Alzheimer’s and the NYTimes revisited

Chuck C highlighted a NYTimes article about familial Alzheimer’s Disease (AD). Today I read a NYTimes article about the use of PET probes to identify AD.

Familial AD has guided current thinking re. the pathophysiology of AD: i.e. the role of amyloid plaques. The three genes implicated are amyloid precursor protein (APP) and presenilin 1 and 2. It is hypothesized that amyloid beta proteins (in particular aβ42) aggregate – and to make a long and complicated and continuously changing story short – cause inflammation and havoc that results in neuron loss. The cortical and subcortical neuron loss manifests as cognitive impairment and dementia, which are the basis for the clinical diagnosis.

Clinical diagnoses are imperfect. The push for markers is strong and lucrative. The NYTimes article that I mentioned earlier highlights the work of Daniel Skovronsky (who is an MD, PhD in industry) and the development of a F18 PET probe targeted against amyloid plaques. In short, the probe identified amyloid plaques that were confirmed in post-mortem autopsies. The work is a technical advancement over the prior C11 amyloid probe. I don’t know the probe’s sensitivity or specificity. And remember that the gold standard is a post-mortem autopsy staining for amyloid plaques.

Amyloid plaques may not be the whole story, though. Transgenic mice that express “abundant” amyloid plaques did not show a strong correlation with neuron loss, in particular the hippocampus. Individuals vaccinated against aβ42 cleared amyloid plaques, but the effects did not protect against neurodegeneration. Other hypothesized processes include i) hyper-phosphorylated tau mediating the formation of neurofibrillary tangles, ii) a decrease in acetylcholine synthesis, and iii) the loss of locus ceruleus neurons that synthesize norepinephrine. The complicated picture correlates with the current understanding of most AD cases, which are sporadic. Out of the many genes screened for associations with sporadic AD, APOE4 is the strongest risk factor. There are probably many more unknown protective and risk factors.

Skovronsky’s probe and other probes (including the ones tested here at UCLA) are baby steps in the right direction. Non-invasive, laboratory diagnostic tests are the holy grail of neurological and psychiatric diseases. And besides their diagnostic applications, in-vivo imagining has the potential to delineate amyloid and tau’s contributions toward the pathology and progression of AD. The NYTimes article states that “20 percent of people over 60 with normal memories had plaque”; these patients “were still statistically in the normal range,” and they “did worse on every memory test than the control group.” What does this mean? I smell longer studies.

But even more lucrative than diagnostic tests are pharmacological treatments. Acetylcholine esterase inhibitors (e.g. donepezil) and NMDA agonists (e.g. memantine) are symptomatic treatments only. I imagine pharmaceuticals have been salivating for some time… Meanwhile, the basic science must continue! Here is some bed-time reading.