Molecular biology and genetics of Alzheimer's disease

The recent progress in molecular biology research has changed the past concepts on Alzheimer's disease (AD) and other nervous system amyloidoses. This paper compiles the basic principles of molecular biology of AD and reviews their clinical impact The new data about the function and metabolism of amyloid precursor protein and the more recent information on the role of the apolipoprotein E have provided new insight into the pathogenesis of this disease. Although further investigations are still required to assemble these data into a theory that completely explains the development of the disease and changes the present symptomatic therapeutic strategies to an entire preventive or curative approach, the recent research results in this field are relevant for the diagnostic and therapeutic management of AD patients.     

"Frontal variant Alzheimer's disease": a reappraisal

Two cases of clinically diagnosed sporadic Alzheimer's disease with early and prominent behavioural features (social disinhibition, emotional blunting, stereotyped verbal utterances) sufficient to prompt an initial diagnosis of frontotemporal dementia are presented. It is suggested that the term "frontal variant AD" be used for this clinically defined phenotype, which has also been described in cases of inherited AD associated with certain presenilin-1 gene mutations. This differs from previous usage of the term "frontal variant AD" to describe AD with predominant frontal lobe neuropathological change (although the clinical phenotype may reflect regional distribution of pathology), but parallels the clinical definition of visual agnosic, aphasic and apraxic presentations of AD. The proposed usage would also emphasise differential diagnosis.     

Contribution of CSF biomarkers to early‐onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the “AD signature” and “FTLD signature.” We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.     

不同严重程度血管性痴呆与老年性痴呆的神经心理特点

目的 探讨不同严重程度的血管性痴呆（vascular dementia,VaD）与老年性痴呆（Alzheimer disease,AD）
的神经心理学特点。
方法 对广东省人民医院神经科门诊及病房的252例痴呆患者（VaD组127例,AD组125例）,和正常对
照组159例进行一组神经心理量表检查。神经心理量表包括：简易精神状态检查（mini-mental state
examination,MMSE）、Fuld物体记忆测验（fuld object memory,FOM）、言语流畅性测验（rapid verbal
retrieve,RVR）、数字广度测验（digit span,DS）和积木测验（block design,BD）。分析这两种类型不同
严重程度的痴呆患者认知障碍的特点。
结果 两种类型的轻、中、重度痴呆患者神经心理检查有统计学差异（P <0.01）。轻度痴呆患者MMSE、
RVR评分在VaD、AD组间存在统计学差异（P <0.05）,在中、重度痴呆患者,神经心理评分在VaD、AD组
间无统计学差异（P >0.05）。
结论 神经心理量表评估有助于VaD、AD的严重程度分级,RVR测验可辅助鉴别诊断轻度VaD和AD。     

Apolipoprotein E4 Genotype and Depressive Symptoms as Risk Factors for Dementia in an Older Korean Population

Objective

Growing evidence suggests the separate associations of apolipoprotein E e4 allele (apo E4) and depression with incident dementia. This study investigated the separate and combined effects of apo E4 and depression on the incidence of dementia in both men and women.

Methods

Of 625 elderly without dementia at baseline, 518 (83%) were followed over a 2.4-year period and were assessed clinically for incident dementia. The apo E polymorphism was ascertained, and depression was identified using the Korean version of the Geriatric Depression Scale (KGDS). Covariates included age, gender, education, disability, alcohol history, physical activity, and vascular risk factors.

Results

The incidence of dementia was significantly higher in elderly Koreans with both apo E4 and depression compared to those without both factors [adjusted odds ratio (95% CI)=5.85 (1.77-19.38)]. This interaction was significant in men (p=0.049), but not in women (p=0.354).

Conclusion

Depressed elderly people are at great risk for incident dementia in the presence of apo E4. Potential gender differences require further evaluation.     

Apolipoprotein E genotype of a Portuguese control population and Alzheimer's disease patients

The present work first describes the frequency of APOE alleles and genotypes in Portuguese populations in relation to AD pathology. We genotyped a group of late onset sporadic AD cases, their pairwise controls and a larger group of randomly selected individuals, to assess the distribution pattern of APOE alleles in the Portuguese population. APOE ?4 relative frequency may significantly vary among different populations—a fact which should be taken into consideration for the correct evaluation of the cossegregation of this allele with AD pathology. We observed a frequency of 0.087 ± 0.029 of the APOE ?4 and 0.043 ± 0.021 of the APOE ?2 allele in the Portuguese random population which as expected showed a marked prevalence of the APOE ?3 form (0.870 ± 0.035). In the AD patients the APOE ?4 allele frequency was significantly higher (0.360 ± 0.081) than in the controls (χ₂ = 31.000, p < 0.00001, df = 2). Consistently APOE ?3 allele frequency (0.640 ± 0.081) was significantly lower than in the controls while APOE ?2 was absent in the studied AD population. Taken together our results demonstrate that the Portuguese population is characterized by a relatively low frequency of the APOE ?4 allele, in good agreement with previous observations of a gradient of ?4 allele frequency in Europe, decreasing from North to South. Several lines of evidence point at APOE?e4 allele as a major genetic susceptibility factor in AD. The APOE ?4 allele was significantly higher [odds ratio (OR) = 5.93, 95% CI 3.55–9.91] in the Portuguese AD patients than in the random non-demented population. The genotype analysis of the Portuguese AD patients here described reveals a marked, increased frequency of ?4 homo- and heterozygous individuals consistent with an APOE ?4 zigosity effect as a further genetic trait predisposing to AD development.     

Caregivers of people with Alzheimer's disease: a qualitative study from the Indian 10/66 Dementia Research Network

BACKGROUND: Dementia is a rapidly growing problem in all parts of the developing world. Such societies are characterised by low levels of awareness regarding dementia as a chronic degenerative brain syndrome, and by an absence of supportive health and welfare services. There is reliance upon families as the cornerstone of support and care. However, surprisingly little is known of the care arrangements for people with dementia and the strain experienced by their family caregivers. METHOD: In a qualitative study of 17 caregivers of people with Alzheimer's disease identified through an innovative case-finding program in Thrissur, South India, we obtained information on the range of care arrangements, attitudes towards care giving roles and sources of strain. RESULTS: The majority of caregivers were young women, often daughters-in-law of women with dementia. The principal sources of caregiver strain were behavioural problems associated with the dementia syndrome, and incontinence. Strain was exacerbated by the lack of supportive response by local health services, and by lack of support and, sometimes, criticism from other family members. Family conflict was commonly encountered. The majority of caregivers experienced significant deterioration in their mental health. One caregiver unfortunately committed suicide after the death of her husband. CONCLUSIONS: There is a clear need for more education, advice and support for families affected by dementia. Community services in developing countries should consider training existing domiciliary outreach services, the community-based multi-purpose health workers, to identify and support family caregivers.     

Seizures and epilepsy in Alzheimer's disease

Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.     

Psychotic symptoms in Alzheimer's disease

The case notes of 37 patients with neuropathologically confirmed Alzheimer's disease were studied for non-cognitive psychiatric features occurring during the course of the illness. Four (11%) exhibited delusions, five (14%) had visual hallucinations and one (3%) had auditory hallucinations. Two (6%) developed a misidentification syndrome, five (14%) developed non-delusional paranoid thinking and six (16%) had significant depressive symptoms with two (5%) developing major depression. Possible explanations for the wide variation in reported rates of psychotic symptoms in Alzheimer's disease in the literature are discussed.     

APOE-ε4 in age-related memory complaints and Alzheimer's disease

APOE-ε4 has been consistently found to be frequent in patients with senile dementia of the Alzheimer type (SDAT). Since forgetfulness may represent an early stage of dementia, APOE-ε4 frequency can be expected to be high in such subjects, particularly in those who later develop dementia. We examined here the proportion of ε4 alleles in patients with SDAT (n = 179), controls (n = 154) and subjects with age-related memory complaints (ARMC, n = 167); 16 of them developed dementia of Alzheimer type and three of them dementia of vascular type. We also evaluated the relative risk of dementia (of Alzheimer type) in ARMC subjects who are ε4-carriers, using a Cox proportional hazards model. The APOE-ε4 allele frequency was 27% in SDAT, 25% in ARMC patients who became demented, 15% in ARMC subjects who remained such after at least 1 year of follow-up, and 10% in controls. APOE-ε4 allele was significantly more frequent in SDAT than in controls or than in stable ARMC (OR = 3.7 [2–6.3] and OR = 2.5 (1.5–4], respectively, p > 0.01). The risk of dementia in ARMC subjects carrying an ε4 allele was three-fold that of those without (expβ = 3.1 [0.98–10], p = 0.05). Older age at onset of memory decline and lower minimental scores at initial visit were also associated with development of dementia in ARMC subjects (exp β = 1.1 [1.0–1.2], p = 0.05 and exp = 0.76 [0.6–0.9]), p = 0.008). In conclusion, the APOE-ε4 allele was found to occur frequently in ARMC who subsequently develop dementia, therefore it can indicate a predisposition for dementia in such patients.     

Pentagon drawing and neuropsychological performance in Dementia with Lewy Bodies, Alzheimer's disease, Parkinson's disease and Parkinson's disease with dementia

OBJECTIVES: Early and accurate diagnosis of Dementia with Lewy Bodies (DLB) to allow the appropriate clinical treatment is a priority, given reports of severe neuroleptic sensitivity and a preferential response to cholinesterase inhibitors in these patients. There have been suggestions that constructional apraxia is prevalent in DLB, and may provide a sensitive marker of the disease. METHODS: This study examined the pentagon drawings of 100 DLB patients, 50 Alzheimer's disease (AD) patients, 81 Parkinson's disease (PD) patients of whom 36 suffered from dementia (PDD). Performance on this task was correlated with cognitive performance on the MMSE and CAMCOG scales. RESULTS: Patients with DLB were found to draw significantly worse pentagons than those with AD or PD, but not those with PDD. Drawing scores were significantly correlated with MMSE scores for the AD and PDD groups but not those with DLB. More detailed analysis of the neuropsychological correlates of constructional performance for patients with AD and DLB, revealed that those with AD showed a broad cognitive basis to their impairment, in DLB drawing was linked only to perception and praxis. CONCLUSIONS: This study has suggests that DLB subjects show an impairment of pentagon copying that is dissociable from more global cognitive impairments, whereas PD patients are relatively unimpaired on pentagon copying and AD and PDD patients show a linkage of their impairment in copying with more global cognitive deficits.     

Mouse models of Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia, affecting 35 million people today. The search for new treatments is made ever more urgent by prospects for increasing prevalence due to population aging. Mouse models are one of the most important research tools for finding new treatments for AD. Here, we review those models. We begin by briefly reviewing the AD genetics on which mouse models are based and then consider the most common mouse models of AD, including mice transgenic for human amyloid precursor protein (hAPP) and beta-amyloid (Aβ), mice expressing mutant presenilin genes, mice modeling tau's role in AD, and apolipoprotein E models. The discussion highlights key features and important differences between these mouse models. We conclude with a discussion about the role of AD mouse models in the translational pipeline.     

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias

BackgroundOverlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-β₄₂ (Aβ₄₂), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD.MethodsWe retrospectively analyzed concentrations of MHPG, Aβ₄₂, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters.ResultsThe currently used combination of Aβ₄₂, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia.ConclusionsOur results confirm in a separate patient cohort that addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.     

Smell identification test as an indicator for cognitive impairment in Alzheimer's disease

OBJECTIVES: The aim of the present study was to assess olfactory dysfunction in patients with Alzheimer's disease (AD) and to compare utility of the olfactory tests as possible clinical markers. METHODS: Two olfactory identification tests (The Cross-Cultural Smell Identification Test [CC-SIT] and the Picture-based Smell Identification Test [P-SIT]) and the Mini Mental State Examination (MMSE) were administered to patients with AD and age-matched controls. Apolipoprotein E (Apo E) genotypes of patients with AD were identified. RESULTS: Patients with AD had significantly lower olfactory identification scores than age-matched non-demented elderly subjects in both olfactory assessments. In the AD group, the coefficient of correlation between the MMSE scores and the P-SIT scores was higher than that between the MMSE scores and the CC-SIT scores. Receiver operating curve (ROC) analyses for both tests indicated that the P-SIT discriminated AD patients from controls more reliably than did the CC-SIT. Within AD patients, those who were carrying one or two ApoE epsilon4 alleles had a higher coefficient of correlation between the MMSE scores and the P-SIT scores than patients without the ApoE epsilon4 allele. CONCLUSIONS: The results suggest that a short and simple non-lexical olfactory identification test can be useful as a clinical marker of AD appropriate for Japanese elderly population.     

Comparison of dementia with Lewy bodies to Alzheimer's disease and Parkinson's disease with dementia.

We compared the clinical and neuropsychological pattern of dementia with Lewy bodies (DLB) to Alzheimer's disease (AD) and Parkinson's disease with dementia (PD-d). Sixteen patients clinically diagnosed with DLB were compared with two groups of patients with PD-d (n = 15) and AD (n = 16) matched for level of dementia. Isolated cognitive impairment was the most common form of presentation in AD (93.8%) and DLB (31.3%) groups, while parkinsonism was in 100% of PD-d subjects. Psychoses associated with cognitive impairment at the beginning of the disease were more frequent in DLB patients (31.3%) than in AD (6.3%) and PD-d (0%) groups. There were no significant differences in Unified Parkinson Disease Rating Scale motor-subscale scores between DLB and PD-d patients. DLB and PD-d patients performed significantly worse on attentional functions and better on memory tests than AD. DLB patients also showed lower scores than AD subjects on visual memory, visuoperceptive, and visuoconstructive tests. No significant differences were found between PD-d group and DLB subjects on any neuropsychological test. We were unable to find any differences in cognitive tasks between PD-d and DLB subjects. Clinical features and neuropsychological deficiencies of DLB (attentional, visuoperceptive, and visuoconstructive deficits) and PD (attentional deficits) compared to AD (amnesic syndrome) can contribute to accurate identification of these entities and to the understanding of the neuropathological and neurochemical substrate underlying these diseases.     

Education and rates of cognitive decline in incident Alzheimer's disease

BACKGROUND: Some (but not all) epidemiological studies have noted faster rates of progression in high education patients with Alzheimer's disease (AD), which has been attributed to harbouring/tolerating a higher pathological burden at the time of clinical dementia for subjects with higher education. We wanted to assess the relationship between education and rates of decline in AD. METHODS: During the course of a community based multiethnic prospective cohort study of individuals aged > or = 65 years living in New York, 312 patients were diagnosed with incident AD and were followed overall for 5.6 (up to 13.3) years. The subjects received an average of 3.7 (up to 9) neuropsychological assessments consisting of 12 individual tests. With the aid of a normative sample, a standardised composite cognitive score as well as individual cognitive domain scores were calculated. Generalised estimating equation models were used to examine the association between education and rates of cognitive decline. RESULTS: Composite cognitive performance declined by 9% of a standard deviation per year. Rates of decline before and after AD incidence were similar. For each additional year of education there was 0.3% standard deviation lower composite cognitive performance for each year of follow up. The association between higher education and faster decline was noted primarily in the executive speed (0.6%) and memory (0.5%) cognitive domains and was present over and above age, gender, ethnicity, differential baseline cognitive performance, depression, and vascular comorbidity. CONCLUSIONS: We conclude that higher education AD patients experience faster cognitive decline.     

The cognitive efficiency profile: Description and validation in patients with Alzheimer's disease

The rigorous diagnosis of dementia, especially in the early stages, requires clinical observation and neuropsychological tests. This article shows how a short strategy-oriented neuropsychological battery, the Cognitive Efficiency Profile (CEP), can contribute to the early diagnosis of Alheimer's disease. The CEP was given to 56 subjects who had been independently diagnosed as being cognitively unimpaired (N = 16), as having probable AD with mild dementia (N = 32) or as having “borderline” deterioration (N = 8). One-year follow-up showed that all the latter patients developed unequivocal dementia. There was a clear-cut separation in the test results between the controls and the probable AD cases when the scores were corrected for age and education. There was some overlap between the borderline cases and the probable AD patients but, in all cases, the corrected scores fell below those of normal controls. The usefulness of the CEP rests on the fact that it assesses the efficiency or the failure of strategies applied to a number of abilities related to cognitive efficiency. Coupled with clinical data, a good or a poor performance on the CEP strongly corroborates the diagnosis of normal cognitive functioning or of dementia in the elderly.     

Cerebrospinal fluid orexin in Alzheimer's disease: a systematic review and meta-analysis

Objective/backgroundA growing body of evidence suggests that sleep and Alzheimer's disease (AD) have a bi-directional relationship. Emerging research also suggests that orexin, a key neurotransmitter involved in sleep-wake regulation, may be altered in persons with AD, however results have not been consistent across prior studies. This investigation was conducted to both evaluate the aggregate literature to minimize the risk of bias and identify potential factors associated with heterogeneity across studies.MethodsSystematic review identified relevant investigations that compared cerebrospinal fluid orexin in persons with AD and controls. Meta-analysis (random effects model) compared effect size (Hedge's g) for orexin between AD and controls. Meta-regression was additionally performed for key variables of interest to evaluate potential causes of heterogeneity among studies.Results17 studies were identified that met inclusion/exclusion criteria. Evidence of publication bias was not identified. Non-significant increases in orexin were observed in AD relative to controls, with moderate to large heterogeneity among studies (Hedge's g = 0.20, p = 0.136, I² = 72.6%). Meta-regression demonstrated both year of publication (β = 0.055, p = 0.020) and effect size for phosphorylated tau in AD versus controls (β = 0.417, p = 0.031) were associated with differences in orexin.ConclusionsResults do not support broad differences in orexin in AD compared to controls, however, evolving diagnostic criteria may have affected findings across studies. Future research that examines orexin in AD over the longitudinal course of the disorder and explores potential links between phosphorylated tau and orexin are indicated.