Alzheimer's Disease


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 characteristic pathology.

Cellular Pathology

A-beta formationExamination of tissue samples taken from brains at autopsy shows characteristic plaques comprised of extracellular aggregates of protein fragments known as β-amyloid or (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.

Amyloid Hypothesis

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.

Treatments

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.

Treatments in Development

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 paper from 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 prodromal phase of 10 years or more during which β-amyloid accumulates, but before cognitive symptoms are seen.  A recent paper in Nature (see below) described a blood test that appears to be able to identify people with high levels of β-amyloid in their brains.  The hope is that these therapies being developed will be more effective at slowing or preventing dementia when tested on patients in the prodromal phase. 

Optional

If you are interested, check out these papers mentioned above:

Sevigny, J. et al. (2016) The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537: 50-56 LINK
URL [http://www.nature.com/nature/journal/v537/n7618/full/nature19323.html]

Reiman, E.M. (2016) Alzheimer's disease:  attack on amyloid-β protein. Nature 537: 36-7 LINK
URL [http://www.nature.com/nature/journal/v537/n7618/full/537036a.html]

Abbott, A. (2018) Simple blood test spots dementia protein. Nature published online LINK
URL [https://www.nature.com/articles/d41586-018-01466-8]


To see a set of excellent recent reviews of Alzheimer's disease research, check out this Nature Outlook Supplement.
URL [http://www.nature.com/nature/outlook/alzheimers/]

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Quick Quiz


Fill in Answer Correct False Correct Answer
1. Which of the following is thought to be most toxic to neurons in the brain? [amyloid precursor protein; insoluble A-beta in plaques; oligomers of A-beta; tau associated with microtubules]
2. Name a chromosomal disorder that shows accumulation of β-amyloid, similar to Alzheimer's disease.
3. Name the part of the brain (important for memory) that is usually first affected in Alzheimer's disease.
4. Name the type of drug that is used to increase acetylcholine at cholinergic synapses.
5. Name the drug for treating Alzheimer's disease that is an NMDA antagonist.
6. Which of the following therapies for Alzheimer's disease is likely to be disease-modifying? [cholinesterase inhibitor; memantine; aducanumab; BACE inhibitor; all of the above]


(Spelling must be correct)