Alzheimer's Disease

Now we're onto Alzheimer's Disease (AD), which is one of the major causes of dementia! (I've already blogged about Alzheimer's disease here, but I'll be going into much more detail in this post.)

Pathology

As mentioned in a previous post, two of the main pathological features of Alzheimer's are neurofibrillary tangles (clumps of neurons caused by hyperphosphorylated Tau protein) and amyloid plaques (insoluble aggregates of amyloid beta peptide, or Aβ for short).

There are several different Aβ peptides (the most common is Aβ42) generated from the cleavage of amyloid precursor protein (APP). APP cleavage can be either amyloidogenic (produces Aβ peptides) or non-amyloidogenic (does not produce Aβ peptides).  Aβ peptides can aggregate to form oligomers, then protofibrils, fibrils and plaques. It has been hypothesised that these plaques may lead to progressive synaptic/neuronal injury, altered neuronal ionic homeostasis, oxidative injury, and abundant oligomerisation and hyperphosphorylation of Tau (which, as mentioned above, is another pathological feature of Alzheimer's).

Contributing Factors

We still aren't 100% sure about what causes Alzheimer's, but there are a few different factors that might contribute. A very small percentage of Alzheimer's patients have defective genes that result in defective proteins. Many others carry genes that aren't defective, but do increase the risk of AD. Changes in hormone levels, as well as lifestyle factors such as diet and exercise, may also affect the risk of developing AD. We could say that Alzheimer's has complex inheritance as it seems that a mix of genetic and environmental factors can lead to AD.

Genetic Factors

There is definitely a genetic component to AD, as first-degree relatives of an affected individual are 3-4x more likely to develop AD than someone who is not directly related to an AD patient. AD with family history is known as familial AD. Of these patients, most have late-onset AD (i.e. they get AD when they're old), but some are unfortunate enough to have early-onset AD (i.e. they can get AD quite young, even as young as 40-50). Most AD (~75%) comes without a family history, however, and is known as sporadic AD. Most sporadic AD cases are late-onset.

The main genes associated with familial early-onset AD are APP (chromosome 21), presenilin1 (chromosome 14) and presenilin2 (chromosome 1). Since one of these genes (APP) is on chromosome 21, having Down's Syndrome increases the risk of developing Alzheimer's. There are four main types of APP mutations:

• Swedish mutation- Increases β-secretase's affinity for APP. Since β-secretase cleaves APP, this mutation increases the amyloidogenic processing of APP.
• Dutch mutation- Induces cerebral amyloidosis.
• Arctic mutation- Enhances β-amyloid protofibril formation.
• London mutation- Affects the cleavage of γ-secretase.

Of the two presenilin genes, presenilin1 (PS1) mutations are relatively common (seen in ~50% of affected families), whereas presenilin2 (PS2) mutations are very rare. Presenilins are aspartyl proteases that are part of a larger protein complex called γ-secretase. They can cleave APP to form Aβ peptides. There are over 70 different mutations on the PS1 gene that can lead to AD, but only two on the PS2 gene.

The main genes associated with late-onset AD are ApoE (chromosome 19) and A2M (chromosome 12). The ApoE gene encodes apolipoprotein E, and comes in three alleles (ε2, ε3 and ε4. No idea what happened to ε1). The ε4 allele is associated with an earlier age of onset.

Lifestyle Factors

A healthier lifestyle is generally associated with a reduced risk of AD, and less cognitive decline in general. Physical activity, for instance, can reduce cognitive decline and increase cognitive functioning, and may also be associated with an increased hippocampal volume. A healthy diet may also slow cognitive decline, but the data is inconsistent. Some studies suggest that the areas most strongly affected by diet are executive and visuospatial function. The Mediterranean Diet is one such healthy diet that might help.

Biomarkers

AD, like many other illnesses, is best managed if detected earlier. Therefore, the hunt is on for biomarkers that might help us detect the disease earlier on. The main kinds of biomarkers that are being tested are neuroimaging biomarkers, CSF biomarkers, and blood biomarkers.

Imaging Biomarkers

Different types of neuroimaging can be used to detect possible Alzheimer's (as mentioned above, AD is associated with brain changes). Imaging techniques include MRI, FDG-PET-F¹⁸ (using fluorodeoxyglucose) and PiB-PET (using Pittsburg compound). Neuroimaging biomarkers are the best that we have so far, but these imaging techniques are expensive and therefore not readily accessible to everyone.

CSF (Cerebrospinal Fluid) Biomarkers

Given that CSF is in direct contact with the brain, it can detect biochemical changes in the brain. This gives it great predictive value. Unfortunately, CSF biomarkers can only be tested via lumbar puncture, which can be risky (not to mention scary for some patients).

Blood Biomarkers

Neuroimaging and CSF may give us good information, but they are not convenient. Blood tests, on the other hand, are. Quantifying the abundance of various proteins in blood may aid in the detection of AD. Perhaps the best answer is to use blood biomarkers, but in combination with some CSF testing and neuroimaging.