Dementia is a severe loss of general cognitive ability. The most common cause of dementia is Alzheimer's disease. Alzheimer's disease is very rare before the age of 60, but by 85 it affects one in three. To give you some idea, here are the typical characteristics of early, mild Alzheimer's given by the NIH:
While none of these symptoms by itself is diagnostic for
Alzheimer's disease, the appearance of a number of them in an
older person suggests the individual should be evaluated by a
clinician who is experienced with neurological disorders. While
there have been some advances in imaging of the brain, at present
Alzheimer's disease is typically diagnosed by clinical assessment
of mental status. A definitive diagnosis can not be made
until postmortem examination of the brain reveals the
Examination of tissue samples taken from brains at autopsy shows characteristic plaques comprised of extracellular aggregates of protein fragments known as β-amyloid or Aβ (also written as "beta-amyloid" or "A-beta"). Aβ is a peptide that is cleaved from a larger membrane protein known as amyloid precursor protein (APP). The exact function of the amyloid precursor protein is unknown; it might have a role in synapse formation and synaptic plasticity. Aβ has a propensity to form aggregates: both insoluble large fibrils that are found in plaques, as well as smaller, soluble oligomers. The oligomers are thought to be the more toxic form.
As the figure shows, two enzymes act in succession to produce Aβ peptides. First, most of the extracellular portion of APP is cleaved by the enzyme β-secretase (also known as BACE for Beta-site APP Cleaving Enzyme). The second step involves intramembrane cleavage by γ-secretase, which is a complex of 4 proteins.
The other characteristic pathological feature of Alzheimer's disease is the presence of neurofibrillary tangles. These consist of intracellular accumulations of the protein tau, which normally functions to stabilize microtubules. In Alzheimer's, tau becomes hyperphosphorylated, which causes it to dissociate from microtubules and form intracellular aggregates.
Usually, the plaques and neurofibrillary tangles appear first in the hippocampus and medial temporal lobe, so that disruption of memory is usually an early symptom. As the disorder progresses, the pathology typically starts appearing in the parietal and frontal cortex. Neuronal death and the general loss of synaptic connections continue progressively.
Most investigators believe that amyloid aggregates are the factor
that initiates neurodegeneration and that Alzheimer's disease
occurs because there is either excessive accumulation or a defect
in the clearance of Aβ (the amyloid
hypothesis). Several lines of evidence support the
amyloid hypothesis. Rare forms of familial early onset
Alzheimer's disease are caused by mutations in APP or in proteins
responsible for its processing, resulting in accumulation of
Aβ. The gene for amyloid precursor protein is located on
chromosome 21, and individuals with Down Syndrome, who
have three copies of chromosome 21, develop plaques of β-amyloid
in early middle age.
The best known genetic risk factor for typical late onset
Alzheimer's disease is a variant of the gene encoding apolipoprotein
E. Recall that an apolipoprotein is the protein part of a lipoprotein
particle, serving as its identification tag. In addition to its
role in lipid transport, apolipoprotein E is thought to play a
role in immune regulation. Studies have also linked apolipoprotein
E to the clearance of Aβ from the brain.
Four drugs are approved by the FDA for use in Alzheimer's. These drugs have been shown to improve symptoms, but they do nothing to slow the course of neurodegeneration, and so are NOT disease-modifying.
Three of the approved drugs are cholinesterase inhibitors. Alzheimer's disease tends to affect cholinergic neurons, so these drugs improve symptoms by increasing acetylcholine at cholinergic synapses.
The fourth approved drug, memantine, is a blocker of the NMDA receptor. Memantine is thought to protect neurons by preventing excitotoxicity. Excitotoxicity is a phenomenon whereby neuronal damage spreads to adjacent cells. Damaged cells release glutamate, which excites cells and leads to Ca++ entry via NMDA receptor channels. Too much Ca++ entry into cells can induce apoptosis. Despite the fact that its mechanism should be neuroprotective, memantine treatment provides only a modest benefit to patients. In treatment, memantine may also be used in combination with a cholinesterase inhibitor.
There are several types of disease-modifying treatments in development. Most of these are anti-amyloid therapies designed to reduce the toxic accumulation of Aβ. Many of these drugs are monoclonal antibody drugs that bind to Aβ, promote its clearance, and prevent plaque formation. Another type of drug in development is a β-secretase inhibitor (also called a BACE inhibitor), which should limit formation of Aβ.
The results from clinical trials testing various anti-amyloid therapies have so far been disappointing. An exception has been the drug aducanumab, a monoclonal antibody drug that preferentially binds to aggregrated Aβ (which is the pathological form) in both soluble oligomers and amyloid plaques. Aducanumab was identified through a screen of antibodies produced by cognitively normal older adults. The reasoning was that cognitively normal older adults may have resisted Alzheimer’s disease through the activity of their immune systems.
A recent paper (September 2016) in the journal Nature reported the results of a 12-month, placebo-controlled trial of aducanumab. This study showed that aducanumab was able to reduce the amount of amyloid plaque in a dose-dependent manner (plaque was measured by imaging using probes that bind β-amyloid). There is some hint that aducanumab may also slow cognitive decline. Clinical trials to show an effect of aducanumab on cognitive function are presently underway.
An important advance necessary for developing disease-modifying treatments is the identification of biomarkers that can be used to accurately identify patients with early disease, and to monitor the effectiveness of treatments. Studies with imaging of β-amyloid in the living brain have shown that there is a "pre-clinical phase" of 10 years or more during which β-amyloid accumulates, but before cognitive symptoms are seen. The hope is that these therapies being developed will be more effective at slowing or preventing dementia when tested on patients in the pre-clinical phase.
If you are interested, check out these papers from September 2016, mentioned above:
Sevigny, J. et al. (2016) The antibody aducanumab reduces Aβ
plaques in Alzheimer's disease. Nature 537:
Reiman, E.M. (2016) Alzheimer's disease: attack on
amyloid-β protein. Nature 537: 36-7 LINK
To see a set of excellent recent reviews of Alzheimer's disease
research, check out this Nature
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