Polygenic hazard scores in preclinical Alzheimer disease

Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ?4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ?4 noncarriers. Beyond APOE , PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484–488     

Alzheimer disease pathology in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons. In some ALS patients, dementia or aphasia may be present (ALS-D). The dementia is most commonly a frontotemporal dementia (FTD), and many of these cases have ubiquitin-positive, tau-negative inclusions in neurons of the dentate gyrus and superficial layers of the frontal and temporal lobes. Identical inclusions have been found in cases presenting with FTD and have been designated motor neuron disease (MND)-inclusions. Cases of ALS-D without MND-inclusions have been reported to show neocortical gliosis, neuronal loss, and superficial spongiosis, but there have also been scattered case reports of ALS with Alzheimers disease (AD). To determine whether AD pathology may play a role in the dementia or aphasia syndromes in ALS, we reviewed 30 cases of sporadic ALS diagnosed at the University of Pittsburgh Medical Center. A clinical history of ALS-D was found in 24.1% of the cases, of which 57% had MND-inclusions. Although the ALS-D cases with MND-inclusions typically had amyloid-beta (A) plaques, there were no neuritic plaques. Three cases of ALS-D had no MND-inclusions, and two of these fulfilled pathological criteria for AD. One ALS-D case showed severe amyloid angiopathy but no neuritic plaques or MND-inclusions. MND-inclusions were not found in any ALS case without dementia; however, four patients without dementia or aphasia showed moderate or frequent numbers of neuritic plaques. In conclusion, we found that approximately 30% of ALS cases with dementia have AD and that some ALS cases without frank dementia have significant AD pathology.     

无症状性临床前期阿尔茨海默病与微量元素组学的关系

随着老龄化社会的日益加剧,阿尔茨海默病（Alzheimer Disease,AD）作为一种老年认知障碍性疾病,发病率持续增高,但目前其发病机理还不明确,至今无法根治。AD是一种与基因突变和环境密切相关的神经退行性疾病,一旦有临床症状则无法逆转。所以最近国际上热点是对该疾病的早期发现、干预,尤其关注无症状性临床前期AD（Preclinical Alzheimer disease,PCAD）的危险因素。而微量元素是一种关键的AD诱发因素。现以微量元素组学为切入点,阐述PCAD中微量元素组学稳态的重要意义,以期能对AD的治疗以及预防有一定的意义。     

临床前期阿尔茨海默症的早期诊断与干预

随着人口老龄化的加剧,以阿尔茨海默病（Alzheimer Disease,AD）为主的老年认知障碍问题日趋严重.作为一种多因素、多阶段并有伴随疾病的临床综合征,老年认知障碍在临床症状出现后将进展成不可逆性痴呆.因此,在无症状性临床前期AD症（PCAD）阶段进行早期诊断与干预成为了国内外研究的热点.现对PCAD的危险因素和针对其诊断干预的探索性研究进行综述,试图寻找在早期病理进程中新的可用于临床早期诊断的生物标记物及早期干预的药物靶点.     

Genome-wide association studies in Alzheimer disease

The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.     

Alzheimer disease pathology as a host response

Identification of amyloid-beta and tau as the major protein components of senile plaques and neurofibrillary tangles, respectively, led to an exponential increase in investigations of these proteins and their corresponding metabolic pathways in Alzheimer disease (AD). The presumptions inherent in most studies and in the dogma of the amyloid cascade concept are that these hallmark lesions in AD brains contain molecules that drive the disease process, and that the proteinaceous accumulations are themselves toxic. On the other hand, the lesions of AD are, by definition, end-stage, and their relationship to the clinical disease is inconsistent; this has long been known but, generally, has not been acknowledged until relatively recently. Some recent attempts to address the etiology and pathogenesis of AD discard the pathology and focus on the interplay between invisible toxic intermediates, that is, amyloid-beta oligomers and the synapse. The concept that the hallmark lesions may be nontoxic (something we have long suggested) is slowly gaining acceptance. We favor the interpretation that senile plaques and neurofibrillary tangles represent a host response to an upstream pathophysiologic process, and that the therapeutic targeting of lesions, including toxic intermediates, will succeed only in the event that the host response is directly deleterious. Therefore, renewed efforts aimed at elucidating fundamental age-related processes such as oxidative stress and/or inflammatory mediators are warranted.     

Classification and basic pathology of Alzheimer disease

The lesions of Alzheimer disease include accumulation of proteins, losses of neurons and synapses, and alterations related to reactive processes. Extracellular Aβ accumulation occurs in the parenchyma as diffuse, focal or stellate deposits. It may involve the vessel walls of arteries, veins and capillaries. The cases in which the capillary vessel walls are affected have a higher probability of having one or two apoε 4 alleles. Parenchymal as well as vascular Aβ deposition follows a stepwise progression. Tau accumulation, probably the best histopathological correlate of the clinical symptoms, takes three aspects: in the cell body of the neuron as neurofibrillary tangle, in the dendrites as neuropil threads, and in the axons forming the senile plaque neuritic corona. The progression of tau pathology is stepwise and stereotyped from the entorhinal cortex, through the hippocampus, to the isocortex. The neuronal loss is heterogeneous and area-specific. Its mechanism is still discussed. The timing of the synaptic loss, probably linked to Aβ peptide itself, maybe as oligomers, is also controversial. Various clinico-pathological types of Alzheimer disease have been described, according to the type of the lesions (plaque only and tangle predominant), the type of onset (focal onset), the cause (genetic or sporadic) and the associated lesions (Lewy bodies, vascular lesions, hippocampal sclerosis, TDP-43 inclusions and argyrophilic grain disease).     

Alzheimer disease and cerebrovascular pathology: an update

Summary. Recent epidemiological and clinico-pathologic data suggest overlaps between Alzheimer disease (AD) and cerebrovascular lesions that may magnify the effect of mild AD pathology and promote progression of cognitive decline or even may precede neuronal damage and dementia.Vascular pathology in the aging brain and in AD includes: 1. cerebral amyloid angiopathy (CAA) with an incidence of 82–98% often associated with ApoEε2 and causing a) cerebral mass hemorrhages (around 70%, mainly in the frontal and parieal lobes), b) multiple or recurrent microhemorrhages (15%), and c) ischemic (micro-)infarcts or lacunes (around 20%). The frequency of these lesions increases with the severity of CAA and shows no correlation with that of senile amyloid plaques. CAA, significantly more frequent in patients with cerebral hemorrhages or infarcts than in aged controls, is an important risk factor for cerebrovascular lesions in AD. 2. Microvascular changes with decreased density and structural abnormalities causing regional metabolic and blood-brain barrier dysfunctions with ensuing neuronal damage. In large autopsy series of demented aged subjects, around 80% show Alzheimer type pathology, 20–40% with additional, often minor vascular lesions, 7–10% “pure” vascular dementia, and 3–5% “mixed” dementia (combination of AD and vascular encephalopathy). AD cases with additional minor cerebrovascular lesions have significantly more frequent histories of hypertension or infarcts than “pure” AD patients. Vascular lesions in AD include cortical microinfarcts, subcortial lacunes, white matter lesions / leukoencephalopathy, small hemorrhages and corticosubcortical infarcts, while in mixed type dementia multiple larger or hemispheral infarcts are more frequent. Small infarcts in AD patients have no essential impact on global cognitive decline which mainly depends on the severity of Alzheimer pathology, but in early stage of AD they may influence and promote the development of dementia. Recent studies showed lower density of plaques and tangles in brains with cerebrovascular lesions, and similar severity of dementia was related to fewer AD lesions in brains with than in those without small vascular lesions. Further studies will help to elucidate the risk factors and impact of cerebrovascular lesions on the development and progression of dementia in AD. Received November 2, 2001; accepted January 16, 2002     

Molecular pathology and disease-modifying therapy of Alzheimer disease

Disease-modifying therapies for Alzheimer's disease are under development based on the outcomes of molecular pathological studies that have progressed over the last 25 years. The current status of basic research on Alzheimer's disease, its translation into clinical applications, and associated problems, will be discussed.     

Sex differences in the clinical manifestations of Alzheimer disease pathology

CONTEXT: Sex differences in risk of clinically diagnosed Alzheimer disease (AD) have been studied extensively, but little is known about the relation of the pathologic indices of AD to the clinical manifestations of the disease in men compared with women. OBJECTIVE: To test whether the relation of AD pathology to the clinical manifestations of the disease differs in men and women. DESIGN: Longitudinal, clinicopathologic cohort study. PARTICIPANTS AND SETTING: Analyses were conducted on 141 older Catholic clergy members who underwent detailed annual clinical evaluations and brain autopsy at death. The number of neuritic plaques, diffuse plaques, and neurofibrillary tangles in a 1-mm2 area sampled from 4 cortical regions was counted, and a global measure of AD pathology (range, 0-2.98 U) and specific measures of each pathology were derived. MAIN OUTCOME MEASURES: Clinical diagnosis of probable AD and level of global cognitive function at the last evaluation before death. RESULTS: Women had more global AD pathology than did men (P = .04), due primarily to more neurofibrillary tangles (P = .02). At the last evaluation before death, 57 persons met clinical criteria for probable AD (34 [60%] of them women). In logistic regression models, sex was not related to odds of clinical AD (odds ratio [OR], 1.35; 95% confidence interval [CI], 0.56-3.25), but the relation of global AD pathology to clinical diagnosis differed for men and women. Each additional unit of AD pathology was associated with a nearly 3-fold increase in the odds of clinical AD in men (OR, 2.82; 95% CI, 1.03-7.65) compared with a more than 20-fold increase in the odds of clinical AD in women (OR, 22.67; 95% CI, 5.11-100.53). Results were unchanged after controlling for potential confounders or using level of cognition as the outcome. CONCLUSION: These data suggest that AD pathology is more likely to be clinically expressed as dementia in women than in men.