Towards the development of a management protocol for subjective cognitive decline: Insights from a cross-sectional and longitudinal analysis of multimodal data from a memory clinic.

White-matter hyperintensity (WMH) is the key magnetic resonance imaging (MRI) marker of cerebral small-vessel disease (CSVD). This study aimed to investigate whether habitat analysis based on physiologic MRI parameters can predict the progression of WMH and cognitive decline in CSVD. Diffusion- and perfusion-weighted imaging data were obtained from 69 patients with CSVD at baseline and at 1-year of follow-up. The white-matter region was classified into constant WMH, growing WMH, shrinking WMH, and normal-appearing white matter (NAWM) according to the T2-fluid-attenuated inversion recovery (FLAIR) sequences images at the baseline and follow-up. We employed k-means clustering on a voxel-wise basis to delineate WMH habitats, integrating multiple diffusion metrics and cerebral blood flow (CBF) values derived from perfusion data. The WMH at the baseline and the predicted WMH from the habitat analysis were used as regions of avoidance (ROAs). The decreased rate of global efficiency for the whole brain structural connectivity was calculated after removal of the ROA. The association between the decreased rate of global efficiency and Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) scores was evaluated using Pearson correlation coefficients. We found that the physiologic MRI habitats with lower fractional anisotropy and CBF values and higher mean diffusivity, axial diffusivity, and radial diffusivity values overlapped considerably with the new WMH (growing WMH of baseline) after a 1-year follow-up; the accuracy of distinguishing growing WMH from NAWM was 88.9%±12.7% at baseline. Similar results were also found for the prediction of shrinking WMH. Moreover, after the removal of the predicted WMH, a decreased rate of global efficiency had a significantly negative correlation with the MoCA and MMSE scores at follow-up. This study revealed that a habitat analysis combining perfusion with diffusion parameters could predict the progression of WMH and related cognitive decline in patients with CSVD.

Background/Aims: Because of controversial results across studies, we evaluated the predictive value of premorbid intelligence and the apolipoprotein E (ApoE) genotype on baseline and progression of cognitive performance in Alzheimer’s disease (AD). Methods: Eighty-five mild AD cases, ApoE genotyped and included in a longitudinal cliniconeuropsychological-genetic study, underwent a premorbid intelligence test and up to 11 (average 5) neuropsychological assessments. We applied linear- and logistic-regression models for cross-sectional data and mixed models for longitudinal ones. Results: Higher premorbid intelligence was associated with higher global, executive and memory performance, while the ApoE Ε4 allele was specifically related to poorer memory performance. The premorbid intelligence-ApoE Ε4/Ε4 interaction was significant, with higher premorbid intelligence scores reducing the detrimental effect of ApoE Ε4 homozygosity on memory performance. Higher premorbid intelligence, but not the ApoE Ε4 allele, was related to faster memory deficit progression. Conclusion: The association of higher premorbid intelligence with better baseline cognitive performance and faster memory decline, as well as its interaction with the ApoE genotype, strengthens the role of cognitive reserve in shaping the disease’s clinical expression. Our findings confirm that the Ε4 allele affects memory deficit at baseline but does not exert any influence on the rate of cognitive decline.

Cognitive Reserve and the Relationship Between Depressive Symptoms and Awareness of Deficits in Dementia

Apolipoprotein E (ApoE) ε4 carriers have a higher risk of developing Alzheimer's disease (AD) and show brain atrophy and cognitive decline even before diagnosis. To predict ApoE ε4 status using gray matter volume (GMV) obtained from magnetic resonance imaging images and demographic data with machine learning (ML) methods. We recruited 74 participants (25 probable AD, 24 amnestic mild cognitive impairment, and 25 cognitively normalolder people) with known ApoE genotype (22 ApoE ε4 carriers and 52 noncarriers) and scanned them with three-dimensional (3D) T1-weighted (T1W) and 3D double inversion recovery (DIR) sequences. We extracted GMV from regions of interestrelated to AD pathology and used them as features along with age and mini-mental state examination (MMSE) scores to train different ML models. We performed both receiver operating characteristiccurve analysis and the prediction analysis of the ApoE ε4 carrier with different ML models. The best model of ML analyses was a cubic support vector machine (SVM3) that used age, the MMSE score, and DIR GMVs at the amygdala, hippocampus, and precuneus as features (AUC=.88). This model outperformed models using T1W GMV or demographic data alone. Our results suggest that brain atrophy with DIR GMV and cognitive decline with aging can be useful biomarkers for predicting ApoE ε4 status and identifying individuals at risk of AD progression.

Apolipoprotein E (ApoE) epsilon4 genotype is a well-established risk factor for Alzheimer's disease (AD). However, its effect on predicting conversion from normal to "cognitive impairment, no dementia" (CIND) and from CIND to AD is less clear. We used a nested case-control design from the population-based Canadian Study of Health and Aging (CSHA) to examine the effect of ApoE epsilon4 genotype on the conversion of subjects from normal to CIND and from CIND to AD. We also contrasted these findings with incident cases of AD and vascular dementia (VaD) in the CSHA cohort. The ApoE epsilon4 genotype was a significant risk factor for conversion from CIND to AD and from normal to AD and VaD. However, it was not a significant risk factor for conversion from normal to CIND. This effect is robust to adjustment for age, sex and education level. There is significant interaction between the ApoE epsilon4 genotype and age for AD and for conversion from CIND to AD. No interaction between ApoE epsilon4 genotype, sex, age, ethnicity and education level was found in other subgroup analyses. The positive predictive value of ApoE epsilon4 for predicting CIND conversion to AD was 0.48, and the negative predictive value was 0.65. Possession of an ApoE epsilon4 allele increases the risk of AD developing from CIND. It is also associated with a decrease in the age at onset of AD. Its predictive values do not support its utility as a diagnostic test for predicting progression from CIND to AD, but it may be useful in research studies to enrich study samples that have a higher rate of progression to AD.

Depressive Symptoms Moderate the Influence of the ApolipoproteinE ɛ4 Allele on Cognitive Decline in a Sample of Community Dwelling Older Adults

Clinical Relevance of Cerebral Small Vessel Diseases.

Chronic rhinosinusitis and progression of cognitive impairment in dementia

BackgroundEducational attainment (EA) is a key contributor towards cognitive reserve, providing the brain with a degree of resilience to Alzheimer's disease pathology (ADP). However, research suggests that the influence of education on cognitive reserve varies across racial and ethnic groups and APOE genotype, highlighting the importance of characterizing these effects in diverse populations. This study explores the relationship between EA, APOE ε4 status, and cognitive function in a Puerto Rican (PR) cohort, focusing on individuals exhibiting elevated ADP as indicated by plasma pTau181 levels.MethodA subset of 793 PR older adults with elevated (>mean+1SD, n = 124) plasma log(pTau181) was analyzed. Cognitive function was estimated using a composite functional score calculated as the sum of the non‐memory items in the Clinical Dementia Rating scale (CDR‐FUNC, range=0‐12). EA was dichotomized as high (>9 years) and low (≤9 years). Associations between CDR‐FUNC, EA, and APOE ε4 carrier status were performed using the Mann‐Whitney U test.ResultAmong individuals with elevated pTau181, those with lower EA exhibited significantly worse cognitive function (p = 6.5×10‐4). When stratified by APOE ε4 status, the association between EA and cognitive function was more pronounced among ε4 carriers (p = 1.52×10‐3) than non‐carriers (p = 0.06). In addition, within the low EA group, APOE ε4 carriers had poorer cognitive function than non‐carriers (p = 0.045). However, this difference was not observed in the high EA stratum.ConclusionThese results suggest that EA may enhance cognitive reserve and promote resilience to ADP in the PR population. Overall, high EA confers a cognitive advantage against functional decline in the presence of elevated pTau181. Furthermore, carrying the APOE ε4 allele increases the risk of cognitive decline in individuals with low EA compared to those with high EA. These findings underscore the importance of considering both educational background and genetic risk factors in efforts to understand and develop interventions to prevent cognitive decline globally.

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

BackgroundThe faster memory decline was associated with the presence of the apolipoprotein E4 (APOε4) allele, a genetic risk factor for late‐onset Alzheimer’s disease (AD). Studies suggest that the relationship between cognitive decline and APOE ε4 allele in healthy elderly may reflect the preclinical risk to AD. This study examined the influence of apolipoprotein E4 (APOε4) genotype on the cognitive function of the older people from Baixada Santista (Brazil).MethodThis study was approved by the Ethical Committee Board from Medical School/UNIMES (Number: CAAE 20938619.4.0000.5509). Seventy‐two participants with ≥65 years old, both sexes. were eligible for the study. Cognitive function and the level of physical activity were assessed by the mini‐mental state examination (MMSE) and Baecke questionnaire for older, respectively. APOE genotyping was performed in 66 out of the 72 participants. Statistical analysis was performed by using the BioEstat version 5.0, Kolmogorov‐Smirnov test, z‐score, student t or Mann‐Whitney test was applied according to the normality. The Chi‐square test was used for comparison between the sexes. Pearson correlation was also performed. P < 0.05 was considered statistically significant.ResultsSeventy‐two older people were assessed (women = 52 and men = 20), and the mean age was 73±7 years old, Baecke score (3.74 ±3.82), MMSE (27±3), and educational status (8 ± 4 years). As expected, a positive correlation was detected between the education level and MMSE score (r = 0.359, p < 0.05). No difference was found between the sexes for age, level of physical activity, MMSE, and education status (p > 0.05). Regarding the APOE genotype, we found the following frequency ɛ2/ɛ2 (1.5%), ɛ2/ɛ3 (16.7%), ɛ2/ɛ4 (1.5%), ɛ3/ ɛ3 (59.1%), and ɛ3/ɛ4 (21.2%). No correlation was found between carriers (presence of the ɛ4 allele) and non‐carrier for the MMSE score, varying between 27 to 30.ConclusionOur preliminary data show that the less educational status influences the cognitive decline in the older Brazilian population. However, no differences between the sexes were observed for all parameters indicating a homogenous population. Additionally, the cognitive function score was not influenced by the presence of the APOɛ4 allele in this population.

β-Amyloid, APOE and BDNF Genotype, and Depressive and Anxiety Symptoms in Cognitively Normal Older Women and Men

APOLIPOROTEIN E POLYMORPHISM IN CHINESE POPULATION WITH VARIOUS TYPES OF COGNITIVE DISORDERS

BackgroundApolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer’s disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers.MethodsWe analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer’s Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups.ResultsAnalyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18–75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers’ estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group.ConclusionsAPOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD.

BackgroundResearch on cognitive reserve (CR) in individuals aged 80 years old and above has resulted in inconsistent findings, mostly showing a relationship with baseline cognitive abilities but not follow up assessments. The effects of amyloid burden on the relationship between CR, cognitive decline and dementia in oldest old warrants further study in the presence of APOE e4. We hypothesised that CR in oldest old (≥80 yrs old) adults will result in different trajectories, depending on being amyloid PET positive or negative. Specifically, this study was to determine whether the relationship between CR and cognition is mediated by amyloid load in very old individuals.MethodData of 115 participants aged 80 years and above at baseline and one follow‐up was analysed for this study. Participants were recruited from the Western Australia Memory Study (WAMS, Perth) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) Study (Sydney, Australia). In both sites participants have undergone amyloid imaging, as well as a comprehensive neuropsychological assessment, APOE genotyping and AD‐related blood‐based biomarkers analysis.ResultPreliminary results indicated a non‐significant relationship between education years, as the proxy for CR, and baseline cognition. Similar not‐significant findings was observed between CR and amyloid load. Individuals positive or negative for amyloid burden on the brain at baseline, as well as carriage of APOE e4 did not differ on years of education. Of interest, APOE e4 allele carriers were not different from not‐carriers on amyloid load in the brain. Due to nonsignificant relationships between the variables of interest, in both cross‐sectional as well as longitudinal data, further mediation analysis was not carried out.ConclusionOur nonsignificant results indicated that the commonly reported relationship between CR, cognitive function, amyloid load in older adults may not be present in individuals aged 80 years old and above. Although these findings are consistent with previous reports, other factors including longevity genetic factors that promote preserving cognition in oldest adults as well as lifestyle factors should be considered. Further analysis of such factors is currently ongoing and may result in interesting outcomes for this cohort.