Talk:Computational models of Alzheimer's disease

Major points

• There is somewhat of a lack of emphasis on the role of interneurons in rhythmic dysfunction in AD. Whether computational models emphasize interneuron dysregulation or not should be noted, and if not, the Conclusions section should list this as another aspect that AD models are lacking in. This is especially important in that insofar as AD is a disease that ultimately results in symptoms due to network dysfunction, and given that interneurons are the primary drivers of network rhythms, it would make sense that future studies make a particular effort to dissect the role of interneurons in AD. Specific areas in the experimental literature that models need to target are PV cell disruption & gamma rhythms (one study is cited, which is good) and cell death of dendrite-targeting interneurons as a very early marker for AD. Some references:
  • Recent (Dec 2016) review article on interneuronal dysfunction in AD: https://www.ncbi.nlm.nih.gov/pubmed/27829687 (Can be mined for areas that computational models need to address)
  • Another PV cell & gamma paper (experimental though): https://www.ncbi.nlm.nih.gov/pubmed/22541439
  • O-LM and HIPP early death as potential marker: https://www.ncbi.nlm.nih.gov/pubmed/16271420
• The "Computational models" section, in particular "Biochemical models", is very long and would benefit tremendously from breaking into smaller sub-sections. It would be best to devise a logical scheme of groups or types of models according to some criterion, whether chronological, level of complexity of the model, type of biochemical process or pathway, etc. It is obvious from reading this section that "Biochemical models" alone encompasses many approaches and that the addition of subdivisions would greatly improve the reader's understanding of the material.

Minor points of clarification

• "Other hypotheses: Oxidative stress, reduced hippocampal volume, cerebrovascular disease and inflammation may be significant in the formation of the pathology." - Cite some example studies for readers to follow up on each of these other hypotheses. Why are they mentioned under "other" rather than having their own bullet point? Are they less prominent hypotheses? Are they more hotly contested, or not considered as seriously as the others? If any of these, I suggest making a point about this, to help clarify for the reader why they are all subsumed under "other".
• "Some of these models focus on hippocampus function yet many suffer from simulating exact effects of amyloid plaques and neurofibrillary tangles." Does this imply that simulating exact effects of plaques or tangles is less desirable (due to the inclusion of "suffer")? Or simply that it makes the models very complex and unwieldy? If the latter, I suggest rewording to make it more precise. "Suffer" is a vague term that can mean almost anything, including subjective bias or judgement against the level of analysis of simulating individual molecules.

Citation usage

• "Importantly, APOE ε4 has been linked to AD pathology more than the other alleles." - is this found in the Dhikav & Anand 2011 citation mentioned in the following sentence? If not, i.e., if this statement is meant to set up the following sentences, then I suggest removing the "Along the same lines" in the next sentence and just have it start with "Carriers of the APOE..." This way it's more clear that the sentence with the citation is an example of the previous statement regarding APOE ε4.
• Related to the above, the part in the sentence with "to have larger temporal atrophy (a brain area implicated in AD)" should be reworded as it is unclear. I suggest: "to have larger atrophy in the temporal lobe, a brain area implicated in AD, and poorer memory functions...".
• "This is in contrast to studies showing that Ach inhibitors increase Ach levels and also improve memory function in animal models and patients with AD." - Give some examples of such studies; so far no citations are included for this point.
• "or CREB down-regulation (Barco & Marie, 2011) throughout the cerebral cortex and hippocampus." - if the part after the citation, i.e., "throughout the cerebral cortex..." is meant to refer to CREB down-regulation, then group that part with the former, so that the citation is at the end. Otherwise, it is a bit confusing and makes it seem like "throughout the cerebral cortex and hippocampus" refers to the entire preceding list.

Grammar, wording, and presentation

• "The formation of the beta-amyloid plaques..." - "the" should be removed.
• "Approximately, 15% of the population carry the APOE ε4 allele" - the comma after "Approximately" should be removed.
• "while memantine is NMDA antagonist" - should read, "while memantine is an NMDA antagonist".
• "memantine was shown to increase acetylcholine (Ach) levels..." - here and elsewhere, the typical spelling of the abbreviation for acetylcholine is ACh, not Ach.
• "synaptic loss" - should say "synapse loss"; "synaptic" is an adjective and you are here rather trying to refer to the synapses themselves (i.e., in noun form).
• The heading for the section "Computational models" has an extra newline above it, unlike the other headings where there is only one blank line. Either add a newline to all other headings or remove the extra one here to make the headings more visually consistent.
• The paragraph in Systems level models discussing Hasselmo's work "Hasselmo provided a two-layer feedforward network" has inconsistent tenses. The first sentence is in past tense ("Hasselmo provided") but the next two are in present tense ("Hasselmo show"; "They also argue"). Suggest changing all sentences to past tense.
• The following paragraph (Meeter et al) also is in present tense. I suggest going over all sentences citing previous work and either choosing to use present tense or past tense throughout the entire article.
• Spelling error: "Moustafa and colleagues provided a two-layer neural network of the basal ganglia and hippocampal region intereaction" - should be interaction.
• Conley et al work: "the input the model was 19,000 words" - based on the context, shouldn't this say, "the input of the model..."? Also, "distance between a words and its neighbors" should be "distance between a word and its neighbors" (singular). Finally, the sentence "However, it is not known, how these representations relate to AD symptoms" has a spurious second comma. This should simply say, "However, it is not known how these representations...".
• Conclusion section: the first sentence says there have been "few" attempts but this is perhaps an understatement based on the plethora of work cited. Perhaps the wording should say "there have been several attempts".