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يحاول ديفيد بينيت في هذا الكتاب إعادة إنتاج المفاهيم الروحية الصوفية شرقية أوغربية بطريقته المبسطة التي تخاطب القراء من غير أهل الاختصاص بما يناسب ثقافتهم وفهمهم العملاني اليومي للحياة بالطبع لا يطلق بينيت على طروحاته صفة الصوفية أو التوحد مع المعشوق (الخالق، الله) بل يقدمها من خلال مصطلحات السماوي والكوني والتماثل والنور والمحبة.

Few data on the pathology of cerebral vessel disease, dementia, and cognition are available. We examined the association of cerebral atherosclerosis and arteriolosclerosis neuropathology with probable and possible Alzheimer's disease dementia and cognitive function. This cross-sectional study included men and women aged 65 years or older who had yearly clinical assessments and had agreed to brain autopsy at the time of death, as part of one of two cohort studies of ageing (The Religious Orders Study and the Rush Memory and Aging Project). Individuals without dementia or with Alzheimer's disease dementia, and with complete neuropathological data, are included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Clinical data recorded between 1994 and 2015 were used to determine presence of Alzheimer's disease dementia. Systematic neuropathological assessments documented the severity of cerebral large vessel (atherosclerosis) and small vessel (arteriolosclerosis) disease. By use of regression analyses adjusted for demographics, gross and microscopic infarcts, and Alzheimer's disease pathology, we examined associations of vessel disease severity (mild, moderate, and severe) with odds of probable and possible Alzheimer's disease dementia and cognitive function. Study enrolment began in January, 1994, and two cohort studies are ongoing. 1143 individuals were included in our analyses (median age at death 88·8 years; 478 [42%] with Alzheimer's disease dementia). Moderate-to-severe atherosclerosis was present in 445 (39%) individuals, and arteriolosclerosis in 401 (35%) individuals. Each level increase in the severity of atherosclerosis or arteriolosclerosis was associated with significantly higher odds of Alzheimer's disease dementia (odds ratio [OR] for atherosclerosis 1·33, 95% CI 1·11–1·58; OR for arteriolosclerosis 1·20, 1·04–1·40). Atherosclerosis was associated with lower scores for global cognition (estimate −0·10 [SE 0·04], p=0·0096) and four cognitive domains (episodic memory −0·10 [0·04], p=0·017; semantic memory −0·11 [0·05], p=0·018; perceptual speed −0·14 [0·04], p=0·00080; and visuospatial abilities −0·13 [0·04], p=0·0080), but not working memory (−0·05 [0·04], p=0·21). Arteriolosclerosis was associated with lower scores for global cognition (estimate −0·10 [0·03], p=0·0015) and four domains (episodic memory −0·12 [0·04], p=0·00090; semantic memory −0·10 [0·04], p=0·013; working memory −0·07 [0·03], p=0·045; perceptual speed −0·12 [0·04], p=0·0012), and a non-significant association was noted for visuospatial abilities (−0·07 [0·03], p=0·052). Findings were unchanged in analyses controlling for the presence of APOE ε4 allele or vascular risk factors. Cerebral atherosclerosis and arteriolosclerosis are associated with Alzheimer's disease dementia, and are also associated with low scores in most cognitive domains. Cerebral vessel pathology might be an under-recognised risk factor for Alzheimer's disease dementia. US National Institutes of Health.

As the US elderly population continues to expand rapidly, Alzheimer's disease poses a major and increasing public health challenge, and older African Americans may be disproportionately burdened by the disease. Although African Americans were generally underincluded in previous research studies, new and growing evidence suggests that they may be at increased risk of the disease and that they differ from the non-Hispanic white population in risk factors and disease manifestation. This article offers an overview of the challenges of Alzheimer's disease in African Americans, including diagnosis issues, disparities in risk factors and clinical presentation of disease, and community-based recommendations to enhance research with this population. [PUBLICATION ABSTRACT]

Alzheimer’s dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer’s disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women ( n  = 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022, p  < 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074, p  < 0.001), and there was a borderline difference between women and men in amyloid-β load (estimate = 0.124, SE = 0.065, p  = 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04–1.58, p  = 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61–0.98, p  = 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.

Some people with substantial Alzheimer's disease pathology at autopsy had shown few characteristic clinical symptoms or signs of the disease, whereas others with little Alzheimer's disease pathology have been diagnosed with Alzheimer's dementia. We aimed to examine whether frailty, which is associated with both age and dementia, moderates the relationship between Alzheimer's disease pathology and Alzheimer's dementia. We did a cross-sectional analysis of data from participants of the Rush Memory and Aging Project, a clinical–pathological cohort study of older adults (older than 59 years) without known dementia at baseline, living in Illinois, USA. Participants in the cohort study underwent annual neuropsychological and clinical evaluations. In the present cross-sectional analysis, we included those participants who did not have any form of dementia or who had Alzheimer's dementia at the time of their last clinical assessment and who had died and for whom complete autopsy data were available. Alzheimer's disease pathology was quantified by a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnosis of Alzheimer's dementia was based on clinician consensus. Frailty was operationalised retrospectively using health variable information obtained at each clincial evaluation using the deficit accumulation approach (41-item frailty index). Logistic regression and moderation modelling were used to assess relationships between Alzheimer's disease pathology, frailty, and Alzheimer's dementia. All analyses were adjusted for age, sex, and education. Up to data cutoff (Jan 20, 2017), we included 456 participants (mean age at death 89·7 years [SD 6·1]; 316 [69%] women). 242 (53%) had a diagnosis of possible or probable Alzheimer's dementia at their last clinical assessment. Frailty (odds ratio 1·76, 95% CI 1·54–2·02; p<0·0001) and Alzheimer's disease pathology (4·81, 3·31–7·01; p<0·0001) were independently associated with Alzheimer's dementia, after adjusting for age, sex, and education. When frailty was added to the model for the relationship between Alzheimer's disease pathology and Alzheimer's dementia, model fit improved (p<0·0001). There was a significant interaction between frailty and Alzheimer's disease pathology (odds ratio 0·73, 95% CI 0·57–0·94; pinteraction=0·015). People with an increased frailty score had a weakened direct link between Alzheimer's disease pathology and Alzheimer's dementia; that is, people with a low amount of frailty were better able to tolerate Alzheimer's disease pathology, whereas those with higher amounts of frailty were more likely both to have more Alzheimer's disease pathology and for it to be expressed as dementia. The degree of frailty among people of the same age modifies the association between Alzheimer's disease pathology and Alzheimer's dementia. That frailty is related to both odds of Alzheimer's dementia and disease expression has implications for clinical management, since individuals with even a low level of Alzheimer's disease pathology might be at risk for dementia if they have high amounts of frailty. Further research should assess how frailty and cognition change over time to better elucidate this complex relationship. This study was funded by the Canadian Institutes of Health Research, including via the Canadian Collaboration on Neurodegeneration in Aging.

In a Perspective, David Bennett makes a case for neural reserve to be considered as a therapeutic endpoint in clinical trials for dementia.In a Perspective, David Bennett makes a case for neural reserve to be considered as a therapeutic endpoint in clinical trials for dementia.

APOE4 is the strongest genetic risk factor for Alzheimer’s disease 1 , 2 – 3 . However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease 4 , 5 , 6 , 7 – 8 . Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE 2 , 3 , 4 , 5 – 6 , APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease. APOE4 is associated with widespread gene expression changes across all cell types of the human brain, altered cholesterol homeostasis and transport signalling pathways, and decreased myelination in the brain.

This paper reports the availability of a new Resource with RNA-seq, DNA methylation and H3K9Ac QTL results from 411 brain samples. Many xQTL SNPs influence multiple molecular features, and the authors observe epigenetic mediation of eQTLs in some cases. Reanalyzing GWAS with an xQTL-weighted approach detected 20 new CNS disease susceptibility loci. We report a multi-omic resource generated by applying quantitative trait locus (xQTL) analyses to RNA sequence, DNA methylation and histone acetylation data from the dorsolateral prefrontal cortex of 411 older adults who have all three data types. We identify SNPs significantly associated with gene expression, DNA methylation and histone modification levels. Many of these SNPs influence multiple molecular features, and we demonstrate that SNP effects on RNA expression are fully mediated by epigenetic features in 9% of these loci. Further, we illustrate the utility of our new resource, xQTL Serve, by using it to prioritize the cell type(s) most affected by an xQTL. We also reanalyze published genome wide association studies using an xQTL-weighted analysis approach and identify 18 new schizophrenia and 2 new bipolar susceptibility variants, which is more than double the number of loci that can be discovered with a larger blood-based expression eQTL resource.

To assess the value of exosomal miRNAs as biomarkers for Alzheimer disease (AD), the expression of microRNAs was measured in a plasma fraction enriched in exosomes by differential centrifugation, using Illumina deep sequencing. Samples from 35 persons with a clinical diagnosis of AD dementia were compared to 35 age and sex matched controls. Although these samples contained less than 0.1 microgram of total RNA, deep sequencing gave reliable and informative results. Twenty miRNAs showed significant differences in the AD group in initial screening (miR-23b-3p, miR-24-3p, miR-29b-3p, miR-125b-5p, miR-138-5p, miR-139-5p, miR-141-3p, miR-150-5p, miR-152-3p, miR-185-5p, miR-338-3p, miR-342-3p, miR-342-5p, miR-548at-5p, miR-659-5p, miR-3065-5p, miR-3613-3p, miR-3916, miR-4772-3p, miR-5001-3p), many of which satisfied additional biological and statistical criteria, and among which a panel of seven miRNAs were highly informative in a machine learning model for predicting AD status of individual samples with 83-89% accuracy. This performance is not due to over-fitting, because a) we used separate samples for training and testing, and b) similar performance was achieved when tested on technical replicate data. Perhaps the most interesting single miRNA was miR-342-3p, which was a) expressed in the AD group at about 60% of control levels, b) highly correlated with several of the other miRNAs that were significantly down-regulated in AD, and c) was also reported to be down-regulated in AD in two previous studies. The findings warrant replication and follow-up with a larger cohort of patients and controls who have been carefully characterized in terms of cognitive and imaging data, other biomarkers (e.g., CSF amyloid and tau levels) and risk factors (e.g., apoE4 status), and who are sampled repeatedly over time. Integrating miRNA expression data with other data is likely to provide informative and robust biomarkers in Alzheimer disease.