Alzheimer's According to Various Brain Tissues

Below is a table of all individual studies that contributed to our "canonically altered in the Alzheimer's brain" lists. The numbers show log(P-values) for the intersections between the canonical upregulated and downregulated lists against individual studies. If this were an academic paper, a referee might (justifiably) complain about our method; technically, one shouldn't intersect a compendium of studies with studies from which the compendium is derived and go on to derive P-values. A better approach would be to remove all contributions of a particular study from the canonical lists, and then perform the Fisher test. This exercise has to be performed for all studies; a lot of work. Practically speaking, however, we entered such a large volume of studies into these canonical lists that the P-values won't be exaggerated to any great extent. 

I've broken down the studies according to brain regions. Hopefully, my inadequacy in basic neuroanatomy won't be too obvious (note that I bundled everything with the terms "cortex" and "cortical" into a single group). The goal is to ascertain whether Alzheimer's, as defined by the "canonical" lists, is particularly potent in particular regions. One could also ask if Alzheimer's trends reverse in particular tissues of Alzheimer's patients.

region	study	up	down
all	downregulated (MS) in Alzheimer's brain (vs controls)(fc/p: s: Large-scale proteomic analysis of Alzheimer’s disease brain)	0.91	-3.98
	downregulated in Alzheimer's brain (all regions incl)(fc/p:  GSE5281: anatomically and functionally distinct regions of the normal aged)	0.21	-25.4
	downregulated in Alzheimer's brain (all regions incl)(fc/p: GSE118553: asymptomatic and symptomatic alzheimer brains)	0.21	-18.17
	downregulated in Alzheimer's disease in three brain tissues (GSE131617)	-2.64	-10.51
	upregulated (MS) in Alzheimer's brain (vs controls)(fc/p: s: Large-scale proteomic analysis of Alzheimer’s disease brain)	-1.45	-0.75
	upregulated in Alzheimer's brain (all regions incl)(fc/p:  GSE5281: anatomically and functionally distinct regions of the normal aged)	-16.78	0.45
	upregulated in Alzheimer's brain (all regions incl)(fc/p: GSE118553: asymptomatic and symptomatic alzheimer brains)	-20.18	0.45
	upregulated in Alzheimer's disease in three brain tissues (GSE131617)	-2.85	0.48
astrocytes	downregulated in alzheimer's astrocytes (with c9orf72 mutations) vs. healthy astrocytes (raw data fc/p: GSE142730)	-0.51	-6.73
	downregulated in astrocytes of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.52	-3.65
	downregulated in astrocytes of alzheimer's patients at braak stage III or greater (GSE29652: astrocyte transcriptome in the aging brain)	0.22	-20.52
	upregulated in alzheimer's astrocytes (with c9orf72 mutations) vs. healthy astrocytes (raw data fc/p: GSE142730)	-1.11	0.49
	upregulated in astrocytes of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	-11.29	0.59
	upregulated in astrocytes of alzheimer's patients at braak stage III or greater (GSE29652: astrocyte transcriptome in the aging brain)	-2.86	0.48
cerebellum	downregulated in cerebellum of "asymptomatic alzheimers" vs normal (GSE118553)	-1.13	-4.9
	upregulated in cerebellum of "asymptomatic alzheimers" vs normal (GSE118553)	-7.57	0.43
choroid plexus	downregulated in choroid plexus of alzheimers patients (GSE61196)	0.19	-1.91
	upregulated in choroid plexus of alzheimers patients (GSE61196)	-1.21	-0.43
cortex	downregulated (MS) in frontal cortex of Alzheimer's patients (s4: fc/p: proteomic analysis of the frontal cortex in Alzheimer’s)	0.32	-4.58
	downregulated in alzheimer's cortex (s3: fc/p: link between amyloidosis and neuroinflammation)	0.22	-12.37
	downregulated in cortex of Alzheimer's patients (fc/p: GSE15222: brain transcript expression in Alzheimer disease)	0.26	-43.23
	downregulated in dorsolateral prefrontal cortex of alzheimer's patients (raw data w/ttest: GSE53697: ELAV-like protein binding to coding and non-coding)	-0.74	0.22
	downregulated in entorhinal cortex of alzheimer's patients (fc/p: GSE48350: normal brain aging are sexually dimorphic)	0.22	-1.14
	downregulated in entorhinal cortex of alzheimer's patients (GSE26972:  loss of hnRNP-A/B in Alzheimer's disease)	0.12	-53.23
	downregulated in frontal cortex of Alzheimer patients (GSE36980: Altered expression of diabetes-related genes in Alzheimer's disease brains)	0.2	-48.11
	downregulated in frontal cortex synaptoneurosome of Alzheimer's patients (fc/p: GSE12685: synaptoneurosomes identifies neuroplasticity genes overexpressed)	-0.45	0.5
	downregulated in neocortex of alzheimer's patients (GSE37263: gene expression in the neocortex of Alzheimer's )	0.24	-96.02
	downregulated in neocortex of alzheimer's patients (GSE37264: alternative splicing in Alzheimer's disease)	0.14	-66.08
	downregulated in parietal cortex of Alzheimer's patients (GSE16759: miRNA and mRNA expression in Alzheimer's disease)	-1.21	-18.78
	downregulated in prefrontal cortex of alzheimer's patients (fc/p: GSE33000: human prefrontal cortex underlies two neurodegenerative)	0.19	-29.5
	downregulated in temporal and frontal cortex of Alzheimer's patients (GSE139384: Pathomechanism of Kii ALS/PDC)	-3.62	0.69
	downregulated in temporal cortex of alzheimers patients (vs. vascular dementia patients)(GSE122063)	0.17	-32.84
	upregulated (MS) in frontal cortex of Alzheimer's patients (s4: fc/p: proteomic analysis of the frontal cortex in Alzheimer’s)	-2.19	0.77
	upregulated in alzheimers (frontal pole and occipital cortex)(GSE84422: regional vulnerability to Alzheimer's disease)	-26.42	0.41
	upregulated in alzheimer's cortex (s3: fc/p: link between amyloidosis and neuroinflammation)	-4.97	0.49
	upregulated in cortex of Alzheimer's patients (fc/p: GSE15222: brain transcript expression in Alzheimer disease)	-13.67	0.59
	upregulated in entorhinal cortex of alzheimer's patients (fc/p: GSE48350: normal brain aging are sexually dimorphic)	-13.4	-0.7
	upregulated in entorhinal cortex of alzheimer's patients (GSE26972:  loss of hnRNP-A/B in Alzheimer's disease)	-16.26	0.19
	upregulated in frontal cortex of Alzheimer patients (GSE36980: Altered expression of diabetes-related genes in Alzheimer's disease brains)	-25.66	0.28
	upregulated in frontal cortex synaptoneurosome of Alzheimer's patients (fc/p: GSE12685: synaptoneurosomes identifies neuroplasticity genes overexpressed)	0.31	-4.64
	upregulated in neocortex of alzheimer's patients (GSE37263: gene expression in the neocortex of Alzheimer's )	-30.18	0.44
	upregulated in neocortex of alzheimer's patients (GSE37264: alternative splicing in Alzheimer's disease)	-15.5	-0.45
	upregulated in parietal cortex of Alzheimer's patients (GSE16759: miRNA and mRNA expression in Alzheimer's disease)	-9.24	-1.83
	upregulated in prefrontal cortex of alzheimer's patients (fc/p: GSE33000: human prefrontal cortex underlies two neurodegenerative)	-19.04	0.42
	upregulated in temporal and frontal cortex of Alzheimer's patients (GSE139384: Pathomechanism of Kii ALS/PDC)	0.78	-6.02
	upregulated in temporal cortex of alzheimers patients (vs. vascular dementia patients)(GSE122063)	-2.48	0.3
endothelial	downregulated in prefrontal cortical endothelial cells of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.09	-4.14
	upregulated in prefrontal cortical endothelial cells of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	-3.67	1.25
gray matter	downregulated in incipient Alzheimers gray matter (Microarray analyses of laser-captured hippocampus)	-3.24	-0.8
	downregulated in severe Alzheimers gray matter (GSE28146: Microarray analyses of laser-captured hippocampus)	0.16	-5.83
	upregulated in incipient Alzheimers gray matter (Microarray analyses of laser-captured hippocampus)	0.17	0.39
	upregulated in severe Alzheimers gray matter (GSE28146: Microarray analyses of laser-captured hippocampus)	-0.57	0.38
hippocampus	downregulated in hippocampus of alzheimer's patients (fc/p: GSE29378: cell type changes in Alzheimer's disease)	0.21	-4.02
	downregulated in hippocampus of alzheimer's patients (raw data fc/p: GSE67333: Alzheimer's Disease Reveal Neurovascular Defects)	0.41	-4.44
	downregulated in hippocampus of alzheimer's patients (raw data w/ttest (p<.01): GSE113524: autism/intellectual disability somatic mutations in Alzheimer's brains)	0.06	0.13
	downregulated in hippocampus of severe Alzheimer's patients (Incipient Alzheimer's disease: microarray correlation analyses)	0.19	-34.13
	upregulated in hippocampus of alzheimer's patients (fc/p: GSE29378: cell type changes in Alzheimer's disease)	-37.91	-0.74
	upregulated in hippocampus of alzheimer's patients (raw data fc/p: GSE67333: Alzheimer's Disease Reveal Neurovascular Defects)	-0.43	0.59
	upregulated in hippocampus of alzheimer's patients (raw data w/ttest (p<.01): GSE113524: autism/intellectual disability somatic mutations in Alzheimer's brains)	0.21	0.46
	upregulated in hippocampus of severe Alzheimer's patients (Incipient Alzheimer's disease: microarray correlation analyses)	-4.23	0.41
microglia	downregulated in prefrontal cortical microglia of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.46	0.64
	upregulated in prefrontal cortical microglia of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	-0.46	0.63
neuron	downregulated in excitatory neurons of alzheimer's patients (S2: fc/p: Single-cell transcriptomic analysis of Alzheimer?s disease)	-0.48	-21.72
	downregulated in prefrontal cortical excitatory neurons of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	-0.43	-8.22
	downregulated in prefrontal cortical inhibitory neurons of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.04	-0.78
	upregulated in excitatory neurons of alzheimer's patients (S2: fc/p: Single-cell transcriptomic analysis of Alzheimer?s disease)	-0.48	-1.47
	upregulated in prefrontal cortical excitatory neurons of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.45	1.27
	upregulated in prefrontal cortical inhibitory neurons of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.04	0.09
nscs	downregulated in neural progenitor cells from sporadic alzheimer's patients (GSE117586: iPSC Models of Alzheimer's Disease)	-0.51	-12.37
	upregulated in neural progenitor cells from sporadic alzheimer's patients (GSE117586: iPSC Models of Alzheimer's Disease)	0.22	-5.74
olfactory	downregulated in olfactory of advanced alzheimers patients (vs. control and initial disease)(GSE93885: olfactory bulb transcriptome during Alzheimer®s disease evolution)	-0.55	-8.59
	upregulated in olfactory of advanced alzheimers patients (vs. control and initial disease)(GSE93885: olfactory bulb transcriptome during Alzheimer®s disease evolution)	-5.57	-0.43
oligodendrocyte	downregulated in prefrontal cortical oligodendrocytes of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	0.39	-0.75
	upregulated in prefrontal cortical oligodendrocytes of alzheimer's patients (single nucleus sequencing) (s3: endothelial cells and neuroprotective glia in Alzheimer’s)	-1.38	0.54
posterior cingulate	downregulated in posterior cingulate of early onset alzheimer's patients (fc/p: GSE39420: sporadic and monogenic early-onset Alzheimer's disease)	0.2	-40.22
	upregulated in posterior cingulate of early onset alzheimer's patients (fc/p: GSE39420: sporadic and monogenic early-onset Alzheimer's disease)	-20.14	0.45
temporal gyrus	downregulated in middle temporal gyrus of alzheimers patients (GSE132903: Alzheimer's Disease Middle Temporal Gyrus: Importance)	0.2	-123.42
	downregulated in temporal gyrus of alzheimer patients (GSE109887: Alzheimer's disease-associated (hydroxy)methylomic)	0.2	-122.84
	upregulated in middle temporal gyrus of alzheimers patients (GSE132903: Alzheimer's Disease Middle Temporal Gyrus: Importance)	-38.49	0.49
	upregulated in temporal gyrus of alzheimer patients (GSE109887: Alzheimer's disease-associated (hydroxy)methylomic)	-43.17	0.4
temporal lobe	downregulated in lateral temporal lobe of Alzheimer's patients (vs healthy elderly)(raw data w/ttest (p<.001): GSE104704: landscape of normal aging in Alzheimer's disease)	0.22	-20.52
	upregulated in lateral temporal lobe of Alzheimer's patients (vs healthy elderly)(raw data w/ttest (p<.001): GSE104704: landscape of normal aging in Alzheimer's disease)	-3.87	0.49

Initially, I included the 5 groups, both up and down-regulated (10 more columns), from the previously mentioned Alzheimer's clustering study. It generated a confusing, difficult-to-post mess, so I simplified. In general, these 10 groups intersected the individual studies as might be expected, with groups B1 and B2 often reversing the trends seen above. 

To answer the initial question: the up/down-regulation patterns in various tissues strongly tended to conform to up/down-regulation in our canonical lists. In other words, these canonical fingerprints don't strongly depend on tissues. Particularly strong intersections were seen between the broad canonical lists and two temporal gyrus studies. The posterior cingulate and general cortex also showed nice P-values.

Red text signifies cases where the direction (+ or -) of the canonical lists versus individual studies are not the same (e.g. intersection of the canonically upregulated list with transcripts downregulated in a particular study generates an interesting P-value). There are only four of these cases. Most interesting, in my opinion, is the case in which transcripts upregulated in Alzheimer's neural stem cells significantly overlap canonically downregulated Alzheimer's transcripts. Is it possible that the levels of particular transcripts (and their accompanying proteins) in NSCs generates a reverse signature in surrounding tissues?

A number of tissues do not strongly overlap with the canonical lists: oligodendrocytes, the choroid plexus, and microglia in particular. One should not naively conclude that such tissues are irrelevant to Alzheimer's...such tissues might be especially relevant.

In general, we can't claim that this exercise was particularly insightful. The main point is to show that the Alzheimer's signature is evident in multiple regions of the Alzheimer's brain.

whatismygene.com 

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