CC and its associated risk of progression to dementia are highly heterogeneous, influenced significantly by CC identification methods, recruitment approaches, and attrition in longitudinal cohort studies. This study aims to inform the inclusion and attrition processes of the GERO cohort.

Method

The GERO cohort is a prospective cohort study of community‐dwelling elderly individuals with CC without dementia, aged 70 or older, living in Santiago, Chile. In this study, two samples were analyzed (dropout and non‐dropout groups) using logistic regression to assess the variables associated with attrition. Binary logistic regression analyses were conducted with dropout as the outcome variable. Prior to the multivariable models, univariate analyses were performed.

Result

Out of 17,759 households approached, we successfully recruited 291 participants. Of the individuals initially recruited, 102 participants withdrew before the first follow‐up assessment. The results showed that the non‐dropout group (64.9%) was characterized by being younger (OR: 1.09; 95% CI: 1.04‐1.14), had better cognitive status according to the MoCA test (OR: 0.92; 95% CI: 0.87‐0.98), had better functionality according to the T‐ADLQ (OR: 1.08; 95% CI: 1.04‐1.12), better performance in instrumental ‐IADL‐ (OR: 1.06; 95% CI: 1.03‐1.09) and advanced ‐aADL‐ (OR: 1.03; 95% CI: 1.01‐1.04) dimensions, and better performance on the ECOG test (OR: 2.56; 95% CI: 1.13‐4.53) compared to the dropout group (35.1%). In the multivariate logistic regression model, dropout was associated with the performance of instrumental activities of daily living IADL (OR: 1.05; 95% CI: 1.01‐1.09), whereas the other variables did not exhibit statistical significance (Table 1).

Conclusion

The rate of participants included, considering the number of households approached, inform on the difficulties to recruit participants with CC in the community. Functionality in daily life emerged as the key factor associated with the risk of dropout. Furthers research is needed to understand the role of functionality in CC.
Persistent Heart Rate Variability Deficits Among Dementia Patients With History of Excessive Alcohol Use
Authors: Elegores Marianne T , Patel Shivani , Elmi Sarah
Published: January 2025

Background

Previous literature has highlighted that excessive alcohol use (EAU) is directly linked with permanent neurological damage. Studies have also highlighted gradual improvements in heart rate variability (HRV) after cessation of alcohol use. Moreover, chronic alcohol consumption has also been correlated with reduced HRV and an increase in skin conductance (SC) among healthy adults, leading to a combined decline in cognitive performance. This study examines the persistence of HRV and SC changes among older adults with dementia and a history of alcohol use disorder (AUD).

Method

Participants were recruited from the Geriatric Transitional Unit at Ontario Shores Mental Health Sciences, Whitby, Ontario. Eligibility included a formal diagnosis of dementia and history of lifelong EAU was recorded based on informants. Behavioral and symptoms of dementia was assessed with the Neuropsychiatric Inventory Clinician rating scale. Empatica E4 wristbands was used to record physiological data. Physiological signals such as electrodermal activity (EDA) and heart rate (HR) were recorded. HRV was analyzed using KUBIOS software. T‐tests were used to determine differences in frequency and severity of BPSD, HRV and SC.

Result

28 participants were recruited, 17 male, average age: 73.4, 10 had EAU history (average age 67.8, 2 female). EAU group had a significantly lower root mean square of successive differences (RMSSD) (p = 0.002) and parasympathetic nervous system (PNS) activity (p = 0.021), but significantly higher sympathetic nervous system activity (SNS) (p = 0.007) than participants without EAU. Additionally, the standard deviation of normal beats (SDNN) and RMSSD scores of EAU group were below the normal range. Moreover, EDA was higher in participants without EAU (M = [1.54], SD = [3.46]) compared subjects with EAU (M = [0.43], SD = [0.94]), but the difference was not significant (p = 0.36). There was no statistically significant difference between NPI scores of the 2 groups.

Conclusion

Our findings indicate that alcohol abuse results in long‐term alterations of peripheral nervous system, causing an increase in sympathetic activity and a consequent decrease in parasympathetic activity. We observed that EAU subjects have a diminished ability to vagally mediate heart rate.