Normal Elderly Research Articles

Relationship Between Actual Intelligence & the CAMCOG-R in Cognitively Normal Elders

Abstract: We examined (1) the relationship between actual intelligence and the CAMCOG-R performance in cognitively normal elders and (2) the presumed impact of age and education on the relationship. Our retrospective study of 94 participants assessed in a specialized setting, measuring actual intelligence (general and specific) with the Wechsler Adult Intelligence Scale-III, the Full-Scale Intelligence Quotient (WAIS-III FSIQ), and the specific subtests thereof. The CAMCOG-R correlated largely with FSIQ (.629, p < .001; .708 when controlled for age). The CAMCOG-R’s scores increased across three different IQ levels as IQ increased. FSIQ accounted for 40% of the CAMCOG-R’s variability. Combined, FSIQ and age accounted for 59% of the CAMCOG-R’s variability. FSIQ had a stronger weight than age (β: .644 and −.439, respectively). Regression analyses with FSIQ’s subtests, age and education, found the best-equilibrated model to include Information, age, and Picture Completion. Combined, they accounted for 55% of the CAMCOG-R’s variability. Information received the strongest weight (β: .411). Overall, education was nonsignificant. Thus, a significant relationship existed primarily between general intelligence and the CAMCOG-R and, to a lesser extent, between the above-mentioned subtests of intelligence and the CAMCOG-R. Adding age increased the prediction rate. Actual intelligence and age should be considered when interpreting the CAMCOG-R’s scores. The practical implementation of the intelligence factor is complex.

Tracing TMEM106B fibril deposition in aging and Parkinson’s disease with dementia brains

Abstract Transmembrane protein 106B (TMEM106B), previously identified as a risk factor in frontotemporal lobar degeneration, has recently been detected to form fibrillar aggregates in the brains of patients with various neurodegenerative diseases (NDs) and normal elders. While the specifics of when and where TMEM106B fibrils accumulate in human brains, as well as their connection to aging and disease progression, remain poorly understood. Here, we identified an antibody (NBP1-91311) that directly binds to TMEM106B fibrils extracted from the brain in vitro and to Thioflavin S-positive TMEM106B fibrillar aggregates in brain sections. We discovered that TMEM106B fibrils deposit in the human brain in an age-dependent manner. Notably, the TMEM106B fibril load in the brains of Parkinson’s disease with dementia patients was significantly higher than in age-matched elders. Additionally, we found that TMEM106B fibrils predominantly accumulate in astrocytes and neurons and do not co-localize with the pathological deposition formed by other amyloid proteins such as α-synuclein, Aβ, and Tau. Our work provides a comprehensive analysis of the burden and cellular distribution of TMEM106B fibrils in human brains, underscoring the impact of both aging and disease conditions on TMEM106B fibril deposition. This highlights the potential significance of TMEM106B fibrils in various age-related NDs.

Causes and Implications of Type I Myofiber Grouping in Parkinson's Disease: A Brief Scoping Review

Purpose: The purpose of this study was to review the alterations in muscle fibers in Parkinson's disease(PD). The following were our review questions. (1)How has research on type I myofiber grouping in PD developed over time? (2)What kinds of muscles are affected in which patients? (3)What are some possible pathophysiology and mechanisms? Does type I myofiber grouping in PD differ from primary sarcopenia that occurs with aging? (4)What are the clinical implications and possible therapeutic approaches for type I myofiber grouping in PD?.
 Method: To investigate the questions, we used combinations of keywords such as “Parkinson”, “skeletal muscle”, “myofiber type”, “fast twitch”, “slow twitch”, “myofiber grouping”, and “motor unit” in PubMed and Google Scholar. Articles on PD patients and normal elderlies that dealt with type I myofiber grouping and motor unit alterations were included. References in the included articles were also considered.
 Results: Research over the past five decades has identified various motor abnormalities and myofiber alterations in PD patients, including the hypertrophy of slow-twitch type I myofibers and atrophy of fast-twitch type II myofibers across different muscles. One important finding is that Type I myofiber grouping, which is common in aging, is more severe in PD, which could be due to the selective activation of low-threshold motor units and could be also linked to abnormal alpha-synuclein aggregation, a factor associated with PD.
 Conclusion: Research suggests that type I myofiber grouping in muscles, not just dopaminergic cell damage in the substantia nigra, could influence motor symptoms of PD, indicating that alternative treatments beyond dopaminergic drugs, such as high-intensity exercise, might be beneficial. However, given the limitations in these studies, such as small participant numbers and the complexity of PD pathophysiology, future research is needed to fully understand the phenomena in different PD subtypes and to develop more effective treatments.

Executive function may underlie cognitive reserve: A 3‐year follow‐up study

AbstractBackgroundThe hypothetical concept of cognitive reserve (CR) has been proposed to explain why someone can manage to function normally even in the presence of brain pathology. However, it still remains to be determined what components constitute such resilience against Alzheimer’s disease (AD) pathology. In the current study we investigated the characteristics of cognitively normal (CN) elders with high CR.MethodWe included CN participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea. We selected a group of CN individuals who showed a significant amyloid‐beta (aß) deposition at baseline and stayed CN over the follow‐up period. They were defined as high CR group. For comparison purpose, individuals with a significant aß deposition at baseline but converted to MCI at follow‐up were also included. In the final analysis, 94 high CR group and 24 control group were included. Group comparisons in socio‐demographic, clinical and cognitive variables were performed using χ2 tests and ANOVA controlling for age, education, gender, and follow‐up month.ResultMean follow‐up month were 43.37. There were no group differences in education, gender, socio‐economic status, family history of dementia or stroke, medical conditions, body mass index, subjective memory complaints, and instrumental activities of daily living. However, high CR group was younger and had shorter follow‐up period, therefore such variables were controlled when cognitive tests were compared. High CR group was more religious (p < 0.001), showed higher complexity in former job (p = 0.009), and higher level of executive functoning (Digit Dpan Backward, p = 0.012; Fluency test, p = 0.008; Boston Naming Test, p = 0.014; Trail Making Test part B, p = 0.017) than control group. There were no group differences in episodic memory tests and visuospatial abilities.ConclusionIndividuals with high CR could cope better with AD pathology. Many factors have been suggested to be associated with CR. Regarding cognitive process involved, our findings suggest that executive function plays an important role in constituting high CR. Preserved executive function may, at least in part, underlie CR.

Air pollution is associated with faster cognitive decline in Alzheimer's disease.

Although chronic exposure to air pollution is associated with an increased risk of dementia in normal elderlies, the effect of chronic exposure to air pollution on the rates of cognitive decline in Alzheimer's disease (AD) has not been elucidated. In this longitudinal study, a total of 269 patients with mild cognitive impairment or early dementia due to AD with the evidence of brain β-amyloid deposition were followed-up for a mean period of 4 years. Five-year normalized hourly cumulative exposure value of each air pollutant, such as carbon monoxide (CO), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), and particulate matter (PM2.5 and PM10 ), was computed based on nationwide air pollution database. The effects of chronic exposure to air pollution on longitudinal cognitive decline rate were evaluated using linear mixed models. Higher chronic exposure to SO2 was associated with a faster decline in memory score, whereas chronic exposure to CO, NO2 , and PM10 were not associated with the rate of cognitive decline. Higher chronic exposure to PM2.5 was associated with a faster decline in visuospatial score in apolipoprotein E ε4 carriers. These effects remained significant even after adjusting for potential confounders. Our findings suggest that chronic exposure to SO2 and PM2.5 is associated with faster clinical progression in AD.

Effects of motor-cognitive interaction based on dual-task gait analysis recognition in middle age to aging people with normal cognition and mild cognitive impairment.

BackgroundMild cognitive impairment (MCI) is considered a transitional stage between cognitive normality and dementia among the elderly, and its associated risk of developing Alzheimer’s disease (AD) is 10–15 times higher than that of the general population. MCI is an important threshold for the prevention and control of AD, and intervention in the MCI stage may be the most effective strategy to delay the occurrence of AD.Materials and methodsIn this study, 68 subjects who met the inclusion criteria were divided into an MCI group (38 subjects) and normal elderly (NE) group (30 subjects). Both groups underwent clinical function assessments (cognitive function, walking function, and activities of daily living) and dual-task three-dimensional gait analysis (walking motor task and walking calculation task). Spatial-temporal parameters were obtained and reduced by principal component analysis, and the key biomechanical indexes were selected. The dual-task cost (DTC) was calculated for intra-group (task factor) and inter-group (group factor) comparisons.ResultsThe results of the principal component analysis showed that the cadence parameter had the highest weight in all three walking tasks. In addition, there were significant differences in the cadence both walking motor task (WMT) vs. walking task (WT) and walking calculation task (WCT) vs. WT in the MCI group. The cadence in the NE group only showed a significant difference between WMT and WT. The only differences between the MCI group and NE group was DTC cadence in WCT, and no differences were found for cadence in any of the three walking tasks.ConclusionThe results show that dual tasks based on cognitive-motor gait analysis of DTCcadence in MCI have potential value for application in early identification and provide theoretical support to improve the clinical diagnosis of MCI.

Integrity of Neuronal Size in the Entorhinal Cortex Is a Biological Substrate of Exceptional Cognitive Aging.

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers ("Normal Elderly"), and individuals with amnestic mild cognitive impairment. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was used to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups. Quantitative measurements found that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p < 0.05)-including younger individuals 20-30 years their junior (p < 0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer's disease-related neurofibrillary tangles in layer II ERC than Normal Elderly (p < 0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggests that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared with individuals 20-30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age.SIGNIFICANCE STATEMENT Average aging is associated with a gradual decline of memory. Previous research shows that an area critical for memory, the entorhinal cortex (ERC), is susceptible to the early formation of Alzheimer's disease neuropathology, even during average (or typical) trajectories of aging. The Northwestern University SuperAging Research Program studies unique individuals known as SuperAgers, individuals ≥80 years old who show exceptional memory that is at least as good as individuals 20-30 years their junior. In this study, we show that SuperAgers harbor larger, healthier neurons in the ERC compared with their cognitively average same-aged peers, those with amnestic mild cognitive impairment, and - remarkably - even compared with individuals 20-30 years younger. We conclude that larger ERC neurons are a biological signature of the SuperAging trajectory.

An intergenerational analysis of cognitive impairment in healthy elders

Cognitive disorders are common in elderly population and are becoming an increasingly important public health problem, partly because of the rapid aging of the population. This study was conducted to find out the differences between cognitive ability between normal adults and healthy elders of north region. The mild cognitive impairment (MCI) resulting in limitations and delayed treatment of dementia, should be considered an entry point for researching recent changes in the lives of healthy elderly. In this study we have applied MoCA test on the 36 normal healthy elders belonging to high socioeconomic status and normal young adults. Results have shown that there was no significant difference amongst the young normal adults; all the participants had normal MoCA scores. The MoCA scores were significantly impaired in all the healthy elders and there was a significant difference between the normal young adults and healthy elders. Age has a significant influence on MOCA score in older adults. Hence there is a need for age specific stratification in cut-off scores.

Culture Effects on the Chinese Version Boston Naming Test Performance and the Normative Data in the Native Chinese-Speaking Elders in Mainland China.

BackgroundThe Chinese version of Boston Naming Test (BNT-C) is administered in China widely. However, the neuropsychological parameter of BNT-C in native Chinese-speaking elders in mainland China has not been explored systematically. The aim of this study was to explore cultural influences on BNT-C performance and establish norms among native Chinese-speaking elders in Beijing.MethodsA total of 161 native, Chinese-speaking, cognitively normal elders aged ≥55 years were enrolled from various communities in Beijing. The BNT-C was conducted on all the participants. The internal consistency, participants' familiarity, and naming accuracy were analyzed and compared with data from Chinese areas outside the mainland and from American published previously. The influencing factors and stratified norms for BNT-C were established.ResultsThe BNT-C showed good internal consistency (α = 0.738). Strong correlation between naming accuracy and object familiarity was found (r = 0.962, P < 0.001). Participants' familiarity and correct naming rate for many items were notably different between the Chinese-speaking elders and English-speaking elders in America. The difference in some items' correct naming rate also existed between Beijing, Taiwan, and Hongkong. Higher education was associated with higher scores, whereas age and gender had no effect on BNT-C performance. The recommended norms of total naming scores for elders with education ≤ 9 and >9 years were 16 and 23, respectively.ConclusionThe participants' familiarity with BNT items differed between different cultures, which further affected the naming accuracy and total scores. The education stratified norms established here are helpful for the better application of BNT-C in mainland China.

A Study on Social Support of the Elderly with Normal Hearing and Elderly Wearing Hearing Aids

Purpose: This study investigates the social support in both elderly who wear hearing aids and elderly who do not report any hearing loss.Methods: The study subjects were 48 seniors age 65 or older who wore hearing aids and 48 seniors who did not wear hearing aids. A Lubben social network scales survey was conducted. The Korean Version of International Outcome Inventory for Hearing Aids, Puretone Audiometry, and Word Recognition Score tests were carried out on the elderly who were wearing hearing aids.Results: A statistical analysis represented that the total social support scores were not significantly different between the two groups. Of all the social support factors, social network was statistically significant between the groups (p &lt; 0.05), but social support was not statistically significant. The correlation between social support and the degree of hearing loss was not statistically significant. Further, there were no significant relationships found for the social support of older adults’ wearing hearing aids and satisfaction with hearing overall, and the level of social support.Conclusion: The results of the study indicated that users hearing aid users have a smaller social network than those who do not wear hearing aids. However, this result can be interpreted as an independent factor regarding satisfaction with hearing aid use and the degree of hearing. As a follow-up study, it will be necessary to proceed to study the diversity of the background factors for those elderly who do have hearing loss.

Specific Gain and Loss of Co-Expression Modules in Long-Lived Individuals Indicate a Role of circRNAs in Human Longevity.

Deep RNA sequencing of 164 blood samples collected from long-lived families was performed to investigate the expression patterns of circular RNAs (circRNAs). Unlike that observed in previous studies, circRNA expression in long-lived elderly individuals (98.3 ± 3.4 year) did not exhibit an age-accumulating pattern. Based on weighted circRNA co-expression network analysis, we found that longevous elders specifically gained eight but lost seven conserved circRNA-circRNA co-expression modules (c-CCMs) compared with normal elder controls (spouses of offspring of long-lived individuals, age = 59.3 ± 5.8 year). Further analysis showed that these modules were associated with healthy aging-related pathways. These results together suggest an important role of circRNAs in regulating human lifespan extension.

Electroencephalography (EEG)-Based Neural Emotional Response to Flower Arrangements (FAs) on Normal Elderly (NE) and Cognitively Impaired Elderly (CIE).

Background: The purpose of this study is to explore the differences and similarities of EEG -based neural emotional response toward flower arrangements (FAs) between the normal elderly (NE) and cognitively impaired elderly (CIE) in arranging flowers. Methods: The study participants included 16 elderly individuals: eight elderly people with normal cognitive function and eight elderly people with cognitive dysfunction. They were divided into two groups to arrange flowers, and six mood indicators (Engagement, Excitation, Focus, Interest, Relaxation and Stress) were measured with EEG before and after the experiment. Results: The similarities were that there was no significant difference in Excitement, Relaxation and Stress between pre-test and post-test for NE and CIE. The differences were that there was a significant difference on Engagement and Interest in CIE, and they both increased, but there was no difference with respect to them in NE. While there was a significant difference on the Focus of NE, it was decreased, but there was no difference for it with respect to CIE. Conclusions: A similarity on EEG-Based Neural Emotional Responses to flower arrangements between NE and CIE was that they both felt relaxation. The differences were that the Focus of NE decreased and the Interest and Engagement of CIE increased. CIEs were more interested and engaged in FAs.

Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer’s disease

Alzheimer’s disease (AD) is the most common multifactorial neurodegenerative disease among elderly people. Genome-wide association studies (GWAS) have been highly successful in identifying genetic risk factors. However, GWAS investigate common variants, which tend to have small effect sizes, and rare variants with potentially larger phenotypic effects have not been sufficiently investigated. Whole-genome sequencing (WGS) enables us to detect those rare variants. Here, we performed rare-variant association studies by using WGS data from 140 individuals with probable AD and 798 cognitively normal elder controls (CN), as well as single-nucleotide polymorphism genotyping data from an independent large Japanese AD cohort of 1604 AD and 1235 CN subjects. We identified two rare variants as candidates for AD association: a missense variant in OR51G1 (rs146006146, c.815 G > A, p.R272H) and a stop-gain variant in MLKL (rs763812068, c.142 C > T, p.Q48X). Subsequent in vitro functional analysis revealed that the MLKL stop-gain variant can contribute to increases not only in abnormal cells that should die by programmed cell death but do not, but also in the ratio of Aβ42 to Aβ40. We further detected AD candidate genes through gene-based association tests of rare variants; a network-based meta-analysis using these candidates identified four functionally important hub genes (NCOR2, PLEC, DMD, and NEDD4). Our findings will contribute to the understanding of AD and provide novel insights into its pathogenic mechanisms that can be used in future studies.

Interactive Effects of Agitation and Cognitive Impairment on Odor Identification in Patients With Late-Life Depression

BackgroundLate-life depression (LLD) is a risk factor for cognitive decline in older adults, and odor identification (OI) deficits are an early indicator of cognitive decline with LLD. However, neuropsychiatric symptoms (NPSs) are common in LLD and are associated with OI deficits. In subjects with LLD, when OI deficits forecast cognitive decline, whether and how NPS affects the relationship between OI and cognition still must be further explored.ObjectiveTo comprehensively explore the potential effects of various NPSs on the relationship between OI and cognition in participants with LLD.MethodsThere were 167 patients with LLD and 105 normal elderly (NE) participants. The odor identification test (Sniffin' Sticks), cognitive function assessments (global cognition, memory, executive function, attention, language, visual space), and an NPS assessment (the neuropsychiatric inventory questionnaire) were performed on the subjects. In patients with LLD, the relationship among OI, cognition and NPSs was examined using correlation analysis and moderation analysis.ResultsIn patients with LLD, OI was positively correlated with cognition (global cognition, memory, executive function, attention, language) and negatively associated with NPSs (agitation and aberrant motor behavior). In NE group, OI was correlated with executive function. Moderation analysis showed that there was an interactive effect of agitation and cognitive impairment (language deficit or attention deficit) on OI in patients with LLD.ConclusionThe coexistence of agitation and language or attention deficit was associated with worse OI in subjects with LLD. Agitation should be considered since OI predicts cognitive decline in patients with LLD.

The Effect of α and SMR Enhancing Neurofeedback Training on Cognitive Function and Emotion in a Normal Elderly Population

본 연구는 α파 및 SMR파 강화 뉴로피드백 훈련이 65세 이상 정상노인의 작업기억, 억제기능, 불안 및 우울에 미치는 영향을 확인하기 위한 목적으로 수행된 실험연구이다. 건강하고 인지기능이정상인 노인을 선별하여 세 개의 집단(α파, SMR파, 가성 뉴로피드백 훈련)에 무선배정한 후 훈련전후 작업기억(단어기억력 검사, 숫자 외우기 검사), 억제기능(스트룹 검사), 불안(K-GAI) 및 우울(S-GDS) 수준을 측정하여 비교하였다. 뉴로피드백 훈련은 주 1회, 총 8번 실시되었으며, 총 37명의데이터를 반복측정분산분석으로 분석하였다. 연구결과 α파 및 SMR파 강화 훈련집단에서 작업기억력의향상, 억제기능 증진, 불안 수준의 완화가 관찰되었다. 이러한 결과를 바탕으로 정상노인의 인지기능과 정서 유지를 위한 뉴로피드백 훈련의 활용과 후속 연구를 위한 시사점들을 기술하였다.

Association of Subjective Cognitive Decline with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

Subjective cognitive decline (SCD) might occur at the early stages of dementia. Individuals with SCD have an increased risk of subsequent objective cognitive decline and greater rates of progression to dementia. We aimed to explore the associations between SCD and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology in cognitively normal individuals. A total of 1,099 cognitively normal elders with available data on CSF biomarkers of AD pathology (Aβ42, P-tau, and T-tau) were included in our analysis. Linear regression was used to examine the associations of SCD status and SCD severity with CSF biomarkers. Additionally, a review was conducted to discuss the associations between SCD and CSF biomarkers of AD pathology. After adjustments for covariates, SCD and SCD severity showed significant associations with CSF Aβ42 (SCD: β= -0.0003, p = 0.0263; SCD severity: β= -0.0004, p = 0.0046), CSF T-tau/Aβ42 ratio (SCD: β= 0.1080, p = 0.0064; SCD severity: β= 0.1129, p = 0.0009) and CSF P-tau/Aβ42 ratio (SCD: β= 0.0167, p = 0.0103; SCD severity: β= 0.0193, p = 0.0006) rather than T-tau and P-tau compared with cognitively normal individuals. In the review, a total of 28 studies were finally included after reviewing 174 articles. CSF Aβ42 was lower in SCD than cognitively normal (CN) individuals, but higher than those with objective cognitive decline. However, CSF tau pathology showed no difference between SCD and CN. The results indicated that pathophysiological changes in CSF Aβ pathology occurred in individuals with SCD, which provide new insights into early intervention of AD.

The Red and Orange Complex Subgingival Microbiome of Cognitive Impairment and Cognitively Normal Elderly with Periodontitis.

Increasing evidence has shown an association between periodontitis and cognitive impairment. Subgingival microbiota play a great role in periodontitis pathogenesis. However, the correlation between the subgingival microbiome and cognitive impairment remains unclear. This study aimed to evaluate the red and orange complex subgingival microbiome of cognitively impaired and cognitively normal elderly Indonesian subjects with periodontitis. Twenty-eight elderly subjects diagnosed with periodontitis underwent two cognitive examinations using the Hopkins Verbal Learning Test and the Mini-Mental State Examination. Gingival crevicular fluid taken from the periodontal pocket, at a depth between 5 and 7 mm, using a paper point was used as the subgingival samples. The subgingival microbiome in the cognitive impairment group (n = 14) and cognitively normal group (n = 14) was compared using the 16S rRNA Metagenomic iSeq™ 100 Sequencing System. There was β-diversity in the subgingival microbiota between the cognitively impaired and cognitively normal subjects. The metagenomic analysis showed a higher abundance of Porphyromonas and Treponema bacteria in the cognitive impairment group than in the normal cognitive group (p < 0.05). The abundance of Porphyromonas gingivalis and Treponema denticola was higher in the cognitively impaired elderly subjects. The role of P. gingivalis and T. denticola in the pathogenesis of cognitive impairment needs further investigation.

Comparison of Cardiovascular Risk Factors between Subjects Having a History of Stroke and Normal Elderly

Comparison of Cardiovascular Risk Factors between Subjects Having a History of Stroke and Normal Elderly

Copy number variation (CNV) identification and association study on 3,928 Alzheimer's disease whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

Estimation of heritability of Alzheimer's Disease (AD) ranges from 49-79%, but the conventional single nucleotide variants (SNVs) identified to date account for <50% of the AD heritability. The involvement of genetic variants, such as SNVs and copy number variations (CNVs), has been proposed to explain part of the missing heritability. To accelerate AD genetic discovery, the Alzheimer's Disease Sequencing Project (ADSP) sequenced cases and cognitively normal elder controls from multiple ethnic groups. Leveraging this large-scale Whole Genome Sequence (WGS) collection, we could detect and conduct AD genetic analyses in full-spectrum of CNVs (small or large, common or rare, and coding or non-coding in genomic regions). We developed a bioinformatics pipeline consisting of four steps. First, we applied three calling algorithms, CNVnator, JAX-CNV, and Smoove, on each sample. Results of each tool were then merged by Svimmer. Second, we employed GraphTyper for genotyping. GraphTyper is a graph-pangenome-based method that may mitigate bias of human references. Finally, we resolved issues of multiple CNVs overlapping in a region by bedtools. Once the CNV callset was obtained, we conducted an association study to identify CNV regions that contribute to AD. We consider conventional association methods as well as a new developed CNV-curve-centric strategy which models CNVs as piecewise constant curves to assess the CNV effect on AD. For each sample, we identified an average of 7,959 CNVs by three algorithms. After merging CNVs of all samples, we obtained 56,316 deletions and 16,390 duplications for GraphTyper joint genotyping. The preliminary results of PLINK permutation-based test on the chromosome 19 indicated significant CNVs (p-value < 0.05 after adjusting for multiple tests) on genes UNC13A, IGSF23, KMT2B, LIN37, PSENEN, IGFLR1, and U2AF1L4. UNC13A, KMT2B, and PSENEN have been discovered to be associated in frontotemporal dementia, dystonia, and AD. Further validations of those CNVs are necessary. We developed a scalable CNV detection pipeline and applied it to 3,928 ADSP WGS samples. The preliminary results of the association study validate some known AD, dementia, and dystonia genes. To the best of our knowledge, this is the first large-scale CNV investigation of AD using WGS data.

Anaemia and cerebrospinal fluid biomarkers of Alzheimer\u2019s pathology in cognitively normal elders: the CABLE study

BackgroundAnaemia has been reported to be associated with cognitive decline and Alzheimer’s disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers.MethodsParticipants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including β-amyloid 1–42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate.ResultsA total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aβ42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aβ42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found.ConclusionCross-sectionally, anaemia was associated with lower CSF Aβ42 levels. These findings consolidated the causal close relationship between anaemia and AD.