What is the mechanism of developing Alzheimer's disease?

From the Guidelines

Alzheimer's disease develops through a complex interplay of genetic, environmental, and lifestyle factors, primarily involving the accumulation of abnormal proteins in the brain, specifically beta-amyloid plaques and tau tangles, as described in the most recent study 1. The primary mechanism involves the accumulation of these abnormal proteins, which clump together between neurons, forming plaques that disrupt cell function, while tau proteins form tangles inside neurons, blocking nutrient transport and causing cell death. These processes lead to inflammation, oxidative stress, and disruption of neurotransmitters like acetylcholine, which is crucial for memory and learning. As the disease progresses, neurons lose connections and eventually die, causing brain tissue to shrink significantly. This neurodegeneration typically begins in the hippocampus, the brain's memory center, before spreading to other regions. Risk factors include aging, family history, and the APOE-e4 gene variant, which increases amyloid buildup, as noted in earlier studies 1. Vascular health issues like high blood pressure, diabetes, and obesity also contribute to disease development by reducing blood flow to the brain and increasing inflammation. Currently, there is no cure for Alzheimer's, though medications like cholinesterase inhibitors and memantine can temporarily improve symptoms by addressing neurotransmitter imbalances. The most recent study 1 highlights the importance of early diagnosis and treatment, with the advent of disease-modifying treatments that slow the clinical progression of AD by acting on the underlying pathophysiological mechanisms. Key points to consider in the development of Alzheimer's disease include:

• The accumulation of beta-amyloid plaques and tau tangles in the brain
• The disruption of cell function and nutrient transport
• The inflammation, oxidative stress, and disruption of neurotransmitters
• The risk factors, including aging, family history, and vascular health issues
• The importance of early diagnosis and treatment, as emphasized in the most recent study 1.

From the FDA Drug Label

Although the etiology of cognitive impairment in Alzheimer's disease (AD) is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer's disease The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaques (a neuropathological hallmark of Alzheimer's disease). Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer’s disease

The mechanism of developing Alzheimer's disease is not fully understood, but it is believed to involve:

• Degeneration of acetylcholine-producing neurons in the brain, which is correlated with the degree of cognitive impairment and density of amyloid plaques
• Persistent activation of NMDA receptors by glutamate, which may contribute to the symptomatology of Alzheimer's disease There is no evidence that these mechanisms are the sole cause of Alzheimer's disease, and the exact mechanism is still unknown 2 3

From the Research

Mechanism of Developing Alzheimer's Disease

The mechanism of developing Alzheimer's disease is a complex process involving multiple factors and pathways. Some of the key factors include:

• Accumulation of amyloid-beta (Aβ) peptides in the brain, which is thought to play a central role in the pathogenesis of Alzheimer's disease 4, 5
• Hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles 4, 6
• Disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP) 4
• Genetic, age-related, and environmental factors that contribute to the development of Alzheimer's disease 4, 7
• Mitochondrial dysfunction and synaptic damage, which are also thought to play a role in the pathogenesis of Alzheimer's disease 5

Pathological Mechanisms

The pathological mechanisms of Alzheimer's disease involve the formation of neuritic plaques and neurofibrillary tangles, which are composed of Aβ peptides and hyperphosphorylated tau protein, respectively 4, 6. These pathological changes lead to neuronal dysfunction and death, resulting in the cognitive and functional impairments characteristic of Alzheimer's disease.

Biomarkers

Biomarkers such as Aβ deposition, tau pathology, and neurodegeneration/neuronal damage (AT(N) biomarkers) are widely validated core humoral markers for the diagnosis of Alzheimer's disease 6. These biomarkers can help diagnose the presence or absence of specific diseases and their pathological processes, and are crucial for the prevention and therapy of Alzheimer's disease.

Disease Progression

Alzheimer's disease progresses through several clinical phases, including:

• Pre-symptomatic (or pre-clinical) phase, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level 4
• Pre-dementia phase, in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology 4
• Clinically defined dementia phase, in which cognitive and functional impairment is severe enough to surmount the dementia threshold 4