Author:
Alan Woodruff

Queensland Science Minister Ian Walker MP recently announced a $2.5M philanthropically funded fellowship at The University of Queensland to investigate stroke-induced dementia. Also known as vascular dementia, this disorder shares many traits with another form of dementia, Alzheimer’s disease, but the two also exhibit notable differences.

Dementia, an umbrella term for age-dependent chronic cognitive decline, affects ~10% of people over the age of 65 and some 35% of people over 85, and is of growing concern as the world’s population ages. Alzheimer’s disease (AD) is the most common form of dementia, accounting for 50–70% of all cases, while vascular dementia (VaD), believed to comprise 10–20% of dementias, is the second most frequently observed (Fig. 1). Here we explore the commonalities and differences between AD and VaD.

Symptoms

The symptoms associated with AD and VaD are similar and overlapping, but the two conditions are nevertheless distinguishable. The hallmark symptom of AD is loss of memory, which can be attributed to the early degeneration and death of neurons in the hippocampus, a structure that’s crucially involved in memory formation. The hippocampus is also important for spatial navigation, as is the entorhinal cortex, which is the stereotypical starting point for cell death in AD (Fig. 2). Consistent with damage in these regions, AD patients exhibit disorientation and confusion in addition to memory problems. Subsequently, symptoms can progress to include motor difficulties and impairments in executive planning and decision making. Importantly, the timecourse of these changes reflects the characteristic spread of pathology seen in AD patients.

In VaD, the symptoms depend on the location(s) at which blood flow is impeded; thus, in contrast to AD, there is no standard pattern or order to the cognitive decline. A stroke that affects motor cortex will impact motor function, a stroke in the language area of the cerebral cortex will affect speech and comprehension, and strokes in subcortical or prefrontal cortical regions can cause slow thought and poor planning, attention and organisation (Fig. 3). Although these latter symptoms appear to be the most common in VaD, it is important to remember that because of variability in where strokes occur, the lack of such executive control symptoms does not rule out a VaD diagnosis.

Underlying cause

Both disorders are caused by the degeneration and death of neurons, but the events triggering this differ for AD and VaD. In AD, a wealth of evidence indicates the involvement of two proteins in particular – amyloid beta (Aβ) and tau (Fig. 4). In brief, it’s thought by many that Aβ causes the tau protein in neurons to become abnormal – hyperphosphorylated, with a bunch of extra phosphate molecules attached to it. The tau then moves from its usual location in the axon of neurons to the dendrites, where it causes synapses to disappear and the neurons to die. Once tau has been recruited by Aβ to the dendritic synapses, it appears to enable Aβ to trigger synapse loss and ultimately cell death. In other words, non-toxic Aβ is essentially recruiting tau to allow the Aβ to become toxic; the toxicity likely occurs via a particular neurotransmitter receptor called the NMDA receptor. The head of The Clem Jones Centre for Ageing and Dementia Research (CJCADR) at QBI, Professor Jürgen Götz, has been instrumental in developing the above theory for how tau and Aβ interact to give rise to Alzheimer’s disease.

Whereas AD pathology depends crucially on tau and Aβ, VaD does not (although as described below, Aβ may play an indirect role). Instead, as the name suggests, vascular dementia is caused by changes to the brain’s blood vessels that hinder delivery of blood and oxygen to regions of the brain. These changes can arise via stroke, which is the primary cause of blood flow irregularities leading to dementia, or through arteriosclerosis (hardening and loss of elasticity of arterial walls) or atherosclerosis (build-up of cholesterol and fatty plaques in blood vessels). Stroke-induced VaD can occur either as a result of several small strokes in different regions of the brain – none of which is necessarily symptomatic at the time but which together become enough to cause cognitive deficits – or more commonly through a major isolated instance of stroke. The obstruction of blood vessels resulting from ischemic stroke prevents oxygen and other nutrients reaching nearby brain regions, causing the surrounding neurons to die, thereby producing cognitive deficits.

Risk factors

Alzheimer’s and VaD share the majority of their risk factors. The primary risk factor for both is age, and as you might expect, risk factors for VaD are essentially the same as those for cardiovascular disease. Thus obesity, smoking, hypertension and insulin resistance, particularly when experienced during mid-life rather than late-life, all increase the likelihood of developing VaD. The fact that AD shares these risk factors likely indicates that proper nourishment of the brain through healthy intact vasculature is important in staving off AD. It’s also worth pointing out that AD and VaD frequently coexist, which is consistent with the shared risk factors.

There are also known genetic risk factors for both dementias, and again some of these are shared, in particular the ApoE4 (apolipoprotein E4) gene, which increases cardiovascular risk, and the APP (amyloid precursor protein) gene, which ultimately results in amyloid β production. The fact that Aβ appears to have cardiovascular effects (in addition to its neuronal effects interacting with tau, in the case of AD) would explain its position as a genetic risk factor for both dementias.  In addition to these shared genetic risk factors, some are unique to either VaD or AD. For VaD, mutations in a gene called Notch3 appear to increase one’s risk, whereas mutations in presenilin genes (which help convert APP into Aβ) and the APP gene are heritable and lead to early-onset familial AD.

Summary

Although AD and VaD are different conditions, they have much in common. The root cause is different – Aβ and tau involvement in the case of AD, and cerebrovascular ill-health in the case of VaD – yet significant overlap exists in the risk factors, genetics and symptoms of the two diseases. It seems likely that studying the two conditions side by side will help us better understand, and ultimately treat, both diseases.

QBI Laboratories working on dementia: Professor Jürgen Götz, Professor Perry Bartlett, Associate Professor Elizabeth Coulson

QBI Laboratories working on stroke: Professor Frederic Meunier, Associate Professor Elizabeth Coulson, Professor Jason Mattingley

Image credits
Figure 1 - www.memorylosstest.com/alzheimers-disease-dementia-memory-loss-cause
Figure 2 - www.wholehealthinsider.com/newsletter/alzheimers-type-3-diabetes
Figure 3 - www.headway.org.uk/executive-dysfunction-after-brain-injury.aspx
Figure 4 – Ittner LM and Götz J (2011) Nat. Rev. Neurosci. Feb;12(2):65-72