ALZHEIMER'S DISEASE
Alzheimer's is the most common form of dementia. Dementia is a general term for memory loss and loss of other cognitive abilities. Alzheimer's is a associated with a progressive loss of brain tissue linked to the abnormal accumulation of specific proteins.
IMPACT
There are ~7 million people in the USA with Alzheimer’s, projected to increase to 13.8 by 2060. Globally, Alzheimer's is estimated at 30-35 million people with a projected increase to 152 million by 2050. Annual health care costs in the USA are over $360 billion, estimated to reach $1 trillion by 2050. Current Alzheimer's treatments are limited to symptomatic relief or antibodies targeting amyloid-beta peptide. Given the state of therapeutic options, a therapeutic approach that is not redundant with current medications presents a significant benefit to patients and care givers.
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Alzheimer’s Association. 2024 Alzheimer’s Disease Facts and Figures. Alzheimer's Dement 2024;20(5).
PROGRESSIVE
Alzheimer's progresses across a continuum. Initially, there is a preclinical phase lasting for ~15-20 years, associated with increasing amyloid-beta peptide (Aβ) accumulation within the brain but without cognitive impairment. A prodromal stage marks the early symptoms, characterized by mild cognitive impairment (MCI) and can last 3-6 years. The dementia stage generally lasts 7-10 years. The dementia stage can be further categorized into mild, moderate, and severe Alzheimer's, based on the level of cognitive impairment. Over time the capacity to speak and perform simple tasks are lost, culminating in immobility and death.
PATHOLOGY
The brains of individuals with Alzheimer's exhibit two cardinal histopathological features, deposits of amyloid-beta peptide (Aβ) in the form of extracellular plaques and intra-neuronal neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated tau protein.
Aβ is chemically "sticky" and gradually builds up into plaques. Aβ accumulates early within the brain, with genetic data supporting an Aβ-Alzheimer's causal relationship. The Aβ-cascade hypothesis proposes that the deposition of Aβ in the brain is the initiating step of Alzheimer's pathology, with subsequent tau deposition and neuronal loss. Soluble Aβ-oligmers are highly toxic forms of Aβ, which precede the formation of Aβ plaques.
NFTs are abnormal accumulations of a protein called tau that collect in neurons. In healthy neurons, tau binds to and stabilizes microtubules in neurons. However, in Alzheimer’s abnormal biochemical changes cause tau to detach from microtubules, forming threads that form tangles inside neurons. These tangles inhibit the neuron’s transport system and contribute to neuron damage and death.
As neurons stop working properly, connections among networks of neurons break down. Brain regions shrink, particularly those involved in memory (cortex and hippocampus). Alzheimer's patients may also exhibit a host of mental health and neuropsychiatric symptoms (apathy, anxiety, fear, agitation, irritability, mood swings, changes in sleeping habits, and psychosis), as well as increased seizure activity. Research suggests that chronic inflammation and vascular damage further contribute to the neuron loss and brain shrinkage.