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Dementia is a complex and multifaceted syndrome characterized by a significant decline in cognitive functions, surpassing what might be expected from normal aging. This decline affects several cognitive domains, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgment. Dementia is not a single disease but a collective term for various neurodegenerative disorders that share the common feature of progressive cognitive deterioration. The global burden of dementia is substantial and growing, with the World Health Organization estimating that around 50 million people worldwide were living with dementia in 2019, a number expected to triple by 2050 due to population aging [1].

The most prevalent form of dementia is Alzheimer's Disease (AD), accounting for approximately 60-80% of cases. Alzheimer's disease is characterized by two primary pathological hallmarks: Amyloid plaques and neurofibrillary tangles. These features are accompanied by significant neuronal loss and brain atrophy, particularly in the hippocampus and cortex, areas crucial for memory and cognitive functions. The amyloid cascade hypothesis, which posits that the accumulation of Amyloid-Beta (Aβ) plaques triggers a cascade of neurodegenerative events, including tau pathology and neuronal death, has been central to understanding AD pathogenesis.

Another common type of dementia is vascular dementia, which results from conditions that impede blood flow to the brain, leading to ischemic and hemorrhagic damage. Vascular dementia often coexists with Alzheimer's disease, a condition known as mixed dementia. The primary pathological features of vascular dementia include lacunar infarcts, large vessel infarctions, microbleeds and white matter lesions, all of which result from cerebrovascular disease. Risk factors for vascular dementia include hypertension, diabetes, smoking and hypercholesterolemia.

Lewy Body Dementia (LBD) encompasses Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). LBD is the second most common form of degenerative dementia after Alzheimer's disease. The defining pathological feature of LBD is the presence of Lewy bodies-intracytoplasmic inclusions composed of alpha-synuclein protein-in cortical and subcortical neurons. Clinically, LBD is characterized by fluctuating cognitive impairment, visual hallucinations and Parkinsonism. The pathogenesis of LBD involves the aggregation and spread of alpha-synuclein pathology, with genetic and environmental factors contributing to its development [2].

Frontotemporal Dementia (FTD) is a heterogeneous group of disorders characterized by degeneration of the frontal and temporal lobes. It is the most common form of dementia in individuals under 60 years of age. FTD includes several pathological subtypes, such as tauopathies (including Pick's disease and corticobasal degeneration), TDP-43 proteinopathies and FUS proteinopathies. These subtypes are defined by the specific proteins that accumulate abnormally within neurons. FTD typically presents with prominent behavioral changes, language dysfunction and executive dysfunction, reflecting the brain regions most affected.

Beyond these more common forms of dementia, there are several less prevalent but equally significant types. Huntington's disease, for example, is an autosomal dominant disorder caused by a mutation in the HTT gene, leading to abnormal expansion of CAG repeats and resulting in the accumulation of mutant Huntingtin protein. This protein accumulation causes neuronal loss in the striatum and cortex, leading to a combination of motor, cognitive and psychiatric symptoms.

Creutzfeldt-Jakob Disease (CJD) is a rare but fatal prion disease characterized by the accumulation of misfolded prion protein (PrP^Sc). The pathological hallmark of CJD is spongiform degeneration, gliosis and neuronal loss, resulting in rapidly progressive dementia and motor dysfunction. CJD can occur sporadically, be inherited or acquired through infection.

Despite the diversity in the etiology and pathology of these various forms of dementia, there are several common mechanisms that underpin their development and progression. Protein misfolding and aggregation are central themes across many dementias, whether it is amyloid-beta in Alzheimer's disease, tau in tauopathies, alphasynuclein in Lewy body dementia or prions in CJD. These misfolded proteins disrupt cellular function, leading to neuronal dysfunction and death [3].

Neuroinflammation is another common feature, with activated microglia and astrocytes releasing cytokines and other inflammatory mediators that contribute to neuronal injury. Chronic neuroinflammation can create a vicious cycle of neuronal damage and immune activation, exacerbating the progression of neurodegeneration.

Synaptic dysfunction and loss are critical events in the progression of dementia, as synapses are essential for neuronal communication. The loss of synapses correlates strongly with cognitive decline, particularly in Alzheimer's disease. Mitochondrial dysfunction and oxidative stress are also implicated in several dementias. Mitochondria are vital for energy production and cellular homeostasis and their impairment can lead to increased production of reactive oxygen species, further damaging neuronal cells.

Advancements in diagnostic techniques have significantly improved our ability to detect and differentiate between various forms of dementia. Neuroimaging techniques, such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) scans, are invaluable tools for assessing structural brain changes and detecting specific pathological features like amyloid and tau deposits. Cerebrospinal Fluid (CSF) biomarkers, including Aβ42, total tau and phosphorylated tau, support the diagnosis of Alzheimer's disease by indicating the presence of its pathological hallmarks. Genetic testing can identify mutations associated with hereditary forms of dementia, such as mutations in the APP, PSEN1 and PSEN2 genes in Alzheimer's disease or the MAPT, GRN and C9orf72 genes in frontotemporal dementia.

Currently, treatments for dementia primarily focus on symptomatic relief, aiming to improve cognitive function and quality of life. Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and NMDA receptor antagonists (memantine) are commonly used in Alzheimer's disease. However, these treatments do not halt disease progression. Research into disease-modifying therapies is ongoing, with efforts focused on targeting the underlying pathology. For instance, in Alzheimer's disease, therapies targeting amyloid-beta (e.g., monoclonal antibodies like aducanumab) and tau (e.g., tau aggregation inhibitors) are under investigation [4].

Preventive strategies are also essential in reducing the risk of dementia. Lifestyle modifications, including physical exercise, cognitive stimulation and a healthy diet, are recommended. Managing cardiovascular risk factors, such as hypertension and diabetes, is particularly important in preventing vascular dementia.

The dementia encompasses a range of neurodegenerative disorders with diverse etiologies and pathologies. Understanding the distinct and shared mechanisms of these disorders is crucial for developing targeted treatments and improving patient outcomes. Continued research into the pathology of dementia, combined with advancements in diagnostic techniques and preventive strategies, holds promise for mitigating the impact of this growing global health challenge. This review delves into the pathology of major forms of dementia, including Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia and other less common types, to provide a comprehensive understanding of these complex disorders [5].

Alzheimer's disease

Alzheimer's disease is characterized by two primary pathological features: Amyloid plaques and neurofibrillary tangles [6].

Amyloid plaques: Amyloid plaques are extracellular deposits primarily composed of Amyloid-Beta (Aβ) peptides. These peptides are derived from the Amyloid Precursor Protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase enzymes. The accumulation of Aβ in the brain is hypothesized to initiate a cascade of events leading to neuronal dysfunction and death.

Neurofibrillary tangles: Neurofibrillary tangles are intracellular aggregates composed of hyperphosphorylated tau protein. Tau is a microtubule-associated protein that, when abnormally phosphorylated, forms paired helical filaments that aggregate into tangles. These tangles disrupt the normal function of neurons and contribute to cell death.

Pathogenesis: The pathogenesis of Alzheimer's disease involves a complex interplay between genetic and environmental factors. The Apolipoprotein E (APOE) ε4 allele is a significant genetic risk factor. The amyloid cascade hypothesis posits that the accumulation of Aβ plaques precedes and triggers tau pathology and neurodegeneration.

Neuroinflammation: Neuroinflammation, mediated by microglia and astrocytes, is a critical component of Alzheimer's pathology. These glial cells respond to amyloid plaques and other pathological changes by releasing pro-inflammatory cytokines, which can exacerbate neuronal damage.

Vascular dementia: Vascular dementia results from conditions that impede blood flow to the brain, leading to ischemic and hemorrhagic damage. Common pathological features include:

• Lacunar infarcts: Small, deep cerebral infarcts caused by occlusion of penetrating arteries.
• Large vessel infarctions: Due to major stroke events.
• Microbleeds: Resulting from small vessel disease.
• White matter lesions: Often associated with chronic hypertension and small vessel disease.

Pathogenesis: The pathogenesis of vascular dementia is primarily linked to cerebrovascular disease. Risk factors include hypertension, diabetes, smoking and hypercholesterolemia. These conditions lead to atherosclerosis and small vessel disease, causing cumulative damage to the brain's vascular network.

Neuroinflammation and blood-brain barrier dysfunction: Similar to Alzheimer's disease, neuroinflammation plays a role in vascular dementia. Endothelial dysfunction and breakdown of the Blood-Brain Barrier (BBB) allow entry of toxic substances into the brain, triggering inflammatory responses that further damage neural tissue.

Lewy body dementia: Lewy Body Dementia (LBD) encompasses Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). The primary pathological feature is the presence of Lewy bodies, which are intracytoplasmic inclusions composed of alphasynuclein protein.

Lewy bodies: Lewy bodies are found in cortical and subcortical neurons. The exact mechanism by which alpha-synuclein aggregates contribute to neurodegeneration is not fully understood, but their presence is associated with disrupted neuronal function and cell death [7].

Pathogenesis: The pathogenesis of LBD involves the aggregation and spread of alpha-synuclein pathology. Genetic factors, such as mutations in the SNCA gene encoding alpha-synuclein and environmental factors, such as exposure to pesticides, have been implicated in disease development.

Clinical correlates: Clinically, LBD is characterized by fluctuating cognitive impairment, visual hallucinations and Parkinsonism. The overlap with Parkinson's disease and Alzheimer's disease often complicates diagnosis.

Frontotemporal dementia: Frontotemporal Dementia (FTD) is a heterogeneous group of disorders characterized by degeneration of the frontal and temporal lobes. The major pathological subtypes include:

• Tauopathies: Including Pick's disease and corticobasal degeneration, characterized by abnormal tau protein deposition.
• TDP-43 proteinopathies: Characterized by deposits of TAR DNA-binding protein 43 (TDP-43).
• FUS proteinopathies: Involving Fused in Sarcoma (FUS) protein aggregates.

Pathogenesis: The pathogenesis of FTD involves genetic mutations in several genes, such as MAPT (encoding tau), GRN (encoding progranulin) and C9orf72. These mutations lead to protein misfolding and aggregation, disrupting normal cellular functions.

Clinical presentation: FTD typically presents with behavioral changes, language dysfunction and executive dysfunction. The specific clinical syndrome depends on the brain regions affected by the pathological process [8].

Other dementias

Huntington's disease: Huntington's disease is an autosomal dominant disorder caused by a mutation in the HTT gene, leading to abnormal expansion of CAG repeats and resulting in mutant Huntingtin protein accumulation. The pathology includes neuronal loss in the striatum and cortex, leading to motor, cognitive and psychiatric symptoms (Figure 1) [9].

 

Figure 1: Physical symptoms, mental and emotional challenges of Huntington’s disease.

Creutzfeldt-Jakob disease: Creutzfeldt-Jakob Disease (CJD) is a prion disease characterized by the accumulation of misfolded prion protein (PrP^Sc). The pathological hallmark is spongiform degeneration, gliosis and neuronal loss, leading to rapidly progressive dementia and motor dysfunction. The CJD is classified into two types such as Sporadic CJD and Variant CJD (Table 1) [10].

Table 1: Sporadiac and variant Creutzfeldt-Jakob Disease (CJD).

Common mechanisms across dementias

Protein misfolding and aggregation: A central theme in dementia pathology is the misfolding and aggregation of proteins, whether it is amyloid-beta in Alzheimer's, tau in tauopathies, alpha-synuclein in Lewy body dementia or prions in CJD. These aggregated proteins disrupt cellular function and trigger neurodegenerative processes [11].

Neuroinflammation: Neuroinflammation is a common pathological feature across various dementias. Activated microglia and astrocytes release cytokines and other inflammatory mediators, contributing to neuronal injury. Chronic neuroinflammation can perpetuate a cycle of neuronal damage and immune activation.

Synaptic dysfunction and loss: Synaptic dysfunction and loss are critical events in the progression of dementia. Synapses are crucial for neuronal communication and their disruption leads to cognitive deficits. In Alzheimer's disease, synaptic loss correlates strongly with cognitive decline [12].

Mitochondrial dysfunction: Mitochondrial dysfunction and oxidative stress are implicated in the pathology of several dementias. Mitochondria are essential for energy production and cellular homeostasis and their impairment can lead to increased production of reactive oxygen species, further damaging neuronal cells.

Diagnosis and biomarkers

Neuroimaging: Neuroimaging techniques, such as MRI and PET scans, are invaluable in diagnosing dementia and assessing disease progression. MRI can reveal structural brain changes, while PET imaging can detect amyloid and tau pathology in Alzheimer's disease.

Cerebrospinal fluid biomarkers: Cerebrospinal Fluid (CSF) biomarkers, including Aβ42, total tau and phosphorylated tau, are used to support the diagnosis of Alzheimer's disease. Reductions in Aβ42 and increases in tau proteins are indicative of AD pathology.

Genetic testing: Genetic testing can identify mutations associated with hereditary forms of dementia, such as mutations in the APP, PSEN1 and PSEN2 genes in Alzheimer's disease or the MAPT, GRN and C9orf72 genes in frontotemporal dementia [13].

Therapeutic approaches

Symptomatic treatments: Current treatments for dementia are primarily symptomatic, aiming to improve cognitive function and quality of life. Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and NMDA receptor antagonists (memantine) are commonly used in Alzheimer's disease.

Disease-modifying therapies: Efforts to develop diseasemodifying therapies focus on targeting the underlying pathology. In Alzheimer's disease, therapies targeting amyloid-beta (e.g., monoclonal antibodies like aducanumab) and tau (e.g., tau aggregation inhibitors) are under investigation [14].

Lifestyle and preventive strategies: Lifestyle modifications, including physical exercise, cognitive stimulation and a healthy diet, are recommended to reduce the risk of dementia. Managing cardiovascular risk factors, such as hypertension and diabetes, is particularly important in preventing vascular dementia [15].

The pathology of dementia is intricate, involving various neurodegenerative processes that challenge the development of effective disease-modifying therapies. Key pathological features, such as protein misfolding, neuro inflammation and synaptic dysfunction, are common across many forms of dementia and represent critical targets for future research. Continued exploration of these mechanisms is essential for creating targeted treatments that address the specific needs of each dementia type. Early diagnosis and timely intervention, supported by advancements in neuroimaging and biomarker identification, are crucial for improving patient outcomes. Additionally, preventive strategies focusing on lifestyle modifications and management of cardiovascular risk factors hold promise in reducing the incidence and impact of dementia. Ultimately, a multifaceted approach combining early detection, preventive measures and innovative research is necessary to mitigate the burden of dementia on individuals and society.

We thank our colleagues for their insightful feedback and support. Special thanks to Dr. Smith for her valuable contributions.

The authors declare no conflicts of interest.

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