Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the e4 allele are at increased risk of AD compared with those carrying the more common e3 allele, whereas the e2 allele decreases risk. Presence of the APOE e4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Summary Background Reliable data on the prevalence and predictors of post-stroke dementia are needed to inform patients and carers, plan services and clinical trials, ascertain the overall burden of stroke, and understand its causes. However, published data on the prevalence and risk factors for pre-stroke and post-stroke dementia are conflicting. We undertook this systematic review to assess the heterogeneity in the reported rates and to identify risk factors for pre-stroke and post-stroke dementia. Methods Studies published between 1950 and May 1, 2009, were identified from bibliographic databases, reference lists, and journal contents pages. Studies were included if they were on patients with symptomatic stroke, were published in English, reported on a series of consecutive eligible patients or volunteers in prospective cohort studies, included all stroke or all ischaemic stroke, measured dementia by standard criteria, and followed up patients for at least 3 months after stroke. Pooled rates of dementia were stratified by study setting, inclusion or exclusion of pre-stroke dementia, and by first, any, or recurrent stroke. Pooled odds ratios were calculated for factors associated with pre-stroke and post-stroke dementia. Findings We identified 22 hospital-based and eight population-based eligible cohorts (7511 patients) described in 73 papers. The pooled prevalence of pre-stroke dementia was higher (14·4%, 95% CI 12·0–16·8) in hospital-based studies than in population-based studies (9·1%, 6·9–11·3). Although post-stroke (≤1 year) dementia rates were heterogeneous overall, 93% of the variance was explained by study methods and case mix; the rates ranged from 7·4% (4·8–10·0) in population-based studies of first-ever stroke in which pre-stroke dementia was excluded to 41·3% (29·6–53·1) in hospital-based studies of recurrent stroke in which pre-stroke dementia was included. The cumulative incidence of dementia after the first year was little greater (3·0%, 1·3–4·7) per year in hospital-based studies than expected on the basis of recurrent stroke alone. Medial temporal lobe atrophy, female sex, and a family history of dementia were strongly associated with pre-stroke dementia, whereas the characteristics and complications of the stroke and the presence of multiple lesions in time and place were more strongly associated with post-stroke dementia. Interpretation After study methods and case mix are taken into account, reported estimates of the prevalence of dementia are consistent: 10% of patients had dementia before first stroke, 10% developed new dementia soon after first stroke, and more than a third had dementia after recurrent stroke. The strong association of post-stroke dementia with multiple strokes and the prognostic value of other stroke characteristics highlight the central causal role of stroke itself as opposed to the underlying vascular risk factors and, thus, the likely effect of optimum acute stroke care and secondary prevention in reducing the burden of dementia. Funding None.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(09)70236-4.pdf

Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.

Heart rate variability (HRV) provides indirect insight into autonomic nervous system tone, and has a well-established role as a marker of cardiovascular risk. Recent decades brought an increasing interest in HRV assessment as a diagnostic tool in detection of autonomic impairment, and prediction of prognosis in several neurological disorders. Both bedside analysis of simple markers of HRV, as well as more sophisticated HRV analyses including time, frequency domain and nonlinear analysis have been proven to detect early autonomic involvement in several neurological disorders. Furthermore, altered HRV parameters were shown to be related with cardiovascular risk, including sudden cardiac risk, in patients with neurological diseases. This chapter aims to review clinical and prognostic application of HRV analysis in diabetes, stroke, multiple sclerosis, muscular dystrophies, Parkinson's disease and epilepsy.

Heart rate variability.

Dementia with Lewy bodies is relatively common cause of degenerative dementia in older people. This debilitating disorder is comprised of core features including dementia, fluctuating cognition, motor parkinsonism, and visual hallucinations, as well as other symptoms such as rapid eye movement sleep behavior disorder, olfactory dysfunction, autonomic dysfunction, sensitivity to neuroleptics, anxiety, depression, and delusions. Pharmacotherapy, so far exclusively symptomatic, should be implemented with caution and only when symptoms are disturbing and after non-pharmacological interventions fail. Treatment with acetylcholinesterase inhibitors (AChEi), such as donepezil and rivastimine, is considered a first line therapy. There is substantial evidence that AChEi address cognitive as well as behavioral symptoms without substantially increasing parkinsonism. Dopaminergic treatment for motor symptoms requires balancing risk of worsened psychosis and is consider only moderately beneficial.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(03)00619-7.pdf

Dementia With Lewy Bodies

Apolipoprotein E (APOE) is a 299-aminoacid protein encoded by the APOE gene. Three common polymorphisms in the APOE gene, ɛ2, ɛ3, and ɛ4, result in a single aminoacid change in the APOE protein. APOE ɛ2, ɛ3, and ɛ4 alleles strongly alter, in a dose-dependent manner, the likelihood of developing Alzheimer's disease and cerebral amyloid angiopathy. In particular, APOE ɛ4 is associated with increased risk for Alzheimer's disease whereas APOE ɛ2 is associated with decreased risk. The effects of APOE genotype on risk of these diseases are likely to be mediated by differential effects of APOE on amyloid-β accumulation in the brain and its vasculature. Response to treatment for Alzheimer's disease might differ according to APOE genotype. Because convincing evidence ties the APOE genotype to risk of Alzheimer's disease and cerebral amyloid angiopathy, APOE has been studied in other neurological diseases. APOE ɛ4 is associated with poor outcome after traumatic brain injury and brain haemorrhage, although the mechanisms underlying these associations are unclear. The possibility that APOE has a role in these and other neurological diseases has been of great interest, but convincing associations have not yet emerged.

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Apolipoprotein E in Alzheimer's disease and other neurological disorders

Lewy bodies are intracytoplasmic, eosinophilic intraneuronal inclusion bodies [1]. They contain phosphorylated and non-phosphorylated microfilaments, β-crystalline, ubiquitin and proteinases [2]. They are therefore indicators of cell response to stress and markers for the degradation and excretion of abnormal proteins from the cell. Although Lewy bodies in the substantia nigra were identified as a key neuropathological element of Parkinson’s disease (PD) early in the century, the importance of cortical Lewy bodies as a feature of some cases of dementia has only recently become evident. A series of single case reports and small case series appeared in the literature between the 1960s and the mid-1980s, suggesting that Lewy bodies in the cerebral cortex could be associated with a rare form of dementia [3, 4, 5, 6]. Hospital-based postmortem series reporting consecutive dementia cases have subsequently identified cortical Lewy bodies in at least 10% of dementia sufferers [7, 8, 9, 10].

Dementia with Lewy Bodies

Background and Purpose— Impaired autonomic function is common in the acute poststroke phase but little is known about the longer term effects, particularly in older people. We sought to determine if autonomic function is impaired after stroke recovery in older patients. Methods— A cross-sectional case-control study comparing autonomic function in 76 nondemented stroke patients with 70 community-living controls aged older than 75 years. Results— Cases were assessed on average 9 months after stroke. From power spectral analysis of heart rate variability, stroke patients had lower total (P=0.032) and low-frequency (P=0.014) spectral densities and impaired baroreflex sensitivity (α low-frequency baroreflex sensitivity, P=0.006). From a series of cardiovascular autonomic reflex tests, heart rate variation during forced respiration, Valsalva ratio, and blood pressure overshoot during Valsalva maneuver were significantly lower in stroke patients (P=0.003, <0.001, and 0.027, respectively). Blood pressure response...

Autonomic Function Is Impaired in Elderly Stroke Survivors

Heart rate variability (HRV) is a sensitive method for the assessment of autonomic function and requires little cooperation from the subject, making it suitable for use in dementia. Preliminary studies have suggested that HRV may be impaired in Alzheimer's disease (AD). HRV has not been studied in vascular dementia (VAD). We investigate autonomic function in AD and VAD, using power spectral analysis of HRV. One hundred and fourteen participants were evaluated (14 AD, 20 VAD and 80 controls). The resting ECG was recorded for 5 min with participants in the supine position. Power spectral analysis used to obtain spectral bands in the very-low-frequency (<0.04 Hz), low-frequency (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) bands and total spectral power (<0.40 Hz) according to international HRV guidelines. There were no differences in HRV in patients with AD or VAD when compared with controls.

Autonomic function assessed by heart rate variability is normal in Alzheimer's disease and vascular dementia.

Heart rate variability is used to assess cardiovascular autonomic function. The cholinesterase inhibitor donepezil potentially affects parasympathetic activity. Twenty participants with Alzheimer's disease or dementia with Lewy bodies were treated with donepezil in a pilot study. Power spectral analysis was used to analyse 5 min of beat-to-beat RR interval data in 15 cases. Heart rate variability was significantly reduced following treatment with donepezil; mainly for high frequency (median changed from 581 to 78 ms2; p = 0.001) but also for total power (median changed from 1,563 to 844 ms2; p = 0.047). Donepezil may adversely influence cardiovascular autonomic control. These results indicate the need for larger controlled trials to further investigate the cardiovascular effects of donepezil.

Cardiovascular effects of donepezil in patients with dementia.

Vasovagal syncope (VSS) is an exaggerated tendency towards the common faint caused by a sudden and profound hypotension with or without bradycardia. The etiology of VVS is unknown though several lines of evidence indicate central and peripheral abnormalities of sympathetic function. Studies however indicate a strong heritable component to the etiology of VVS in over 20% of cases. Here, we report the findings from a family that shows apparently autosomal dominant VVS in at least three generations. Clinical findings included an absence of any discernible cardiac or autonomic abnormalities and reproducible hypotension on tilt table testing in affected family members.

Andrew McLaren

Papers

Dementia with Lewy Bodies

Autonomic Function Is Impaired in Elderly Stroke Survivors

Autonomic function assessed by heart rate variability is normal in Alzheimer's disease and vascular dementia.

Cardiovascular effects of donepezil in patients with dementia.

Familial neurocardiogenic (Vasovagal) syncope