bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating updated LATE‐NC staging criteria using National Alzheimer’s Coordinating Center data: stage 1 subtypes matter
Authors: Woodworth Davis C. , Nguyen Katelynn M. , Sordo Lorena , Scambray Kiana A. , Head Elizabeth , Kawas Claudia H. , Corrada María M. M. , Nelson Peter T , Sajjadi S. Ahmad
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is a common cause of dementia in older age. LATE‐NC was first coined in 2019 with proposed staging criteria of TDP‐43 progressing from amygdala (stage 1), to hippocampus (stage 2), to middle frontal gyrus (stage 3). Criteria were updated in 2023 to further categorize stage 1 to either TDP‐43 inclusions in amygdala alone (stage 1a) or hippocampus alone (stage 1b). We applied this updated LATE‐NC staging criteria to data from participants in the National Alzheimer’s Coordinating Center (NACC) and examined associations with clinical diagnosis and other neuropathologic changes (NCs).

Method

We selected participants in NACC with regional TDP‐43 assessments, excluding those with frontotemporal dementia‐related and rare NCs, or with a non‐Alzheimer’s disease (AD) etiologic clinical diagnosis. LATE‐NC stages were assigned according to updated criteria. We performed logistic regressions with LATE‐NC stages as predictors and clinical diagnosis (dementia, cognitive impairment, memory impairment), other neuropathologic changes (ADNC, Lewy bodies, hippocampal sclerosis of aging (HS‐A), and vascular NCs), or gross atrophy at autopsy (cortical, hippocampal, frontal/temporal lobar) as outcomes. We also examined the association of LATE‐NC stages with dementia and memory impairment while accounting for other NCs.

Result

Of N = 1365 participants, LATE‐NC was present in 519 (37%): 31% stage 1 (78% 1a, 22% 1b), 56% stage 2, 13% stage 3 (Table‐1). Participants with stage 1a were younger at death compared to higher stages. Stage 1a and 1b had similar associations with cognitive problems (Figure‐1). However, while other stages were associated with ADNC and Lewy bodies, stage 1b was not. Meanwhile stage 1b was associated with HS‐A more strongly than stage 1a and to a similar degree as stage 2. We observed expected associations of higher LATE‐NC stages with dementia and other NCs (Figure‐1). Lastly, LATE‐NC stage 1b was significant (and stage 1a trended) for associations with dementia and memory impairment, while higher LATE‐NC stages had associations eclipsed in strength only by highest level ADNC (Figure‐2).

Conclusion

These findings highlight the utility of the updated LATE‐NC staging criteria in general, and stage 1 subtypes in particular, in capturing broad associations with cognitive impairment and specific associations with other neuropathologic changes.
Alzheimer’s disease genetic risk factors’ influence on tau onset age
Authors: Deming Yuetiva , Teague Jordan P , Heston Margo B. , Hammad Yazan , De Chavez Elena Ruiz , Morse Jacob , Chappell Richard J , Langhough Rebecca E. , Zuelsdorff Megan L. , Engelman Corinne D. , Betthauser Tobey J. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

New methods developed to estimate when AD biomarkers became abnormal in individuals have shown considerable heterogeneity in amyloid and tau pathology onset age. This work used polygenic scores (PGS) generated from CSF Aβ42 and ptau181 GWAS, individual‐level genetic data, and estimated tau onset age (ETOA) to identify genetic influences on tau onset beyond APOE.

Method

Participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with genetic data, CSF biomarkers (Aβ42 and ptau181), and longitudinal [18F]Flortaucipir (FTP) tau PET were analyzed (N = 462). Sampled iterative local approximation (SILA) was used to model longitudinal FTP meta‐temporal SUVR and generate ETOA for T+ and T‐ participants who could become T+, based on tau‐positivity (T+) defined using Gaussian mixture modeling (SUVR>1.41). Amyloid‐ and ptau‐PGS were generated from publicly available summary data, excluding the APOE region (±500kb). APOE neuropathology‐based scores (APOEscore) were used to test APOE. We analyzed individually a set of 14 SNPs that were previously associated with AD risk (P<1 × 10‐5) and both CSF biomarkers (P<0.05). Amyloid‐PGS, ptau‐PGS, APOEscore, and individual SNPs were tested as ETOA predictors using Cox regression modeling.

Result

73 (16%) participants were T+ by their last tau PET (Table 1). APOEscore was significantly associated with earlier ETOA (P = 1.10 × 10‐13; Figure 1) as was the amyloid‐PGS (P = 0.036), but ptau‐PGS was not (P = 0.166; Table 2). An intronic variant in complement receptor 1 (CR1), rs1408077 (A allele, MAFEUR = 0.19) which was previously associated with higher AD risk and AD‐associated changes of CSF biomarkers, was also significantly associated with earlier ETOA (P = 0.005; Figure 1). The association remained significant (P = 0.017) after adding the APOEscore (P = 3.93 × 10‐13) and both were still significantly associated with ETOA (Prs1408077 = 0.022 and PAPOEscore = 1.50 × 10‐6) after accounting for amyloid‐positivity (P = 3.91 × 10‐5; Table 2).

Conclusion

Our preliminary results support a key role for CR1 in the age when tau pathology becomes abnormal in AD. The tested variant, rs1408077, is in high linkage disequilibrium with a missense variant, rs2296160, and was previously associated with CR1 expression in the temporal cortex. This adds to previous studies that reported an interaction between CR1 and APOE‐ε4 associated with episodic memory decline. Future work will include genome‐wide analyses of biomarker timing and multi‐trait analyses.
The associations between CYP19A1 polymorphisms and serum 17ß‐estradiol levels in Chinese patients with Alzheimer’s disease
Authors: Chen Lu Hua , Fan Yan Hui , Song You‐Qiang , Chu Leung‐Wing
Published: January 2025

Background

Accumulating evidence has shown the neuroprotective effects of estrogen on cognition function, for example delaying the cognitive deterioration in patients with Alzheimer’s disease (AD). However, the clinical usage of estrogen in AD remains controversial. The cytochrome P450 aromatase encoded by CYP19A1, is a key enzyme catalyzing the C19 androgen conversion to C18 estrogen, which induces testosterone to estradiol and androstenedione to estrone. The aromatase thus has been suggested to be an important partner of estrogen by controlling estrogen biosynthesis. Although increasing evidence has demonstrated the associations between CYP19A1 polymorphisms and AD susceptibility, previous studies are mainly carried out in Caucasian populations, little is known about the role of this gene and its impact on serum estrogen levels in Chinese population.

Method

We recruited 689 subjects including both AD patients and non‐demented controls in Hong Kong. Subjects’ serum 17ß‐estradiol were measured based on a chemiluminescent immunoassay principle. Genomic DNA was isolated from the whole blood and subsequent genotyping for 27 SNPs was analyzed on high‐throughput Sequenom® genotyping platform according to the manufacturer’s protocols. Statistical analysis was done using SPSS and PLINK.

Result

After quality control, 3 SNPs were filtered and 24 SNPs spanning 122kb of this gene were included in data analysis. There was no significant difference for serum17ß‐estradiol levels between AD patients and non‐demented controls. The APOE ε4 allele was consistently associated with an increased AD risk (p<0.001). While the distribution of CYP19A1 polymorphisms was very similar between AD patients and non‐demented controls and no significant differences were observed for each individual polymorphism in the sample. However, using multiple linear regression analyses, we found significant associations between 4 (rs2008691, rs1902586, rs7181886, and rs17647719) CYP19A1 polymorphisms with serum17ß‐estradiol levels (p = 0.004, 0.039, 0.046 and 0.047, separately) after permutation by 10,000 times in Chinese population.

Conclusion

In conclusion, our findings suggest a novel link between CYP19A1 polymorphisms and variation of serum 17ß‐estradiol levels in Chinese elderly. This novel evidence may reflect inter‐individual differences of estrogen exposure according to different CYP19A1 genotypes during aging and dementia process. Our findings may highlight a new perspective to understand the underlying mechanisms of AD.
Measuring technology use as an instrumental activity of daily living in those with late life cognitive disorders
Authors: Benge Jared F
Published: January 2025

Background

Older adults increasingly rely on digital technologies to perform instrumental activities of daily living (iADLs), including commerce, managing accounts online, using texting and websites for social connection, and accessing health services via web platforms. Despite the increasingly central role of technology to daily life, current iADL measures do not regularly capture the digital approach to daily activities. The current study had three broad aims 1) determine the applicability of technology‐based iADLs to the daily lives of older adults being evaluated for Alzheimer’s disease and related dementias (ADRD), 2) compare the level of dependence for tech and traditional iADL items, and 3) determine if adding technology related iADL items improves the diagnostic accuracy of iADL assessments.

Methods

264 care partners (58.7% spouses) of older adults referred for evaluations of cognitive disorders (34.5% with MCI; 51.9% with dementia) completed the Functional Activities Questionnaire (traditional ADL measure) and 11 technology‐based iADL items (i.e. remembering passwords, managing online accounts, using a device for messaging, etc.).

Results

Rates of “not applicable, never did” were uncommon for technology‐based items, including microwave use (3.8%), smartphone use for calls (5.3%), and remembering passwords (8.3%). Increasing age and decreasing education predicted more not applicable responses to technology items. Average dependence ratings of technology items were less than for traditional ADLs (t(263) = 4.29, p<.0001; figure 2), and increased as a function of ADRD severity. Adding technology ‐based items marginally increased diagnostic accuracy of ADL measures for detecting dementia (AUC .85 vs. .83; z = ‐2.07, p = .03).

Conclusions

Technology use amongst older adults presenting for evaluations of cognitive decline is common for a range of daily activities. That being said, a digital divide still exists, with older age and less education predicting less applicability of technology‐based iADLs. Despite stereotypes to the contrary, overall degree of dependence for technology was less than for traditional, largely analog based iADLs, likely due to the ability to automate some tasks (i.e., automatic bill pay). We discuss how these findings broadly fit in the larger technological reserve hypothesis, implications for clinical assessment of iADLs, and approaches for future proofing iADL measures.
Novel VCP gene mutation in three siblings with frontotemporal dementia and amyotrophic lateral sclerosis in a Turkish family
Authors: Gultekin Murat , Basak Ayse NazlI
Published: January 2025

Background

Valosin Containing Protein (VCP) mutations are responsible some genetic etiologies of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Method

A 67‐year‐old, male patient, applied to the clinic due to behavioral changes and difficulty swallowing. According the patient history it was reported that his first complaint started 6 years ago (at the age of 61). The patient’s irritability, behavioral and character changes increased over time. The patient consulted a psychiatrist and diagnosed depression then, antidepressant treatment was started.

Genetic investigation was performed for the preliminary diagnosis of FTD‐ALS association. First, the C9orf72 gene report was normal. Then, all exon sequencing was performed. A heterozygous missense mutation p.Arg453Trp (c.1357C>T) was detected in the 11th exome of the VCP gene. This mutation, which was identified for the first time, was also detected in the other two sisters of the patient who had similar complaints.

Result

The patient’s premorbid personality traits were conservative, helpful, social and interested in his family. However, it has been stated that in recent years his sexual desire has increased and he has been making inappropriate conversations in social environments. Difficulty in swallowing was added to the complaints within a year, and in the last two years, speech disorder such as slurring words, increase in appetite, desire to travel and spending money were added.

There was no known history of neuropsychiatric disease in his parents. Three of the four siblings had a similar clinical picture. On examination, the patient’s speech was dysphonic, fasciculation and atrophy was seen in the tongue. 4/5 motor muscle strength in the neck muscles were detected. There was bilateral Hoffman positivity and deep tendon reflex brisk in the lower extremities. Swallowing reflexes could not be obtained. Brain magnetic resonance imaging scan revealed atrophy in the frontotemporal regions. ENMG examination was compatible with motor neuron disease.

Conclusion

ALS and FTD have been considered for many years as two different pathologies with distinct pathology. But, in recent years some studies have revealed that these disorders belong to a continuum, the so‐called ALS‐FTD spectrum disorders. Many causative genes are shared in both diseases.
What can animal studies tell us about EWB and AD
Authors: Wang Kuan Hong
Published: January 2025

Emotional well‐being (EWB) is considered to play an important role in the health of individuals over their lifespan. Clinical studies suggest an association between EWB and the risk or progression of AD. However, the mechanistic link and causal relationship between EWB and AD remain unknown, due to limited experimental access and control of the underlying brain processes in human. Animal models offer powerful tools for neural circuit analysis and control of AD genetic risk factors, but subjective feelings of EWB cannot be assessed through self‐report. To study EWB across species, we adopt a conceptual framework that views emotions as measurable states of brain networks that integrate exteroceptive and interoceptive affective stimuli and cause multiple cognitive, somatic and behavioral changes. Moreover, recent neuroanatomical and functional imaging studies have revealed evolutionarily conserved brain circuits, including mesocortical association areas and their connections with subcortical limbic areas, underlying the experienced and evaluative components of EWB. We will review recent progress in animal models to elucidate the functional activities of these circuits in emotional processing, the vulnerability of these circuits to AD pathology, and potential neuromodulation strategies to improve circuit functions. We will also offer our perspectives on the challenges and opportunities to link these neural representations to EWB and AD risk.
Long Pause Ratio in Speech Reflecting Dementia Severity and Hippocampal Atrophy in Early Alzheimer's Disease
Authors: Lin Bo‐Xiang , Chou Chia‐Ju , Chang Chih‐Ting , Lee Chia‐Ying , Fang Chuang Yi‐ , Chiu Yen‐Ling , Liu Yi‐Chien
Published: January 2025

Background

It has been found that speech analysis is a sensitive method for early Alzheimer’s disease (AD) detection. Among the various linguistic features, silent pause has emerged as a fair indicator, exhibiting higher prevalence in individuals with AD compared to general population. This study aimed to further examine the relationship between long pause ratio (LPR) in speech and traditional markers of disease progression, like biomarkers, neuroimaging features and neuropsychological tests.

Method

Since 2021 to 2023, we recruited 104 participants from memory clinic of Cardinal Tien hospital, Taipei, Taiwan. All participants received amyloid PET, 3.0 T brain MRI, and comprehensive neuropsychological tests. The determination of amyloid positivity came from consensus visual rating and quantitative methods utilizing SUVR (standardized uptake value ratio). Speech samples were collected using the picture description test, in which the participants describe three Taiwanese‐culture‐based pictures in one minute. LPR was defined as the number of pauses greater than two seconds divided by the number of words.

Result

The research study revealed a distinct pattern, with LPR being highest with AD (mean: 0.02), followed by aMCI (mean: 0.01), and nearly zero with normal controls (AD vs aMCI: p = 0.033; aMCI vs Normal: p<0.001). There was also positive correlation between LPR and CDR‐SB (p<0.001) as well as other cognitive tests such as MMSE (p = 0.001) and CASI (p = 0.003), and negative correlation between LPR and hippocampus volume (p<0.001). In multiple regression analysis, our study further showed that LPR alone, could effectively predict CDR‐SB and hippocampus volume (CDR‐SB: β = 57.01, t = 2.93; hippocampus volume: β = ‐21.90, t = ‐3.63). However, no association between LPR and amyloid burden has been found.

Conclusion

Long pause ratio appears rarely in normal controls of our participants. However, LPR increases as the severity of dementia worsens. Moreover, it also correlates with hippocampal size in our cohort. LPR should be considered as a critical linguistic feature in speech analysis.
Leveraging a multi‐day learning paradigm to reveal early amyloid‐ and tau‐ related cognitive deficits in preclinical Alzheimer’s disease
Authors: Jutten Roos J , Soberanes Daniel , Molinare Cassidy , Hsieh Stephanie , Farrell Michelle E. , Rentz Dorene M , Marshall Gad A , Johnson Keith A , Sperling Reisa A , Amariglio Rebecca E , Papp Kathryn V
Published: January 2025

Background

Individuals with preclinical Alzheimer’s disease (AD) show reduced practice effects on annually repeated neuropsychological testing, suggesting a decreased ability to learn over repeated exposures. Remote, digital testing enables the assessment of learning over more frequent time intervals, thereby facilitating a more rapid detection of those early learning deficits. We previously showed that multi‐day learning on the Boston Remote Assessment for Neurocognitive Health (BRANCH) was indeed diminished in Αβ+ cognitively unimpaired (CU) older adults. Here, we further investigated the impact of tau pathology on BRANCH multi‐day learning curves (MDLCs).

Method

N = 136 CU older adults (age = 73.4±7.6, 66% female, 16.6±2.4 years education) from three well‐characterized cohorts completed multi‐day BRANCH on their personal device. The assessment includes two associative memory tests (Face Name and Groceries Prices) and a processing speed test with an associative memory component (Digit Signs) with identical stimuli repeated for seven consecutive days. An MDLC score is computed using an area under the curve method allowing for the combination of day 1 performance with a non‐linear learning trajectory over the subsequent six days. All participants had [11C]Pittsburgh compound‐B and [18F]flortaucipir PET within 0.7±0.5 years of BRANCH and were classified as A ± (global amyloid burden, DVR cutoff 1.14) and T ± (inferior‐temporal tau SUVr, cutoff 1.30), resulting in n = 91 A‐T‐, n = 29 A+T‐ and n = 16 A+T+. Linear regression analyses adjusting for age, sex, and education were used to examine differences in BRANCH day 1 and MDLC scores across A/T groups.

Result

No A/T group differences were detected using day 1 scores. However, MDLC scores increasingly diminished across groups, with the A+T‐ group performing marginally worse (ß = ‐0.04,95%CI[‐0.08–0.01], p = 0.11) and the A+T+ group significantly worse (ß = ‐0.06,95%CI[‐0.11–0.01], p = 0.03) than A‐/T‐ (Figure 1). A+ status regardless of T‐status was associated with diminished Digit Signs MDLCs, whereas being T+ drove worse performance on Face Name and Groceries Prices MDLCs (Table 1).

Conclusion

Subtle differences in learning among CU older adults with different A/T biomarker profiles are observable using MDLCs. These findings further support the notion that a multi‐day learning paradigm can provide unique information about cognition that is not captured using a single time‐point assessment and is particularly relevant in preclinical AD.
How do short‐term practice effects compare to biomarkers of Alzheimer’s disease?
Authors: Duff Kevin , Hammers Dustin B. , Koppelmans Vincent , King Jace B , Hoffman John M.
Published: January 2025

Background

Practice effects on cognitive testing in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) remain understudied, especially with how they compare to biomarkers of AD. The current study sought to add to this growing literature.

Method

Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) repeated a brief battery of cognitive tests twice across one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE e4 status.

Result

The intact participants showed significantly larger practice effects than the other two groups on an overall composite measure, and those with MCI showed significantly larger practice effects than those with AD. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact>MCI>AD). For APOE e4, the intact had significantly fewer copies of e4 than MCI and AD. Overall, the effect sizes of practice effects were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons (see Table).

Conclusion

Short‐term practice effects on cognitive tests appear to be a sensitive marker in late life cognitive disorders, as they separated groups better than commonly‐used biomarkers in AD. Further refinement of short‐term practice effects as a tool for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.
Examining Practice Effects at Multiple Retest Intervals in Older Adults at Risk for Alzheimer's Disease
Authors: Wilks Hannah M , Welhaf Matthew S. , Aschenbrenner Andrew J. , Cruchaga Carlos , Morris John C. , Hassenstab Jason J.
Published: January 2025

Background

Practice effects (PEs) on cognitive tests are improvements in performance from repeated testing. We and others have shown that reductions in PEs on standard tests administered annually are associated with neurodegenerative disease. Using mobile technology, cognition can be assessed at much higher frequencies than standard in‐clinic assessments. These high‐frequency assessments offer a unique opportunity to measure PEs at multiple timescales, including retest intervals across months, weeks, days, within‐day, and even trial‐to‐trial. It is unclear if PEs observed across these different retest intervals are equally sensitive to clinical status and genetic risk of Alzheimer’s disease (AD).

Method

We examined timescales of PEs using a very brief, smartphone‐based processing speed test in 399 well‐characterized older adults (Table 1). Cognition was assessed four times per day over a week every six months for up to 2.5 years. PEs from the task were modeled at multiple timescales, including biannually, weekly, daily, and at the trial level. Additional mixed effects models compared PEs across clinical status and genetic risk for AD.

Result

Across all 399 participants, there were significant practice effects at all timescales, with an average improvement in speed of 0.10s over a 6‐month retest interval, 0.02s within each day of testing, and 0.005s each individual testing session. Performance improved throughout each week, and the most performance gains occurred on the first day of testing. Comparing clinical status using the Clinical Dementia Rating (CDR®) revealed that CDR>0s had significantly slower overall processing speed (Cohen's d = 0.9) than CDR0s, however, CDR>0s displayed much more performance gains than CDR0s on their first three days of testing (Figure 1; d = 1.4). Across biannual visits, CDR>0s lost more performance gains than CDR 0s, indicating less retention over time. Comparing APOE e4 carriers and e4 noncarriers revealed similar patterns. Carriers of the e4 allele were slower than noncarriers (d = 0.3) and lost more performance gains across biannual visits.

Conclusion

Magnitudes of PEs across multiple retest intervals are sensitive indicators of clinical status and genetic risk for AD. PEs observed at the daily level appear to be the most sensitive to clinical status and genetic risk for AD.
Association between short‐term memory binding performance and tau burden in the medial temporal lobe
Authors: Huyghe Lara , Quenon Lisa , Salman Yasmine , Colmant Lise , Gérard Thomas , Malotaux Vincent , Boyer Emilien , Dricot Laurence , Lhommel Renaud , Ivanoiu Adrian , Hanseeuw Bernard J
Published: January 2025

Background

The ability to discriminate very similar objects by implementing the binding between their multiple features is assumed to be supported by the medial temporal lobe (MTL). MTL is the first brain region that shows abnormal tau accumulation in Alzheimer’s disease (AD). However, whether binding ability is impaired since the preclinical stage of AD and relates to MTL tau burden is not well‐established.

Method

We included 35 amyloid‐negative cognitively normal individuals (Aβ‐CN), 16 amyloid‐positive CN (Aβ+CN) and 17 Aβ+ individuals with Mild Cognitive Impairment (Aβ+MCI). Aβ status was determined using lumbar punction or [18F]‐Flutemetamol Positron Emission Tomography (PET). Participants underwent a [18F]‐MK6240 tau‐PET to quantify tau burden in the MTL (entorhinal cortex, hippocampus, parahippocampus). They performed the Visual‐Short‐Term‐Memory‐Binding‐Test (VSTMBT), a test which is underpinned by the proper functioning of the MTL (Parra et al., 2010) and assess the ability to discriminate perceptually close items. In VSTMBT, participants had to determine whether a set of shapes was identical to the set presented before a 900ms blank retention interval. There were 4 conditions in which the number of shapes (2 or 3) and the color (white = ”Shape‐Only Condition” or colored) of the shapes varied. The colored conditions implied to memorize the binding between shapes and their respective color (“Binding‐Condition”)(Figure.1). We calculated the accuracy score (AS) and the mean reaction time (RT) for each condition.

Result

AS was lower in both Aβ+ groups than in Aβ‐CN participants in all conditions except the Shape‐Only‐2‐items, while Aβ+CN and Aβ+MCI did not differ (Figure.2). The Aβ+CN group was slower than Aβ‐CN only in the Binding‐2‐items‐Condition.

Total AS was associated with MTL tauopathy over the entire sample (even after controlling for age and education) and when restricting to all CN participants. Finally, MTL tauopathy was more associated to AS in the Binding‐Condition than in the Shape‐Only‐Condition (Figure.3).

Conclusion

Impaired visual short‐term memory performance was evidenced since the preclinical stage of AD, including in Binding‐Condition. Performance in Binding‐Condition was related to tau burden in the MTL, suggesting that impairment in visual short‐term memory binding abilities may constitute an early cognitive marker of accumulating tau pathology in the MTL.
Social determinants of health and not global genetic ancestry predicts cognitive performance and dementia risk in Latinos
Authors: Llibre‐Guerra Jorge J. , Jiang Miao , Acosta‐Castillo Isaac , Ortiz Ana Luisa Sosa , Acosta Daisy M , Velazquez Ivonne Z. Jimenez , Guerra Mariella , Salas Aquiles , Rodriguez‐Salgado Ana M , Guerra Juan C Llibre , Sánchez Nedelys Díaz , Prina Matthew , Renton Alan E. , Yokoyama Jennifer S. , Llibre‐Rodriguez Juan J. ,   1066 Dementia Research Group
Published: January 2025

Background

Alzheimer’s disease and related dementias (ADRD) disproportionately affect Latinos compared to non‐Latino whites. Leveraging the non‐monolithic structure of Latin America, which represents a large variability in social determinants of health (SDoH) and high levels of genetic admixture, we aimed to determine contributors to ADRD disparities within Latinos, focusing on genetic ancestry and SDoH.

Method

Community‐dwelling participants aged 65 and older (n = 4000) from Cuba, Dominican Republic, Mexico, and Peru completed the 10/66 protocol assessments, including sociodemographic and risk factors questionnaire, neurological exam, cognitive assessment, and blood draw. Dementia was diagnosed using the cross‐culturally validated 10/66 algorithm. Individual admixture proportions were determined using sixty ancestry‐informative markers. To evaluate the effect of global ancestry on dementia and cognitive performance, we used multivariate linear regression models adjusted for SDoH (e.g., gender, education level, socioeconomic status (SES), rural area, and vascular risk factors).

Result

We observed extensive three‐way (African/European/Native American) genetic ancestry variation between countries (Figure 1). Individuals with higher proportions of Native American (>70%) and African American (>70%) ancestry were more likely to exhibit factors contributing to worse SDoH, such as lower educational levels (p < 0.001), lower SES (p < 0.001), and higher frequency of vascular risk factors (p < 0.001). As a result, in unadjusted analysis, individuals with predominant African ancestry exhibited a higher dementia frequency (p = 0.03) and both Native American and African ancestry predominant groups showed lower cognitive performance relative to those with higher European ancestry (p<0.001). However, after adjusting for measures of SDoH, there was no association between ancestry proportion and dementia probability, and ancestry proportions no longer significantly accounted for the variance in cognitive performance (African predominant p = 0.31 [‐0.19, 0.59] and Native predominant p = 0.74 [‐0.24, 0.33]).

Conclusion

We report a comprehensive characterization of the role of global genetic ancestry in cognitive performance and dementia in Latin America while controlling for SDoH. In our study, adjustment of SDoH attenuated associations between genetic ancestry, dementia probability, and cognitive performance. These findings highlight that social and environmental factors likely play more critical roles than genetic ancestry in determining racial/ethnic disparities in cognitive performance and subsequent dementia risk.
Proteomics identification of novel proteins dysregulated in Alzheimer’s Disease with potential as blood‐based biomarkers and related to Amyloid‐Beta Plaques
Authors: Montero‐Calle Ana , Coronel Raquel , de los Ríos Vivian , Fernández‐Aceñero María Jesús , Peláez‐García Alberto , Martínez‐Useros Javier , Mendes Marta L. , Liste Isabel , Barderas Rodrigo
Published: January 2025

Background

Despite being the most common cause of dementia worldwide, the mechanisms underlying the progression of Alzheimer’s disease (AD) are not clear and effective treatments are still needed. Hence, further investigation regarding the pathogenesis of AD is required, which might allow for a better understanding of the disease, as well as for an early diagnosis of AD, thus improving the clinical management of AD patients. Here, to identify key proteins in AD pathogenesis, we performed two proteomics strategies, TMT (Tandem Mass Tags) 10‐plex quantitative proteomics and LFQ (Label Free Quantification).

Method

For the TMT analysis, proteins were extracted from frozen left prefrontal cortex brain tissue samples from AD at Braak IV‐VI, and from VD (vascular dementia) and FTD (frontotemporal dementia) patients, and healthy individuals as controls, trypsin digested, differentially labeled with the TMT reagents, and analyzed by tandem mass spectrometry coupled to liquid chromatography (LC‐MS/MS) using a Q‐Exactive mass spectrometer. For the LFQ analysis, a pull‐down with in vitro synthesized Abeta (Amyloid‐beta) fibers incubated with protein extracts from AD patients and healthy individuals was performed, and interacting proteins were analyzed on a Q‐Exactive. Proteomics data were analyzed with MaxQuant and the R program to identify dysregulated proteins.

Result

Among the 3281 proteins quantified by TMT, 15 and 154 proteins were found statistically significant ≥1.5‐fold upregulated and downregulated in AD patients in comparison to controls, respectively. After bioinformatics analysis, 10 candidate dysregulated proteins in AD were selected for further validation by orthogonal techniques to elucidate their role as tissue‐ or blood‐biomarkers, using tissue and plasma samples of AD patients and controls. Regarding the pull‐down, 332 proteins were identified as potential interactors of Abeta fibers, with 23 out of them selected for validation by WB and immunofluorescence.

Conclusion

The dysregulation of selected targets in AD patients was confirmed at protein level in a different cohort of tissue samples. Importantly, two proteins showed potential as blood‐based diagnostic biomarkers of AD, and eighteen candidate proteins were validated as novel Abeta plaques interactors, highlighting a major role of these proteins in AD development and progression.
Machine learning‐based classification of aMCI and non‐aMCI using gait and MRI‐based characteristics
Authors: Kim Yeo Jin , Park Ingyu , Lee Sang‐Kyu , Choi Hui‐Chul , Ahn Moo‐Eob , Ryu Ohk‐Hyun , Jang Daehun , Lee Unjoo
Published: January 2025

Background

In patients with mild cognitive impairment (MCI), the presence or absence of memory deficits is associated with divergent clinical presentations, etiologies, and prognostic outcomes. These differences may also manifest in additional neurologic signs beyond cognitive impairments and are often reflected in distinct magnetic resonance imaging (MRI) profiles. Gait is one of the clinical characteristics that reflects brain function along with cognitive function. Therefore, we aim to distinguish between amnestic MCI (aMCI) and non‐aMCI (naMCI) using gait and MRI‐based biomarkers.

Method

Eighty patients diagnosed with MCI from three dementia centers in Gangwon‐do, Korea were recruited for this study. We defined MCI as having a Clinical Dementia Rating global score of 0.5, with a memory domain score at or above 0.5. All participants underwent the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) assessment for cognitive evaluation, gait assessment using GAITRite electronic walkway system and brain MRI. Based on CERAD, individuals with a verbal memory delayed recall score at or below ‐1.0 standard deviation from the norm were classified as aMCI, while those with scores higher than this threshold were categorized as naMCI. We trained a machine learning model using gait and MRI data parameters.

Result

The CNN resulted in the best classifier performance in separating aMCI from naMCI; its performance was maximized when only feature patterns that included GAIT set were used. (accuracy = 0.99 ± 0.04) The standard deviation of stride velocity and the standard deviation of stride length were the strongest predictors. Subsequently, machine learning analyses using the GAIT + WM data set (accuracy = 0.96±0.07) and the GAIT + GM dataset (0.95±0.08) demonstrated high accuracy.

Conclusion

Machine learning using GAIT data set achieved the highest accuracy in distinguishing between aMCI and naMCI.
Alterations in brain structure and functional connectivity associated with hearing loss and olfactory loss
Authors: Phillips Natalie , Best Paul T. , Grant Nicole , Kabir Ameera
Published: January 2025

Background

Sensory loss in hearing, vision, and olfaction are highly prevalent in older adults and are each associated with a higher risk of developing dementia. This study sought to identify the extent to which these sensory factors are associated with alterations in brain function and structure older adults with or at risk for dementia. We examined groups who range from relatively low risk (those with normal cognition and no cognitive complaints (NC)), to those with higher risk, namely individuals with subjective reports of cognitive decline (SCD) but normal cognition and those with mild cognitive impairment (MCI).

Method

We used data from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study (Release 7). Hearing loss was assessed with a pure‐tone screening protocol, vision was assessed with the MARS test for contrast sensitivity, and olfaction was assessed with the Brief Smell Identification Test (BSIT). We examined the frequency of sensory deficits in 128 NC (mean age = 69 years; mean education = 16 years), 135 participants with SCD (age = 70; education = 17), 241 with MCI (age = 72; education = 16), and 93 with Alzheimer’s disease (AD, age = 75; education = 15). Participants were matched on age and education, except for AD participants who were older.

Results

As shown in Figure 1, normal sensory performance in all three modalities was observed in the minority of participants and decreased in prevalence across the dementia risk spectrum groups (e.g., NC: 29%; SCD: 29%; MCI: 11%; AD: 2%). Olfactory deficits (hyposmia or anosmia) were the most frequent (ranging from 45% in NC to 61% in AD), followed by hearing impairment, and then deficits in visual contrast sensitivity. Deficits in multiple sensory domains were highly prevalent, with 37% of participants with AD having deficits in two or more domains. Preliminary analyses indicate that hearing loss is associated with altered connectivity in the default mode network in MCI participants and olfactory loss is associated with reduced hippocampal volumes in SCD.

Conclusion

These analyses indicate that sensory loss is highly frequent and co‐morbid in persons with or at risk for dementia. These findings have implications for cognition, brain function, functional activities, and care delivery for persons with or at risk for dementia.
Addressing the Unmet Hearing Care Needs of Persons Living with Cognitive Impairment: A Qualitative Study of End‐Users, Care Partners, and Experts
Authors: Nieman Carrie L , Blinka Marcela D , Hope Peter , Lee Paul , Tu Xueting , Wang Natalie , Yasar Sevil , Oh Esther S
Published: January 2025

Background

Hearing loss is highly prevalent and can have significant consequences for older adults aging with cognitive impairment. However, few older adults use hearing aids and disparities in care exist by race, ethnicity, and socioeconomic position.

To understand the intersection of hearing loss and cognitive impairment with the ultimate goal of developing an affordable, accessible hearing care intervention responsive to the needs of end‐users, a series of semi‐structured interviews was conducted.

Method

We conducted 20 semi‐structured interviews with 10 participants with mild cognitive impairment (end‐users) and their 10 care partners and 9 experts. End‐users were recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center. Experts were identified professionals with expertise in dementia, hearing, neuropsychiatric symptoms, healthcare delivery, intervention development, and program implementation and dissemination. We used a heterogeneous purposive sampling to recruit participants from diverse race/ethnicities, education, and income levels. Qualitative content analysis was used to identify themes related to the impact of hearing loss on work, relationships, family life, and neuropsychiatric symptoms along with considerations for the development of a hearing care intervention.

Result

Among end‐users and care partners, 30% self‐identified as African American, 45% as male, and 40% reported less than a college degree (Table 1). End‐users and care partners identified barriers to accessing hearing care, including the stigma associated with hearing loss, the cost of hearing aids, the lack of availability of hearing care, and the participants’ denial of hearing difficulties (Table 2). Suggested facilitators for improving access to hearing care include more affordable hearing aids and incorporating hearing screenings into routine medical care. The participants’ desire to improve communication and care partner support motivate accessing hearing care. Measures of hearing intervention success include strengthened social connections, reduced tension with care partners, and increased social activity. Experts emphasize the importance of education on hearing and dementia, the role of care partners, minimizing burden, and reliance on practical, affordable technology.

Conclusion

In a diverse sample of persons living with cognitive impairment, their care partners, and experts, participants identified unique barriers, facilitators, motivators, and measures of success to guide the development of an affordable, accessible hearing care intervention.
Effect of hearing intervention on three‐year change in brain morphology
Authors: Pike James Russell , Huang Alison R , Deal Jennifer A. , Reed Nicholas S , Burgard Sheila , Chisolm Theresa , Couper David , Glynn Nancy W. , Gmelin Theresa , Goman Adele M , Gravens‐Mueller Lisa , Hayden Kathleen M. , Mitchell Christine , Pankow James , Sanchez Victoria A , Schrack Jennifer A , Albert Marilyn S. , Jack Clifford R. , Knopman David S. , Coresh Josef , Lin Frank R ,   ACHIEVE Collaborative Research Group
Published: January 2025

Background

Prior longitudinal studies among older adults have documented associations between hearing loss and changes in brain morphology. Whether interventions involving hearing aids can reduce age‐related atrophy is unknown. A substudy within the Aging and Cognitive Health Evaluation in Elders (ACHIEVE, Clinicaltrials.gov Identifier: NCT03243422) randomized controlled trial tested the effect of a best‐practices hearing intervention versus health education control on three‐year change in cortical thickness among older adults with hearing loss.

Method

The ACHIEVE study enrolled 977 community‐dwelling adults aged 70‐84 years at baseline (2018‐2019) with untreated hearing loss (better ear pure tone average [0.5‐4 kHz] ≥30 and <70 dB HL) and without substantial cognitive impairment from four sites across the U.S. (Jackson, MS, Forsyth County, NC, Minneapolis, MN, Washington County, MD). Participants were randomized to a hearing intervention (provision of hearing aids and related technologies, counseling, and education) or a health education control (individual sessions with a health educator covering topics relevant to chronic disease and disability prevention). Three‐dimensional magnetic resonance imaging was performed on 3 Tesla Siemens scanners in a subsample of 445 participants at the ACHIEVE baseline and three‐year follow‐up. Linear mixed effects models were used in intention‐to‐treat analyses to estimate three‐year change in cortical thickness. All models adjusted for baseline measures of hearing loss, recruitment source, site, age, sex, and education. Missing outcome and covariate data was imputed to mitigate bias caused by informative attrition.

Result

At baseline, 224 participants were women (50.3%), 52 participants were Black (11.7%), and the mean (SD) age was 76.4 (4.0) years old (Table 1). Compared to the health education control, the hearing intervention exhibited a nominally protective effect on three‐year change in average cortical thickness (Figure 1). The greatest effect size for cortical thickness was observed in the occipital lobe, while the smallest effect size was detected in the temporal lobe. Statistically significant effects were detected in the pars orbitalis, rostral anterior cingulate, posterior cingulate, and isthmus cingulate (Figure 2).

Conclusion

Hearing aid use may reduce decline in cortical thickness among older adults. The effects of hearing aids may be greatest in regions other than those associated with the auditory cortex.
Emotional Distress Following Amyloid PET Disclosure: A Preliminary Analysis Across Cognitive Spectrum
Authors: Kim Jeong Eun , Ren Dianxu , Cohen Annie , Lopez Oscar L. , Lingler Jennifer H
Published: January 2025

Background

Gaining insight into the emotional consequences of disclosing amyloid Positron Emission Tomography (PET) results is essential for offering effective support to patients of varying cognitive status. This analysis aimed to examine variations in emotional distress levels following the disclosure of amyloid PET results among participants that are cognitively normal, with Mild Cognitive Impairment (MCI), or dementia.

Method

This investigation was a preliminary analysis of 55 participants, using 1‐month follow‐up call data of an ongoing brain imaging data repository study, obtaining baseline PET imaging on a subset of Alzheimer’s Disease Research Center (ADRC) participants. Multiple linear regression modelling was used to examine the relationship between emotional distress scores, measured by Impact of Genetic Testing questionnaire modified for amyloid PET disclosure, and diagnostic categories, while controlling for participants’ sex, age, level of education, and amyloid status. Additionally, pairwise comparisons were conducted to examine specific differences between diagnostic categories. Bonferroni correction was applied to adjust for multiple comparisons.

Result

Participants were predominantly White (94.5%), Non‐Hispanic (94.5%), highly educated (average of 16.6 years) individuals, with a mean age of 70.8. Of the 55 participants, 13 were cognitively normal, 17 with MCI, and 25 diagnosed with dementia. Approximately 54% were amyloid negative. During the 1‐month follow‐up call, participants exhibited a mean depression score (measured by Center for Epidemiological Studies Depression Scale) of 6.93 (SD = 7.57) and a mean anxiety score (measured by Spielberger State‐Trait Anxiety Inventory) of 28.55 (SD = 10.56). Participants’ diagnostic categories were marginally significantly associated with their emotional distress scores post disclosure (b = 4.945, SE = 2.577, p = 0.062). However, individual diagnostic categories revealed a positive direction in mean emotional distress scores: normal cognition (M = 7.320, SE = 4.306), MCI (M = 16.955, SE = 3.382), and dementia (M = 18.572, SE = 2.791).

Conclusion

These preliminary findings suggest that the disclosure of amyloid PET results does not result in discernible differences in the level of emotional distress among cognitively symptomatic and asymptomatic individuals. This contributes to our understanding of the emotional impact of amyloid PET disclosures and may have implications for counseling and support strategies in the context of Alzheimer’s disease research and clinical settings. Further investigation with a larger sample size is recommended to validate these findings.