What is mixed-brain dementia?

Mixed dementia is the combination of multiple dementias coexisting within a patient.

More than 1 in 10 dementia patients have mixed dementia, the likelihood increasing with age. Typically, this is Alzheimer’s Disease (AD) and Vascular Dementia (VD), however, mixed dementias with Frontotemporal Dementia (FTD), Parkinson's, Lewy Bodies, or Pick Bodies are also present. When defining mixed dementia, it is primarily recognised as AD and VD.⁶

Cumulative progression

AD is a disease that starts near the hippocampus involving amyloid plaques and tau. They cause issues with cellular signalling, structure, health and more.² The accumulation of these factors affects not only synaptic health but brain health on a larger scale. One such effect is the change in blood flow to the brain, which causes damage to nearby areas due to the toxic nature of its constituents.²

AD occurs sporadically most of the time. Often, it is asymptomatic for an extended period, clinical dementia more clearly presents itself when AD is paired with strokes and cerebrovascular-related brain changes.¹

These cerebrovascular-related brain changes stack, making small changes larger and larger over time, potentially causing strokes.³ The accruing damage leads to VD.⁴

VD is dementia that affects the brain through damaged/altered/reduced blood flow to areas of the brain, affecting cellular and brain health, causing hypoxia and reduced nutrient delivery. This can occur sporadically due to injury and is a common form of dementia in the elderly. VD can occur as a result of ischemic injuries caused by cerebrovascular disease (CVD), which is preceded by vascular risk factors.⁴

CVD and ischemic injury can lead to AD development. As stroke incidence increases with age, the likelihood of risk for dementia and worsening dementia symptoms also increases.⁵

AD and VD are both interconnected to each other, so it’s not surprising that they are the most common form of mixed dementia. However, they are both unique in their effects and pathologies, and the combination can accelerate neuronal degeneration.⁶

Areas of the brain affected

Alzheimer’s

Early AD begins with neuronal atrophy in the basal forebrain and neocortex.⁷

• Increased cortical atrophy in posterior cortical areas:
  • Posterior cingulate gyrus & precuneus
  • Enlargement of frontal and temporal horns of lateral ventricles
• Medial temporal atrophy
  • Amygdala
  • Hippocampus
  • Enlargement of the temporal horn
• Frontal and temporal lobes
  • Enlarged sulcal spaces and gyri atrophy

Volume loss due to white matter loss.²

AD progression is due to the propagation of amyloid plaques and neurofibrillary tangles (NFT) to various areas of the brain as the disease continues, with placement becoming more robust and spreading over time:

 Stages of amyloid plaque spread and development:²⁸

• Stage 1 – Neocortex
• Stage 2 – Allocortex
• Stage 3 – Subcortical nuclei (eg. Striatum)
• Stage 4 – Brainstem
• Stage 5 – Cerebellum

Amyloid plaques are deposited into brain blood vessels, spreading towards various areas and causing cerebral blood vessel damage. Severe cases impair blood flow, causing ischemic injury.²⁵  

Vascular dementia

VD affects the vascular system within the brain and so doesn’t follow a typical degeneration pathway like Alzheimer’s or Parkinson’s, the damaged/atrophied areas due to injury as blood flow is improper.⁴

VD is defined by the presence of cortical infarcts in at least 3 areas without subcortical lesions.¹⁰

Due to the wide variety of vasculature within the brain, there are various areas in which VD affects and various types of VD. Depending on the injured area the pathology, progression, and symptoms can all differ. The variety of effects and various possibilities in the brain means that the degeneration of neurons causes cognitive decline in a unique way:⁴

• Multi-infarct dementia
  • Multiple cortical infarcts across the brain
• Small vessel dementia
  • Lacunes (small sharply defined regions of tissue loss), extensive white matter lesions, demyelination of neurons, gliosis
• Hypoperfusion dementia
  • White matter lesions, watershed (incomplete) infarcts
• Strategic infarct dementia
  • Strategically damaged areas such as the hippocampus or thalamus
  • Angiogenesis of amyloid plaques from AD has a similar pathology. Angiogenesis can lead to atherosclerosis in larger arteries, causing lesions in key arteries and leading to large and small infarcts or haemorrhages⁵  
• Haemorrhagic dementia
  • Haemorrhagic changes causing dementia related to amyloid angiopathy
• Hereditary vascular dementia
  • Multiple lacunes, white matter lesions, especially in the temporal lobe
• Alzheimer’s with CVD
  • Vascular changes and atrophy of neurons in areas such as the medial temporal lobe. Presents a combination of vascular changes and AD pathology

Both AD and VD work together in degeneration, each influencing the other to provide greater degeneration. This leads to greater dementia symptoms and cognitive decline.⁶ This is dependent on the type of VD and damaged area.⁴ However, due to the cumulative effects of vascular damage as age increases and these microinfarctions add up, the frequency of neurodegeneration increases.³

Symptomatic and behavioural results

Mixed dementia can have a wider range and increased severity of symptoms than any single dementia. The combination of pathologies introduces new symptoms and by increasing atrophy of targeted areas, it can speed up degeneration. Mixed dementia is extremely unstable for diagnosis and accelerates quickly, with life expectancy being low.⁶

Combined pathological changes

There is a marked increase in the blood level of amyloid-beta and in MRI scans there are notable factors observed such as:²⁶

• Marked areas of brain atrophy and degeneration²
  • White matter tract irregularities
  • Hippocampus, thalamus and basal ganglia
• Neurofibrillary tangles, amyloid plaques
• Areas of vascular damage and ischemic injury/infarctions in various areas of the brain⁴⁵
• Reduced blood flow to the brain, especially in subcortical areas, temporal and parietal areas^4,5

Along with these features, there’s an increased mortality rate due to the increased likelihood of strokes and cerebrovascular damage.⁶

Cognitive decline

Cognitive decline is accelerated due to the increased ischemic injuries, which cause increased neuronal atrophy.^4,5,11 It is also increased by the propagation of the neurofibrillary tangles and amyloid plaques and leads to further dysfunction and progression along the stages.^2,8,9

Due to the unique nature of VD, the specific areas of cognitive decline are individual to the patient. Commonly vascular areas that deal with attention, information processing, and executive function. Functions in other areas are very variable, but there is prominent depression and apathy.⁴

The cognitive decline seen in AD goes from issues in areas associated with:¹²

• Memory, short and long
• Mobility – Gait disorder
• Word finding
• Vision/spatial – Focal motor
• Reasoning/Judgement
• Confusion and depression

These issues worsen as the disease progresses, heightened by increased infarctions along with issues attributed to:¹²

• Language
• Reasoning
• Conscious thought
• Sounds and smells
• Recognition of people and places

By the end of the patient’s life, they are unable to communicate and extremely dependent. Their physical issues have spread, and they often are bedridden as their body shuts down all cognitive functions.¹²

Less common mixed dementia¹⁰

In less common mixed dementias such as Alzheimer’s and Lewy Body Dementia, there is a combination of symptoms and increased atrophy in specified areas, however, it is more restricted and predictable.

Issues arise in hallucinations, movement, executive function and cognition, sleep and alertness, along with a marked increase in agitation and anxiety. These symptoms are typical of one and as the disease progresses, the pathologies intersect and present themselves as atrophy spreads.

Other types are possible but do not appear often, such as frontotemporal dementia (FTD). Clinical aspects are typical of having FTD and other dementia.

Conclusion

Mixed dementia is commonly AD and VD, with the potential to be other dementia types. AD and VD are interlinked with each other, with possibilities for either causing the other.

Clinical AD is much more prevalent when it is accompanied by cerebrovascular issues. Cerebrovascular issues can both increase AD pathology and be caused by AD pathology. Issues such as infarcts and strokes that cause damage to the brain through the vascular system cause atrophy and cellular death/degeneration, which accumulates in both small and large quantities. Increased infarcts and damage cause further dysfunction and increase the damage. However, this damage is not patterned and can affect a variety of areas. 

AD propagates throughout the brain in a usually typical manner and is boosted by the increased damage caused by VD. The issues caused by AD are related to memory and reasoning, and the symptoms increase as dementia propagates throughout the brain. Damage to the brain speeds up the propagation and reduces life expectancy.

Other forms of mixed dementia are much less common. These dementias appear to have little connection to each other, and both are usually sporadic. The associated symptoms are more easily tracked and typical of both dementias, with increased atrophy as degeneration occurs independently in various areas.