Cognitive integrity in Non-Demented Individuals with Alzheimer's Neuropathology is associated with preservation and remodeling of dendritic spines.

INTRODUCTION: Individuals referred to as Non-Demented with Alzheimer's Neuropathology (NDAN) exhibit cognitive resilience despite presenting Alzheimer's disease (AD) histopathological signs. Investigating the mechanisms behind this resilience may unveil crucial insights into AD resistance. METHODS: DiI labeling technique was used to analyze dendritic spine morphology in control (CTRL), AD, and NDAN post mortem frontal cortex, particularly focusing on spine types near and far from amyloid beta (Aß) plaques. RESULTS: NDAN subjects displayed a higher spine density in regions distant from Aß plaques versus AD patients. In distal areas from the plaques, NDAN individuals exhibited more immature spines, while AD patients had a prevalence of mature spines. Additionally, our examination of levels of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), a protein associated with synaptic plasticity and AD, showed significantly lower expression in AD versus NDAN and CTRL. DISCUSSION: These results suggest that NDAN individuals undergo synaptic remodeling, potentially facilitated by Pin1, serving as a compensatory mechanism to preserve cognitive function despite AD pathology. HIGHLIGHTS: Spine density is reduced near Aß plaques compared to the distal area in CTRL, AD, and NDAN dendrites. NDAN shows higher spine density than AD in areas far from Aß plaques. Far from Aß plaques, NDAN has a higher density of immature spines, AD a higher density of mature spines. AD individuals show significantly lower levels of Pin1 compared to NDAN and CTRL.

[Assessment of the safety and clinical efficacy of the Brainmax in therapy of non-demented patients with a mild cognitive impairment]. / Otsenka klinicheskoi effektivnosti i bezopasnosti preparata Breinmaks v terapii patsientov s nedementnymi kognitivnymi narusheniyami.

OBJECTIVE: The assessment of the clinical efficiency and safety of the drug Brainmax and its influence on the degree of functional recovery in the treatment of patients with non-dementia cognitive disorders with this drug. MATERIAL AND METHODS: An open multicenter randomized study included 60 patients of 18-55 years with light and moderate CI, having complaints of the cognitive spectrum. They used a clinical and neurological study using generally accepted scales and tests (MoCA, MMSE, MFI-20 tests, Schulta, DSST tests and an assessment of the quality of life of SF-36). Patients were randomized in two groups comparable by age and gender. Group 1 was treated with Brainmax per os twice every day for 14 days. After 10-days rest they received same medication for another 14 days. Group 2 was treated with Brainmax per os twice every day for 14 days, without the continuation. The total duration of the study was 40 days, the assessment of their condition was carried out on the 1st day (visit 1), after 15 days (visit 2) and after 40 days (visit 3) using the indicators of the above scales and tests in comparison with the background data. Safety assessment was carried out by the presence and structure of undesirable phenomena. RESULTS: The use of Brainmax led to a significant improvement in cognitive performance according to all generally accepted scales and tests (concentration and maintaining of attention, working memory, visual-constructive skills, volume and speed of attention speed, information processing and executive functions), as well as to the decrease severity of asthenia and improvement of the quality of life. CONCLUSION: Brainmax has shown a good safety profile, tolerability and clinical efficacy in the treatment of young and middle-aged patients with non-demented cognitive impairment. Significant improvement was observed both with single and double course administration of the drug, but a significantly better effect was noted after its repeated course, which reflects, among other things, the cumulative effect of the active substances of this drug and makes longer use of the drug Brainmax justified and appropriate in these categories of patients. The data obtained allow us to recommend the wider use of the drug Brainmax in clinical practice for the treatment of CI in patients of different ages, which will optimize therapy and improve the course and outcome of the disease.

Association between CSF biomarkers of Alzheimer's disease and neuropsychiatric symptoms: Mayo Clinic Study of Aging.

INTRODUCTION: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. METHODS: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aß42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Lower CSF Aß42, and higher t-tau/Aß42 and p-tau/Aß42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. DISCUSSION: CSF Aß42, t-tau/Aß42, and p-tau/Aß42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.

Medium-chain triglycerides may improve memory in non-demented older adults: a systematic review of randomized controlled trials.

BACKGROUND: Ketosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment. METHODS: A systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment. RESULTS: Six trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored. CONCLUSIONS: MCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.

Association of Cerebral Small Vessel Disease Burden with Neuropsychiatric Symptoms in Non-Demented Elderly: A Longitudinal Study.

BACKGROUND: The links between cerebral small vessel disease (CSVD) burden and neuropsychiatric symptoms (NPS) have not been fully studied. OBJECTIVE: We aimed to explore the associations of the CSVD burden with Neuropsychiatric Inventory (NPI) total scores and its subsyndromes in the elderly without dementia. METHODS: We investigated 630 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative. All of them had NPI assessments and 3 Tesla MRI scans at baseline and 616 had longitudinal NPI assessments during the follow-up. Linear mixed-effects models were used to investigate the cross-sectional and longitudinal associations of CSVD burden with NPI total scores and its subsyndromes. RESULTS: Higher CSVD burden longitudinally predicted more serious neuropsychiatric symptoms, including NPS (p < 0.0001), hyperactivity (p = 0.0006), affective symptoms (p = 0.0091), and apathy (p < 0.0001) in the total participants. Lacunar infarcts (LIs), white matter hyperactivities (WMHs), and cerebral microbleeds (CMBs) might play important roles in the occurrence of NPS, since they were longitudinally associated with specific neuropsychiatric subsyndromes. LIs contributed to hyperactivity (p = 0.0092), psychosis (p = 0.0402), affective symptoms (p = 0.0156), and apathy (p < 0.0001). WMHs were associated with hyperactivity (p = 0.0377) and apathy (p = 0.0343). However, CMBs were only related to apathy (p = 0.0141). CONCLUSION: CSVD burden was associated with multiple neuropsychiatric symptoms, suggesting the importance of monitoring and controlling vascular risk factors. Different markers of CSVD were associated with specific subsyndromes of NPS, suggesting that different markers tended to occur in different encephalic regions.

Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer's Disease Neuropathology.

Alzheimer's disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-ß plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and 'von Economo neurons'. Furthermore, in NDAN brains, binding of Aß oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD.

Antipsychotic Medication Risk of Dementia and Death: A Propensity Matched Cohort Study.

OBJECTIVE: This study aimed to compare the incidence of dementia and all-cause mortality up to 20 years post-treatment in an index non-demented cohort between antipsychotic (AP) medication treatment and non-AP treatment groups. METHODS: All patients in Kaiser Permanente Northern California with a major psychiatric diagnosis between 01/01/1996 and 12/31/2000, age ≥ 50 years, and without dementia diagnosis were included. The study cohort was divided into a "user group", patients treated with AP for ≥ 365 days (n = 1,829), and a "non-user group", propensity score-matched on age, sex, and race (n = 9,145). The association between AP exposure and dementia or mortality during the follow-up period (01/01/2001-12/31/2015) was evaluated using Cox proportional hazard models adjusted for psychiatric diagnosis, comorbidities, and other medications. RESULTS: The user group had a hazard ratio (HR) of 2.2 (CI 1.8-2.7) for dementia and 1.3 (CI 1.2- 1.5) for death. The onset of dementia in the user group was significantly higher in patients aged ≤ 65 years (p < 0.001). The user group was sub-grouped into atypical, typical, and both; HR for dementia was 1.7 (CI 1.2-2.4), 2.5 (CI 1.9-3.1), and 1.8 (CI 1.4-2.4), respectively. Dementia and mortality were significantly higher in patients concurrently treated with benzodiazepine (HR 1.3; CI 1.2-1.5 and HR 1.4; CI 1.3-1.5) or tricyclic antidepressants (HR 1.2; CI 1.1-1.4 and HR 1.1; CI 1.0-1.2), respectively. CONCLUSION: Our preliminary results reveal an association between AP treatment and increased rates of both dementia and mortality. Future research is needed to substantiate our current findings.

Social commitment toward prospective memory tasks in cognitively impaired non-demented individuals.

Prospective memory, which is the ability to remember to perform an intended action in the future, has been found to be diminished in cognitively impaired non-demented individuals (CIND). This study investigated whether providing CIND with a social motive would improve their prospective memory performance. Accordingly, CIND and controls were asked to perform a prospective memory task which includes one of the following three conditions: a reward (i.e., a candy bar), no feedback, or a social motive (i.e., that performing the prospective memory task would be a favor for the experimenter). The participants also rated their commitment to achieve the three prospective conditions. Results showed lower prospective memory in CIND than in controls. Unlike controls, CIND did not benefit from the social motive; however, both populations demonstrated commitment toward this condition relative to the "reward" or "control" conditions. Although social motivation did not ameliorate prospective memory, CIND seem to demonstrate commitment to perform prospective memory tasks that involve social benefits for others.

The 18 kDa translocator protein is associated with microglia in the hippocampus of non-demented elderly subjects.

Increase in the brain expression of the 18 kDa translocator protein (TSPO) is considered as a marker of neuroinflammation in the context of brain diseases, such as Alzheimer's disease (AD). However, in non-demented subjects with Alzheimer's neuropathology, TSPO accumulation in hippocampus subdivisions has not been fully characterized. To determine if TSPO is associated with the presence of amyloid ß plaques and/or phosphorylated Tau accumulation, we analyzed hippocampal sections using immunohistochemistry of 14 non-demented subjects with positive staining for Aß and/or phosphorylated Tau. TSPO expression was heterogenous with higher accumulation in the CA2/3 and subiculum subfields of the hippocampus. Its distribution closely resembled that of the microglial IBA1 marker and of the Aß42 amyloid form. In addition, positive correlations were observed between TSPO and IBA1 densities in CA4, CA2/3 and the subiculum but not with either the astrocyte GFAP marker or the AD-type Aß and Tau markers. This study sustains the hypothesis that TSPO is mainly associated with microglia and in Aß42-rich subdivisions in the hippocampus of non-demented elderly individuals.

Agitation and apathy increase risk of dementia in psychiatric inpatients with late-onset psychiatric symptoms.

BACKGROUND: A diagnosis of dementia in middle-aged and elder people is often complicated by physical frailty and comorbid neuropsychiatric symptoms (NPSs). Previous studies have identified NPSs as a risk factor for dementia. The aim of this study was to figure out to what extent individual NPS and certain demographic factors increased the risk of dementia in middle-aged and senior psychiatric inpatients. METHODS: One hundred twenty-seven middle-aged and senior patients admitted to psychiatric wards for late-onset (age ≥ 50 years) psychiatric symptoms were included and categorized into dementia or non-demented psychiatric disorders (NDPD). The patients' demographic information and medical records were collected during the first hospitalization and subjected to statistical analyses. RESULTS: 41.73% of the registered psychiatric inpatients were diagnosed as dementia in which Alzheimer's disease (AD) was the dominant subtype. The NDPD group consisted of nine individual diagnoses, except for schizophrenia. The frequencies of dementia inpatients increased with first episode age while that of NDPD inpatients decreased with first episode age. In the enrolled inpatients, most of dementia patients were males while females accounted for a higher proportion of NDPD patients. 58.49% of enrolled dementia inpatients presented cognitive deficit (CD) as the initial symptom while the remaining 41.51% showed NPS as initial symptom. Of the 12 NPSs, agitation and apathy greatly and significantly increased risk of dementia in psychiatric inpatients with late-onset psychiatric symptoms. CONCLUSIONS: These results added evidence that the demented patients admitted to psychiatric ward are more likely to be male, older first episode age, and have characteristic NPS including aberrant motor behavior (AMB), hallucinations, agitation, irritability and apathy. Further, this study emphasized the importance of agitation and apathy of NPSs functioning as risk factors of dementia in these inpatients.

[Pain treatment in old age: special features and recommendations]. / Schmerztherapie im Alter: Besonderheiten und Empfehlungen.

BACKGROUND: For geriatric patients with chronic pain, a comprehensive well-coordinated pain management is pivotal to ensure the best possible pain relief and to minimize as far as possible preventable negative side effects of treatment. OBJECTIVE: Description of the difficulties in pain management of geriatric patients with respect to general basic rules that are worth paying attention to and presentation of pharmacological and non-pharmacological treatment options. METHODS: This article describes the special features of pain management in older patients and gives recommendations on the use of analgesics and potential drug interactions in geriatric patients with organ dysfunction. Furthermore, individual substance groups are described with respect to their use in geriatric patients based on the recent literature. CONCLUSION: The aim of an individualized pain treatment in older and multimorbid patients is the relief of pain to an appropriate level, preservation of mobility, self-reliance and autonomy of each individual. The ability to participate in social activities as well as improvement in the quality of life need to be the focus of pharmacological and non-pharmacological treatment.

Cross-sectional associations of amyloid burden with semantic cognition in older adults without dementia: A systematic review and meta-analysis.

Previous research suggests the presence of subtle semantic decline in early stages of Alzheimer's disease. This study investigated associations between amyloid burden, a biomarker for Alzheimer's disease, and tasks of semantic impairment in older individuals without dementia. A systematic search in MEDLINE, PsycINFO, and Embase yielded 3691 peer-reviewed articles excluding duplicates. After screening, 41 studies with overall 7495 participants were included in the meta-analysis and quality assessment. The overall weighted effect size of the association between larger amyloid burden and larger semantic impairment was 0.10 (95% CI [-0.03; 0.22], p = 0.128) for picture naming, 0.19 (95% CI [0.11; 0.27], p < 0.001) for semantic fluency, 0.15 (95% CI [-0.15; 0.45], p = 0.326) for vocabulary, and 0.10 (95% CI [-0.14; 0.35], p = 0.405; 2 studies) for WAIS Information. Risk of bias was highest regarding comparability, as effect sizes were often not calculated on covariate-adjusted statistics. The relevance of the indicated amyloid-related decline in semantic fluency for research and clinical applications is likely negligible due to the effect's small magnitude. Future research should develop more sensitive metrics of semantic fluency to optimize its use for early detection of Alzheimer's disease-related cognitive impairment.

High pulse pressure is a risk factor for prodromal Alzheimer's disease: a longitudinal study.

It has been increasingly evident that pulse pressure (PP) is associated with Alzheimer's disease (AD) but whether PP increases AD risk and the mechanism responsible for this association remains unclear. To investigate the effects of PP in the process of AD, we have evaluated the cross-sectional and longitudinal associations of PP with AD biomarkers, brain structure and cognition and have assessed the effect of PP on AD risk in a large sample (n= 1,375) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Multiple linear regression and mixed-model regression were employed in cross-sectional and longitudinal analyses respectively. Clinical disease progression was assessed using Cox proportional hazards models. High PP was associated with lower ß-amyloid 42 (Aß42) (P= .015), and higher total tau (T-tau) (P= .011), phosphorylated tau (P-tau) (P= .003), T-tau/Aß42 (P= .004) and P-tau/Aß42 (P = .001), as well as heavier cortical amyloid-beta burden (P= .011). Longitudinally, baseline high PP was significantly associated with hippocampal atrophy (P= .039), entorhinal atrophy (P= .031) and worse memory performance (P= .058). Baseline high PP showed more rapid progression than those with normal PP (P <.001). These results suggest PP elevation could increase AD risk, which may be driven by amyloid plaques and subclinical neurodegeneration.

Selected microRNAs Increase Synaptic Resilience to the Damaging Binding of the Alzheimer's Disease Amyloid Beta Oligomers.

Alzheimer's disease (AD) is marked by synaptic loss (at early stages) and neuronal death (at late stages). Amyloid beta (Aß) and tau oligomers can target and disrupt synapses thus driving cognitive decay. Non-demented individuals with Alzheimer's neuropathology (NDAN) are capable of withstanding Aß and tau toxicity, thus remaining cognitively intact despite presence of AD neuropathology. Understanding the involved mechanism(s) would lead to development of novel effective therapeutic strategies aimed at promoting synaptic resilience to amyloid toxicity. NDAN have a unique hippocampal post-synaptic proteome when compared with AD and control individuals. Potential upstream modulators of such unique proteomic profile are miRNA-485, miRNA-4723 and miRNA-149, which we found differentially expressed in AD and NDAN vs. control. We thus hypothesized that these miRNAs play an important role in promoting either synaptic resistance or sensitization to Aß oligomer binding. Using an in vivo mouse model, we found that administration of these miRNAs affected key synaptic genes and significantly decreased Aß binding to the synapses. Our findings suggest that miRNA regulation and homeostasis are crucial for Aß interaction with synaptic terminals and support that a unique miRNA regulation could be driving synaptic resistance to Aß toxicity in NDAN, thus contributing to their preserved cognitive abilities.

Regression analysis in an illness-death model with interval-censored data: A pseudo-value approach.

Pseudo-values provide a method to perform regression analysis for complex quantities with right-censored data. A further complication, interval-censored data, appears when events such as dementia are studied in an epidemiological cohort. We propose an extension of the pseudo-value approach for interval-censored data based on a semi-parametric estimator computed using penalised likelihood and splines. This estimator takes interval-censoring and competing risks into account in an illness-death model. We apply the pseudo-value approach to three mean value parameters of interest in studies of dementia: the probability of staying alive and non-demented, the restricted mean survival time without dementia and the absolute risk of dementia. Simulation studies are conducted to examine properties of pseudo-values based on this semi-parametric estimator. The method is applied to the French cohort PAQUID, which included more than 3,000 non-demented subjects, followed for dementia for more than 25 years.

Long-chain omega-3 polyunsaturated fatty acids and cognitive decline in non-demented adults: a systematic review and meta-analysis.

CONTEXT: Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) are widely considered as nootropic agents that may be beneficial in reversing cognitive impairment. OBJECTIVE: The present systematic review of randomized controlled trials was conducted to determine the changes in cognitive function after intervention with LCn-3PUFA supplementation in non-demented adults, including those with mild cognitive impairment. DATA SOURCES: Five databases (MEDLINE, CINAHL, Scopus, EMBASE, and the Cochrane Library) were searched systematically along with reference lists of selected articles. STUDY SELECTION: Studies were eligible for inclusion if they measured the effect of LCn-3PUFA supplementation on cognition in non-demented adults. DATA EXTRACTION: A total of 787 records were screened, of which 25 studies were eligible for inclusion. Treatment effects were summarized as global cognitive function for primary outcome and measured using the Mini-Mental State Examination and individual cognitive domains for secondary outcome. The pooled effect sizes were estimated using Hedge's g and random-effects modeling. DATA ANALYSIS: Results from randomized controlled trials indicate that LCn-3PUFAs have no effect on global cognitive function (Hedge's g = 0.02; 95% confidence interval, -0.12 to 0.154), and among the specific cognitive domains, only memory function showed a mild benefit (Hedge's g = 0.31; P = 0.003; z = 2.945). CONCLUSION: The existing literature suggests that LCn-3PUFA supplementation could provide a mild benefit in improving memory function in non-demented older adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42017078664.

Severity of white matter hyperintensities: Lesion patterns, cognition, and microstructural changes.

White matter hyperintensity (WMH) is a common finding in aging population and considered to be a contributor to cognitive decline. Our study aimed to characterize the spatial patterns of WMH in different severities and explore its impact on cognition and brain microstructure in non-demented elderly. Lesions were both qualitatively (Fazekas scale) and quantitatively assessed among 321 community-dwelled individuals with MRI scanning. Voxel- and atlas-based analyses of the whole-brain white matter microstructure were performed. The WMH of the same severities was found to occur uniformly with a specific pattern of lesions. The severity of WMH had a significant negative association with the performance of working and episodic memory, beginning to appear in Fazekas 3 and 4. The white matter tracts presented significant impairments in Fazekas 3, which showed brain-wide changes above Fazekas 4. Lower FA in the superior cerebellar peduncle and left posterior thalamic radiation was mainly associated with episodic memory, and the middle cerebellar peduncle was significantly associated with working memory. These results support that memory is the primary domain to be affected by WMH, and the effect may potentially be influenced by tract-specific WM abnormalities. Fazekas scale 3 might be the critical stage predicting a future decline in cognition.

Genome-wide association study identifies CD1A associated with rate of increase in plasma neurofilament light in non-demented elders.

As a marker of neuroaxonal injury, neurofilament light (NFL) in blood is robustly elevated in many neurodegenerative conditions. We aimed to discover single nucleotide polymorphisms (SNPs) associated with longitudinal changes in plasma NFL levels that affect the risk of developing neurodegenerative disease and clinical disease progression. 545 eligible non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with longitudinal plasma NFL data were included. Three SNPs (rs16840041, p=4.50×10-8; rs2269714, p=4.50×10-8; rs2269715, p=4.83×10-8) in CD1A were in high linkage disequilibrium (LD) and significantly associated with the increase in plasma NFL levels. We demonstrate a promoting effect of rs16840041-A on clinical disease progression (p = 0.006). Moreover, the minor allele (A) of rs16840041 was significantly associated with accelerated decline in [18F] Fluorodeoxyglucose (FDG) (estimate -1.6% per year [95% CI -0.6 to -2.6], p=0.0024). CD1A is a gene involved in longitudinal changes in plasma NFL levels and AD-related phenotypes among non-demented elders. Given the potential effects of these variants, CD1A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for monitoring disease trajectories and treating disease.

Decreased Function of Delayed Recall in Non-demented Elderly Subjects With Apolipoprotein E ε4 Allele.

Apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Inconsistent results about the role of APOE ε4 alleles on cognitive decline of community non-dementia elderly have been reported. This study aimed to examine the relationship between APOE ε4 allele and cognitive abilities in the subjects aged 60 years or above from a community in Shanghai, China. A total of 1445 participants voluntarily accepted the analysis of APOE genotype and global cognitive assay using the Mini Mental Status Evaluation (MMSE). There were no significant differences in total MMSE scores between APOE ε4 carriers and non-carriers. In addition, the performances of orientation, registration, attention, calculation, and language had no significant differences between subjects with and without APOE ε4 allele. However, stratified analysis showed that the performance of delayed recall in subjects with APOE ε4 allele was inferior to that in non-ε4 carriers (p = 0.041). Further, the multiple linear regression analysis showed the significant correlations between the presence of APOE ε4 allele and the scores of the delayed memory subdomain if age, gender, and education were adjusted but no significant correlations if the related factors were not adjusted. The results indicate that significant impact of APOE ε4 allele only on the delay memory but not on global or other sub-domains of cognitive abilities.

Effects of CD33 Variants on Neuroimaging Biomarkers in Non-Demented Elders.

Two CD33 common variants, rs3826656 and rs3865444, have been identified to be correlated with Alzheimer's disease (AD). Our study examined the effects of the two AD-related CD33 common variants (rs3826656 and rs3865444) on the chosen AD-related brain regions (including hippocampus, amygdala, parahippocampus, middle temporal, entorhinal cortex, and total brain volume) in non-demented elders recruited from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during four-year follow-up. We further tested the effects in an Aß-positive group (including preclinical and prodromal stage of AD) and an Aß-negative group. In the total non-demented elderly population, no associations reached significant levels after FDR correction. In the Aß-positive group, we found that rs3826656 was associated with hippocampal and amygdala volumes (Hippocampus-R: pc = 0.0022; Amygdala-L: pc = 0.0044; Amygdala-R: pc = 0.0066), and rs3865444 was associated with right entorhinal volume (pc = 0.0286). The associations of rs3826656 with hippocampal and amygdala volumes in the Aß-positive group were successfully replicated in the prodromal AD group (Hippocampus-R: pc = 0.0022; Amygdala-L: pc = 0.0022; Amygdala-R: pc = 0.0088). These changes became more obvious over time during four-year follow-up. No associations were found between the two CD33 variants and neuroimaging biomarkers in the Aß-negative and preclinical AD groups after FDR correction. These results suggested that the two CD33 common variants (rs3826656 and rs3865444) influenced volumes and atrophy rates of AD-related brain regions in non-demented elders. Subgroup analyses showed the effects mainly existed in the Aß-positive group instead of the Aß-negative group, and the effects began in the prodromal AD stage.