Alzheimer’s disease (AD) is a degenerative disease of the central nervous system that occurs in old age and pre-mature aging and is the most common type of dementia in old age. It has a clinically insidious onset and presents with persistent deterioration in memory and cognitive function, progressive decline in activities of daily living, and may be accompanied by a variety of psychiatric symptoms and behavioral disturbances. Its etiology and pathogenesis remain unclear. The pathology is characterized by neuroinflammatory plaques, neurogenic fiber tangles, neuronal loss and amyloid angiopathy.
I. Pathogenesis of Alzheimer’s disease The exact pathogenesis of AD is still unclear and is thought to be the result of a combination of aging, genetic and environmental factors. There are several theories, among which the amyloid cascade hypothesis is the most influential one.
The amyloid cascade hypothesis suggests that the deposition of Aβ in the brain is central to the pathological changes in AD and can trigger a series of pathological processes that further promote Aβ deposition, thus forming a cascade amplification response.
Aβ is a normal product in the brain, formed by the hydrolysis of amyloid precursor protein (APP) by β-secretase and γ-secretase. three main types of Aβ are Aβ1-40, Aβ1-42 and Aβ1-43. Aβ42/43 is a β-sheet structure, hydrophobic, easily deposited and neurotoxic. Normally, 90% are Aβ40 and only a small amount of Aβ42/43. Due to genetic and other factors (such as APP gene, progerin 1 gene, progerin 2 gene mutation, etc.), the Aβ42/Aβ40 ratio is imbalanced and Aβ42/43 is increased in the brain of AD patients. The increased Aβ42/43 is deposited in the brain to form the core of senile plaques, which can activate microglia and trigger inflammatory reactions; it can damage mitochondria causing impaired energy metabolism and excessive oxygen radical generation, leading to oxidative stress damage; it can activate apoptotic pathways and mediate apoptosis; it can also promote abnormal tau protein phosphorylation by activating protein kinases; Aβ can also damage cholinergic neurons and cause acetylcholine system disorders. cause lesions in the acetylcholine system. These pathological changes can in turn promote increased Aβ production and abnormal deposition, resulting in a positive feedback cascade amplification effect, which ultimately leads to neuronal reduction and transmitter abnormalities, triggering clinical cognitive and behavioral symptoms. Some studies found that amyloid plaques appear before neuronal tangles and neuronal loss, but other studies found that AD pathological changes first appear in the internal olfactory region, where neuronal tangles appear in the absence of Aβ deposition.
The tau protein is a microtubule-associated protein that binds to microtubules to maintain the stability of the cytoskeleton. tau protein is abnormally hyperphosphorylated in the brain of AD patients, and the hyperphosphorylated tau protein aggregates to form double-stranded helical filaments, forming the main component of neurogenic fiber tangles and producing neurotoxicity. On the other hand, the reduction of normal tau protein leads to microtubule collapse, which aborts or disrupts axoplasmic transport, leading to axonal degeneration and neuronal death. However, it is uncertain whether tau protein phosphorylation is the initiating link of AD pathological changes or secondary to Aβ abnormalities.
3. Other factors and hypotheses Regarding the pathogenesis of AD, there are other hypotheses, such as genetic hypothesis, oxidative stress hypothesis, microcirculatory disorder hypothesis, cholinergic hypothesis, etc. However, all these factors are related to Aβ, or lead to increased Aβ, or participate in Aβ cascade reaction, which support the amyloid cascade hypothesis from different aspects.
(1) Genetic hypothesis Based on the age of onset, AD can be divided into early-onset AD (<65 years old) (early-onset Alzheimer's disease, EOAD) and late-onset AD (≥65 years old) (late-onset Alzheimer's disease, LOAD). The two types of AD are familial Alzheimer's disease (FAD) and sporadic Alzheimer's disease (SAD), which can be classified according to the presence or absence of family history. FAD is mostly early-onset, accounting for about 10% of all AD, and is autosomal dominant. Three mutations have been identified that cause FAD: APP on chromosome 21, presenilin 1 (PS1) on chromosome 14, and presenilin 2 (PS2) on chromosome 1. Apolipoprotein E (ApoE) ε4 genotype (ApoEε4) is a predisposition gene for late onset familial AD and disseminated AD. ApoE protein is an important apolipoprotein component of plasma lipoproteins, and ApoE4 can inhibit the clearance of Aβ by astrocytes and neurons. It can be seen that genetic factors promote the development of AD by affecting the production or clearance of Aβ. (2) Neurotransmitter hypothesis There are abnormalities of various neurotransmitters in the brain of AD patients, such as excitatory amino acids, norepinephrine, 5-hydroxytryptamine and dopamine, but the cholinergic system is the most severely impaired and is most closely related to cognitive and behavioral impairment of patients. Cholinergic neurons in the brain are mainly located in the Meynert nucleus and medial septal nucleus of the basal forebrain, projecting to the hippocampus and cerebral cortex. Studies have shown that cholinergic nerve cells in the basal forebrain of AD patients are significantly absent, choline acetyltransferase is reduced, and acetylcholine synthesis and release are significantly reduced, the extent of which correlates with cognitive testing. The drugs currently used to treat AD also target the acetylcholine system to improve the patient’s symptoms. Therefore, the low activity of the cholinergic system may be an important part of the pathogenesis of AD. (3) Other hypotheses include oxidative stress, immunoinflammatory mechanisms, microcirculatory disorders, neurotransmitter abnormalities, etc. However, their roles in the pathophysiological process of AD are still unknown and are mostly related to abnormal Aβ deposition, which may fall under the category of amyloid cascade hypothesis. The pathophysiological changes of Alzheimer’s disease are mainly brain atrophy; microscopically, neuroinflammatory spots, neurogenic fiber tangles, neuronal reduction, cerebral amyloid angiopathy, and other major pathological changes are seen in AD patients. 1. Gross pathology The main pathology is brain atrophy. Patients have narrowing of the gyrus, widening of the sulcus, and enlargement of the ventricles. Brain atrophy begins in the internal olfactory cortex and gradually extends to the hippocampus, internal temporal lobe, and frontoparietal region as the disease progresses, while primary sensory and motor cortex (occipital visual cortex, precentral gyrus and postcentral gyrus) are relatively preserved. Microscopic pathology The microscopic pathological changes are mainly neuroinflammatory spots, neurogenic fiber tangles, neuronal reduction, amyloid vascular degeneration, in addition, hippocampal neuronal granular vacuolar degeneration, glial cell hyperplasia, neural felt filaments, etc. (1) Neuroinflammatory plaque, also known as senile plaque (SP), is one of the major lesions in AD. The SP can be divided into three stages: primitive or early plaque, classic or mature plaque, and burned-out or dense plaque, which may be related to the development of AD from early to late stages. The distribution of SP in the brain is not uniform and varies greatly between individuals, but generally the hippocampus, temporal lobe and frontal lobe are the areas of concentration. (2) Neurofibrillary tangles (NFTs) are another major pathological change in AD, located in the cytoplasm of neurons, and their main component is abnormally phosphorylated microtubule-associated tau protein. Under normal conditions, tau proteins bind to microtubules to maintain the stability of the cytoskeleton; in AD brain, tau proteins are abnormally phosphorylated, with fewer binding sites for microtubules, and the abnormally phosphorylated tau proteins bind themselves to form double-stranded helical filaments, which eventually lead to the formation of NFTs. and temporoparietal joint cortex. Their distribution and density correlate with the degree of dementia. (3) Various pathological processes eventually lead to the loss of neurons in the AD brain, especially in the hippocampus and basal forebrain, where cholinergic neurons are severely lost, with up to 47% of neurons missing. As the disease progresses, severe neuronal loss also occurs in the temporal and frontal cortex, with less involvement in the primary sensory and motor cortex. (4) Amyloid cerebral vasculopathy is common in AD patients, with an incidence close to 90%, and the amyloid material in the vessels is the same protein as Aβ in neuroinflammatory plaques and other deposits, and the lesions are mainly located in the soft meninges and cerebral cortex.