Introduction

What is dementia

Dementia is a neurological condition characterised by acquired cognitive decline, severe enough to interfere with daily functioning, especially in social and occupational domains.¹ Dementia can develop due to several different factors that can be both genetic or sporadic. These factors ultimately result in brain atrophy, meaning the loss of neurons and neuronal connections, leading to cognitive decline that gradually worsens throughout the year. 

Dementia can result from the dysfunction of certain molecular pathways, leading to the accumulation of neurotoxic substances such as Amyloid-β or hyperphosphorylated Tau proteins, associated with Alzheimer’s, and Parkinson’s disease, respectively. Another cause of brain atrophy can be abnormalities of the brain vasculature, where blood supply is prevented to certain parts of the brain tissue, thus some form of vascular dementia develops.¹

What is mixed dementia?

Patients might develop two types of dementia simultaneously, which is referred to as mixed dementia. These patients can experience a mixture of symptoms that are associated with the two conditions, as well as the exacerbation of overlapping symptoms. The associated symptoms vary not just based on the dementia types, but also based on the brain regions affected.² It is most prevalent in older age groups, typically affecting people 75 years and above.

The biggest concern regarding these mixed conditions is that it is easy to miss one of the neuropathies during the diagnosis and focus on the other. That is why thorough clinical testing is required to ensure appropriate disease management for all components of this condition.² Early detection is important as these patients might only present a mild cognitive impairment at first, this can develop into dementia in as little as 5 years.^3,4

Common types of mixed dementia 

Alzheimer's disease and vascular dementia

The simultaneous development of Alzheimer’s disease (AD) and Vascular Dementia (VD) is the most prevalent form of mixed dementia. This combination is not surprising, given that Alzheimer’s disease alone accounts for over 66% of dementia cases in individuals aged over 65 years³ and some form of vascular aetiology is the second most common underlying cause behind dementia.⁴ Thus, mixed neurodegenerative and vascular pathophysiologies are common, especially at an older (>75 years) age.²

Risk factors for developing this condition include: 

• Genetic predisposition, such as mutations to the APOE4 gene, was linked to AD, or a family history of thrombosis or stroke
• In old age, dementia usually develops above 65 years of age, and mixed dementia is over 75
• High blood pressure and other cardiovascular risk factors (obesity, diabetes, smoking, high stress levels)
• Lower cognitive capacity or lack of education^3,4

The presence of this condition is characterised by: 

• The presence of Amyloid-β plaques, which are small spherical brain lesions close to axons where the Amyloid-β protein accumulates on the surface
• Neurofibrillary tangles (NFTs): Complexes formed of hyperphosphorylated tau proteins, another marker of Alzheimer’s Disease³
• Vascular damage, including white matter hyperintensities, micro-infarcts, and cerebral amyloid angiopathy, where amyloids build up in arterial walls⁴

It must also be noted that interaction between AD and vascular pathologies can exacerbate cognitive decline and increase the severity of dementia. The presence of subcortical infarcts, for example, might increase the risk of dementia by 4-fold.^2,4 These effects of the interplay between dementia subtypes highlight the importance of managing vascular risk factors in individuals with or at risk for AD.

Alzheimer's disease and lewy body dementia

The co-occurrence of Alzheimer’s Disease and Lewy Body Dementia (LBD) is probably the second most significant form of mixed dementia. While we already established the prevalence of AD, it must be also noted that LBD is present in 20-30% of all dementia cases, making it the third most common dementia subtype.⁵ LBD can be divided into 2 conditions, dementia with Lewy bodies and Parkinson’s disease dementia, which distinction is based on the locations where Lewy bodies first develop. LBD’s associated symptoms highly overlap with AD and Parkinson’s Disease, including a neurotransmitter imbalance with decreased acetylcholine signalling and up-regulation of muscarinic M1 receptors.⁵ Consequently, one might also appreciate how hard it is to diagnose this form of mixed dementia.

Signs of this condition include: 

• Amyloid-β plaques and neurofibrillary tangles: The markers of AD pathology, as already mentioned
• Lewy bodies: Specific cytoplasmic substrates containing aggregates of alpha-synuclein and ubiquitin, characteristic of LBD
• Neuronal atrophy: Mainly in certain brain areas, including the substantia nigra, locus ceruleus, and Meynert nucleus
• Neurotransmitter imbalance, including decreased acetylcholine signalling and up-regulation of muscarinic M1 receptors^5,6

The cognitive profile of mixed AD-LBD dementia can also be complex and variable, and clinical manifestation of the condition can include:

• Memory deficits: Typically more pronounced than in pure LBD, reflecting the AD component
• Executive function and visuospatial deficits: Often more severe when LBD pathology extends to the cerebral cortex
• Fluctuating cognition: A hallmark of both AD and LBD
• Visual hallucinations: More common in LBD but can be exacerbated by AD pathology
• Parkinsonism: Features like muscular rigidity, tremors, and bradykinesia may be present

It is also important to mention, that while these symptoms are usually more associated with either AD or LBD, the co-occurrence of the 2 conditions magnifies the severity of all of these characteristics.

Vascular dementia and lewy body dementia

The co-occurrence of Vascular Dementia & Lewy body dementia is also a prominent combination, given the high occurrence rate of the diseases in older generations as we already mentioned. The pathological features of this mixed dementia subtype overlap with the previous two cases, which is not surprising given the shared components. Features associated with this form of mixed dementia include: 

• Cerebrovascular damage, which can be present in the form of white matter hyperintensities, micro infarcts, and microbleeds
• Lewy bodies: Intraneuronal cytoplasmic inclusion bodies containing aggregates of alpha-synuclein
• Small vessel disease: Both amyloid and non-amyloid microangiopathy may be present^4,7

The distribution and severity of these pathologies can significantly influence the clinical presentation. The location of both vascular lesions and the Lewy bodies is an important factor which determines the clinical characteristics of each case and, thus the cognitive profile of mixed Vascular-LBD dementia can be complex and variable, with symptoms including:

• Executive dysfunction: Often prominent due to both subcortical vascular disease and LBD pathology
• Visuospatial deficits: Common in both Vascular dementia and LBD
• Fluctuating cognition: A hallmark of LBD that may be exacerbated by vascular pathology
• Visual hallucinations: More common in LBD but can be influenced by vascular lesions
• Parkinsonism: Again including rigidity, bradykinesia, and gait disturbance, which are potentially worsened by vascular lesions
• Mood and behavioural symptoms: Including apathy, depression, and anxiety

Alzheimer's disease and frontotemporal dementia

We are going to touch on the co-existence of Frontotemporal dementia (FTD) and AD in dementia patients. This mixed dementia proposes significant diagnostic challenges, while also being crucial to recognise as both underlying pathologies are common causes of early-onset dementia, easily affecting the population even below the age of 65.^3,8 FTD account for approximately 10% of dementia cases and causes the most prominent behavioural changes associated with dementia cases.⁸

The pathophysiology of this disease combination includes:

• Brain atrophy, or neuronal loss in the frontal and temporal lobes of the brain, which are areas regulating decision making, the limbic system (which is responsible for our feelings and behaviour, and processing sensory information)
• Elevated levels of tau or TDP-43, which are mainly associated with FTD
• Amyloid-β plaques, and neurofibrillary tangles (NFTs) - the hallmarks of AD pathology^3,8

The combination of FTD and AD leads to a myriad of clinical symptoms, which can include: 

• Behavioural changes or personality changes, usually leading to disengagement, apathy, loss of empathy
• Visuospatial deficits, that make movement coordination challenging
• Memory impairment, which progressively declines and affects more and more domains
• Heightened neuropsychiatric symptoms such as hallucinations
• Impaired speech and language processing⁸

During the co-occurrence of FTD and AD, almost always the behavioural variant of FTD is present, while Alzheimer’s Disease can be divided into either “typical” or “behavioural” subcategories.⁸ The variety of the clinical representation of this mixed dementia between patients develops from the unique blend of clinical aspects associated with the underlying components. The usual characteristics of these dementia subtypes can be seen in the figure below. 

Diagnosis and management

Diagnostic tools

Diagnosis can consist of the following: 

• Clinical history of the patient including, the family history of any neurodegeneration, and in some cases of vascular disease as well as the monitoring of the patient’s cognitive decline and behavioural changes
• Neuroimaging such as MRI or PET scan, to visualise lesions, brain atrophy, vascular damage, metabolic impairments, and even amyloid accumulation
• Analysis of the cerebrospinal fluid (CSF) to look at serum levels of proteins indicated in disease pathology. For instance, decreased Aβ42 with increased tau levels indicate AD, while decreased Aβ42 but normal tau levels usually indicate vascular pathology or Lewy body disease
• Cognitive assessment via tests specifically engineered for this purpose, usually covering multiple cognitive domains from visuospatial to social nature
• Behavioural assessment, looking at changes in personality and the usual behavioural patterns of patients^3,4,5,6,8

Management

While there is currently no cure for dementia, a combination of therapeutic approaches can slow down disease progression and make living with this condition easier both for the patients and their carers. This is usually achieved through pharmacological approaches, for instance, to elevate acetylcholine levels in AD and LBD, to manage hypertension in vascular dementia, or to regulate mood changes associated with the disease. Non-pharmacological therapies involve cognitive stimulation therapy, occupational therapy to exercise the brain, and speech and language therapy in certain cases. Regular exercise and a healthy diet are also important, together with the elimination of other risk factors of dementia such as high stress levels or smoking.

Summary

Mixed dementia is a complex condition characterized by the co-occurrence of two or more types of dementia pathologies in a single patient. This article has explored the most common forms of mixed dementia, including:

• Alzheimer's disease and vascular dementia: The most prevalent form, combining amyloid plaques, neurofibrillary tangles, and vascular damage
• Alzheimer's disease and lewy body dementia: Featuring AD pathology alongside alpha-synuclein aggregates, leading to a complex cognitive and behavioural profile
• Vascular dementia and lewy body dementia: Characterised by cerebrovascular damage and Lewy body formation, resulting in a mixture of cognitive, motor, and behavioural symptoms
• Alzheimer's disease and frontotemporal dementia: A challenging combination that can present with significant changes in behaviour and cognitive decline

Each mixed dementia subtype presents a unique diagnostic challenge due to the overlapping symptoms. For accurate diagnosis, a comprehensive approach of assessing detailed clinical history, neuroimaging, cerebrospinal fluid analysis, and cognitive assessments must be performed. Management strategies involve both pharmacological and non-pharmacological interventions which aim to address the specific combination of symptoms present in each individual.

Understanding mixed dementia is crucial, as it allows for more accurate management by personalising treatment plans. As the population ages, the prevalence of mixed dementia is also likely to increase and, thus continuing related research and improving the diagnostic and treatment approaches is crucial.