From the Guidelines
Alzheimer's disease is characterized by progressive neurodegeneration resulting from the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, with the most recent evidence suggesting that the pathophysiology begins with abnormal processing of amyloid precursor protein, leading to beta-amyloid peptide formation that aggregates into toxic plaques outside neurons, as supported by the 2024 study published in Alzheimer's and Dementia 1.
Pathophysiology of Alzheimer's Disease
The pathophysiology of Alzheimer's disease is complex and involves multiple factors, including:
- Abnormal processing of amyloid precursor protein, leading to beta-amyloid peptide formation that aggregates into toxic plaques outside neurons
- Hyperphosphorylation of tau protein, causing it to form neurofibrillary tangles, disrupting cellular transport systems
- Chronic inflammation, oxidative stress, and synaptic dysfunction, ultimately leading to neuronal death
- Disruption of neurotransmitter systems, particularly acetylcholine, contributing to cognitive decline
Key Factors Contributing to Disease Progression
Key factors that contribute to disease progression include:
- Genetic factors, such as the APOE ε4 allele, which increase risk
- Vascular damage, metabolic dysfunction, and reduced brain glucose metabolism, which further contribute to disease progression
- Environmental factors, such as head trauma, that may influence the progression of the pathophysiological sequence or the clinical expression of the pathology
Recent Evidence and Recommendations
Recent evidence from the 2024 study published in Molecular Neurodegeneration 1 highlights the importance of blood-based biomarkers for Alzheimer's disease, including the Aβ42/40 ratio for amyloid pathology, phosphorylated tau (p-tau) for tau pathology, and neurofilament light-chain (NfL) and brain-derived tau for neurodegeneration/axonal injury. The use of these biomarkers has the potential to revolutionize the diagnosis and treatment of Alzheimer's disease, enabling earlier intervention and more effective management of the disease.
From the Research
Pathophysiology of Alzheimer's Disease
The pathophysiology of Alzheimer's disease (AD) is a complex and multifactorial process, involving various molecular and cellular mechanisms.
- The accumulation of amyloid beta plaques and tau protein tangles in the brain are hallmark features of AD, contributing to neuroinflammation and synaptic dysfunction 2, 3.
- Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, play a significant role in increasing the risk of acquiring AD 2.
- The abnormal accumulation of amyloid-b (Ab) and neurofibrillary tangles (NFTs) containing phosphorylated tau proteins are the main histopathological features of AD, with synaptic damage and loss being earlier events than amyloid plaques and NFTs 3.
- Soluble oligomeric Aß initiates the progression of AD, and tau mediates the subsequent synaptic impairments at an early stage of AD, with Aß-triggered synaptic deficits being dependent on tau 3.
Molecular Mechanisms
- Recent research has shown that tau and amyloid beta (Aβ) have crucial physiological roles, including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection 4.
- Aβ is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood-brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor 4.
- The characteristic features of AD include the appearance of extracellular amyloid-beta (Aβ) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner 5.
Cellular Mechanisms
- Excitotoxicity results from continuous, low-level activation of N-methyl-D-aspartate (NMDA) receptors, contributing to premature synaptotoxicity, changes in neurotransmitter expression, neurophils loss, accumulation of amyloid β-protein deposits, and neuronal loss and brain atrophy 5.
- Glial contributions to various molecular and cellular pathways in AD pathogenesis, including glial dysfunction, have been implicated in the disease process 6.
- Other critical factors that may affect AD pathogenesis include genetics, aging, variables related to environment, lifestyle habits, and the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota 6.