Table 3.
Top biomarkers. Convergent functional evidence for relevance to short-term memory tracking and Alzheimer disease (AD)
| Genesymbol/Gene name | Probeset | Step 1 Discovery in blood (Direction of change tracking increased memory) method/ score/ % up to 6pts |
Step 2 External CFG evidence for involvement in AD score up to 12 pt |
Step 3 Best significant prediction of state Low memory retention ROC AUC/ p-value up to 6 pts ALL 4pts gender 2pts gender /Dx |
Step 3 Best significant predictions of trait future positive neuropsych OR/OR p-value Up to 6 pts ALL 4pts gender 2pts gender /Dx |
Other psychiatric and related disorders evidence(change in opposite direction to increased me mory) |
Pharmacogenomics Drugs that modulate the biomarker (Change in Same Direction to Increased Memory) |
CFE polyevidence score |
|---|---|---|---|---|---|---|---|---|
|
RAB7A RAB7A, member RAS oncogene family |
227602_at |
(I) AP/2 43.8% (I) DE/4 69.6% |
7 |
ALL L: (17/111) 0.66/1.7 3E−02 Gender Dx F-BP L: (2/9) 1/2.02 E−02 M-BP L: (1/27) 1/4.76E−02 M-PSYCHOSIS L: (8/27) 0.76/1.68E−02 M-SZ L: (5/14) 0.8/3.59E−02 M-SZA C: (12/33) 0.67/4.98E−02 |
Gender Male C: (7/91) 2.51/3.08E−02 |
BP Brain arousal depression MDD neuropathic pain |
TCA Valproate |
21 |
|
NPC2 Niemann-Pick disease, type C2 |
200701_at |
(D) DE/6 80.8% |
8 |
ALL L: (17/111) 0.65/2.38E−02 Gender Male L: (12/79) 0.65/4.65E−02 Gender Dx M-MDD L: (3/18) 0.96/7.58E−03 M-SZA L: (3/13) 0.9/2.13E−02 |
Aging alcohol SZ |
20 | ||
|
TGFB1 transforming growth factor beta 1 |
203084_at |
(I) AP/4 54.5% |
9 |
ALL C: (68/238) 0.58/2.88E−02 Gender Male C: (53/176) 0.6/2.29E−02 Gender Dx M-PTSD C: (4/10) 1/5.26E−03 M-SZ C: (15/34) 0.68/3.99E−02 |
Aging ASD BP Chronic stress Depression Longevity Pain Phencyclidine PTSD Suicide SZ |
Omega-3 fatty acids | 19 | |
|
GAP43 growth associated protein 43 |
204471_at |
(I) DE/4 50.8% |
7 |
Gender Dx M-SZA L: (3/13) 0.867/3.15E−02 |
ALL C: (11/111) 2.07/2.08E−02 L: (3/50) 6.14/1.51-02 Gender Male C: (7/91) 2.94/1.17E−02 L: (3/43) 5.54/1.47-02 Gender-Dx M-Psychosis L: (2/22) 5.4/2.96-02 M-SZ L: (2/13) 4.08/3.83-02 |
BP depression SZ stress |
Valproate Benzodiazepines |
19 |
|
ARSB arylsulfatase B |
1554030_at |
(I) DE/6 91.7% |
6 |
ALL L: (17/111) 0.72/2.19E−03 Gender Male L: (12/79) 0.74/4.92E−03 Gender Dx F-BP L: (2/9) 0.93/3.95E−02 M-PSYCHOSIS L: (8/27) 0.88/1.04E−03 M-SZ L: (5/14) 0.8/3.59E−02 M-SZA L: (3/13) 1/5.61E−03 |
Alcohol Depression MDD Suicide |
18 | ||
|
PER1 period circadian clock 1 |
242832_at |
(I) DE/4 61.3% |
6 |
Gender Female C:(15/62) 0.7/9.17E−03 Gender Dx F-BP C: (6/19) 0.83/1.13E−02 M-BP L: (1/27) 1/4.76E−02 |
Gender Male L:(3/43) 5.2/4.97E−03 |
Alcohol Anxiety ASD Autism BP Circadian abnormalities Depression MDD PTSD Sleep Duration Suicide SZ |
Lithium Clozapine Quetiapine Avibactam |
18 |
|
GUSB glucuronidase, beta |
202605_at |
(D) DE/4 55.7% |
8 |
ALL L: (17/111) 0.65/2.16E−02 Gender Female L: (5/32) 0.79/2.29E−02 Gender Dx F-BP C: (6/19) 0.81/1.76E−02 M-MDD L: (3/18) 0.89/1.91E−02 |
Aging Methamphetamine |
Clozapine | 18 | |
|
MAPT microtubule associated protein tau |
203930_s_at |
(I) DE/2 33.7% |
10 |
ALL L: (11/111) 1.96/2.95E−02 Gender Male C: (7/91) 3.54/4.62E−02 Gender Dx M-PSYCHOSIS C: (5/47) 2.84/3.34E−02 M-SZ C: (4/27) 4.65/4.06E−02 |
Aging Alcohol Intellect MDD Methamphetamine Phencyclidine Stress Suicide SZ |
Lithium Omega-3 fatty acids |
18 | |
|
FCGR1A Fc fragment of IgG, high affinity Ia, receptor (CD64) |
216951_at |
(I) DE/4 64.6% |
7 |
ALL L: (3/49) 20/3.50-02 Gender Male L: (3/40) 15.4/4.37E−02 |
17 | |||
|
UBE2L3 ubiquitin conjugating enzyme E2L 3 |
200682_s_at |
(D) DE/6 91% |
4 |
ALL L: (17/111) 0.63/4.13E−02 Gender Male L: (12/79) 0.65/4.92E−02 Gender Dx M-BP C: (10/54) 0.7/2.25E−02 M-SZA L: (3/13) 0.9/2.13E−02 |
Aging Alcohol ASD Depression Stress SZ |
Clozapine | 16 | |
|
NKTR natural killer cell triggering receptor |
1570342_at |
(D) AP/6 85% |
4 |
ALL C: (68/238) 0.59/1.40E−02 Gender Male C: (53/176) 0.62/5.55E−03 Gender Dx M-BP C: (10/54) 0.68/3.56E−02 M-PSYCHOSIS C: (27/67) 0.63/3.19E−02 M-PSYCHOSIS L: (8/27) 0.72/3.55E−02 M-SZ C: (15/34) 0.72/1.38E−02 M-SZ L: (5/14) 1/1.35E−03 |
Alcohol BP Depression MDD Social Isolation Stress Suicide SZ |
16 | ||
|
RHEB Ras homolog enriched in brain |
243008_at |
(D) AP/6 84.4% (D) DE/4 64.1% |
4 |
ALL C: (11/111) 1.51/3.05E−02 Gender Male C: (7/91) 1.63/2.46E−02 Gender Dx M-PSYCHOSIS C: (5/47) 2.12/5.45E−03 L: (2/22) 9.69/1.68E−02 M-SZ C: (4/27) 1.82/1.78E−02 L: (2/13) 6.22/3.32E−02 |
Suicide Pain SZ |
Antidepressants | 16 | |
|
PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) |
1554997_a_at |
(D) DE/4 76% |
10 |
Gender Dx M-PTSD C: (4/10) 0.88/2.75E−02 |
Aggression Alcohol ASD BP Chronic Fatigue Syndrome Depression Depression-Related MDD Neurological Pain Phencyclidine Social Isolation Stress Stress Substances/Addictions Suicide |
Antipsychotics Lithium Vorinostat |
16 | |
|
RGS10 regulator of G-protein signaling 10 |
214000_s_at |
(I) DE/4 63.5% |
6 |
ALL L: (17/111) 0.7/3.89E−03 Gender Male L: (12/79) 0.74/4.73E−03 Gender Dx F-BP L: (2/9) 0.93/3.95E−02 M-BP L: (1/27) 1/4.76E−02 M-MDD L: (3/18) 0.87/2.53E−02 M-SZ C: (15/34) 0.68/3.70E−02 |
Aging BP Female specific interpersonal-traumas Methamphetamine Post-Deployment PTSD PTSD Stress Suicide SZ |
16 | ||
|
MAPT microtubule associated protein tau |
203928_x_at |
(I) DE/4 57.5% |
10 |
Gender Dx F-BP C: (6/19) 0.81/1.76E−02 |
Aging Alcohol Intellect MDD Methamphetamine Phencyclidine Stress Suicide SZ |
Lithium Omega-3 fatty acids |
16 | |
|
ITPKB inositol-trisphosphate 3-kinase B |
232526_at |
(I) DE/4 51.9% |
6 |
ALL L: (17/111) 0.73/1.60E−03 Gender Male L: (12/79) 0.7/1.44E−02 Female L:(5/32) 0.79/2.29E−02 Gender Dx M-BP L: (1/27) 1/4.76E−02 |
Aging Alcohol MDD Phencyclidine Stress Suicide,SZ SZ |
16 | ||
|
KIDINS220 kinase D-interacting substrate 220 kDa |
214932_at |
(I) DE/4 51.9% |
6 |
Gender Dx F-BP L: (2/9) 0.93/3.95E−02 |
Gender Male C: (7/91) 2.49/3.78E−02 Gender-Dx M-BP C: (2/16) 6.06/4.18-02 |
Alcohol MDD Psychosis Pain Suicide Stress |
Clozapine | 16 |
|
GSK3B glycogen synthase kinase 3 beta |
209945_s_at |
(D) DE/4 50.3% |
10 |
Gender Dx M-SZA L: (3/13) 0.93/1.40E−02 |
Aging Alcohol ASD BP BP,SZ MDD Stress Suicide SZ |
Astaxanthin-DHA Antipsychotics Lithium Omega-3 fatty acids Ketamine lipoteichoic acid Valproate enzastaurin, glycogen synthase kinase-3beta inhibitor |
16 | |
|
SERTAD3 SERTA domain containing 3 |
219382_at |
(D) DE/6 81.4% |
5 |
Gender Female L: (5/32) 0.79/2.29E−02 Gender Dx F-BP C: (6/19) 0.81/1.76E−02 F-PSYCHOSIS L: (2/13) 1/1.50E−02 F-SZA L: (2/8) 1/2.28E−02 |
Alcohol ASD Aging |
15 | ||
|
APOE apolipoprotein E |
212884_x_at |
(D) AP/2 34.1% |
11 |
Gender Dx M-PTSD C: (4/10) 0.88/2.75E−02 Gender Dx M-SZ L: (5/14) 0.89/9.82E−03 |
Aggression Aging Alcohol Anxiet ASD BP Brain arousal MDD PTSD Stress Suicide SZ TBI |
Omega-3 fatty acids | 15 | |
|
UBE2I ubiquitin conjugating enzyme E2I |
233360_at |
(D) DE/6 86.8% |
6 |
Gender Dx F-PSYCHOSIS L: (2/13) 0.91/3.78E−02 F-SZA L: (2/8) 0.92/4.78E−02 |
Aging Alcohol ASD Hallucinations Mood State Stress |
Clozapine | 14 | |
|
FOXO3 forkhead box O3 |
231548_at |
(I) AP/2 38.9% (I) DE/6 82.3% |
4 |
Gender Dx F-SZA C: (5/15) 0.78/4.32E−02 |
Gender Dx M-PSYCHOSIS C: (5/47) 4.14/4.58E−02 |
BP Cocaine Longevity PTSD Stress Suicide |
Clozapine | 14 |
|
THRA thyroid hormone receptor, alpha |
214883_at |
(I) DE/4 61.3% |
8 |
Gender Dx F-BP C: (6/19) 0.79/2.18E−02 M-BP L: (1/27) 1/4.76E−02 |
Alcohol PTSD Stress Suicide SZ |
3,5-diiodothyropropionic acid,denosumab/levothyroxine,amiodarone,levothyroxine,dextrothyroxine,L-triiodothyronine | 14 | |
|
ITPKB inositol-trisphosphate 3-kinase B |
1554306_at |
(D) AP/4 61.1% (D) DE/4 55.7% |
6 |
Gender Female L:(5/32) 0.81/1.37E−02 Gender Dx F-BP C: (6/19) 0.91/2.50E−03 F-BP L: (2/9) 1/2.02E−02 |
Acute Stress Aging Alcohol ASD BP MDD Neurological Suicide SZ |
Omega-3 fatty acids | 14 | |
|
IGF1 insulin-like growth factor 1 (somatomedin C) |
209542_x_at |
(I) DE/4 54.1% |
8 |
Gender Dx F-BP C: (6/19) 0.79/2.18E−02 |
Aggression Aging Alcoho Anxiety BP Depression Longevity PTSD SZ |
Lithium Clozapine Fluoxetine (SSRI), Venlafaxine (SNRI) MEDI-573,BI 836845 |
14 | |
|
NPTX2 neuronal pentraxin II |
213479_at |
(I) DE/4 52.5% |
8 |
Gender Dx F-BP L: (2/9) 0.93/3.95E−02 |
Alcohol Brain arousal Cocaine Depression MDD MDD,SZ Mood Disorders NOS Stress Suicide |
Clozapine Fluoxetine |
14 | |
|
GSTM3 glutathione S-transferase mu 3 (brain) |
235867_at |
(D) DE/4 52.1% |
8 |
Gender Dx F-SZA C: (5/15) 0.78/4.32E−02 |
BP MDD SZ |
14 | ||
|
BACE1 Beta-Secretase 1 |
222463_s_at |
(I) DE/2 44.8% |
8 |
Gender Male C: (7/91) 1.97/3.78E−02 |
MDD Stress Suicide |
14 | ||
|
PSEN1 presenilin 1 |
203460_s_at |
(D) DE/4 54.5% |
9 |
Aging Alcohol Autism Depression Emotional Stability Neuroticism Suicide SZ |
Omega-3 fatty acids | 13 | ||
|
GFAP glial fibrillary acidic protein |
203540_at |
(I) DE/2 34.3% |
9 |
Gender Dx F-BP C: (6/19) 0.77/3.28E−02 |
Addictions Alcohol BP MDD Stress Suicide SZ Yohimbine |
Omega-3 fatty acids Clozapine |
13 | |
|
TREM2 triggering receptor expressed on myeloid cells 2 |
219725_at |
(I) DE/2 37.6% |
11 |
BP SZ |
13 | |||
|
NOCT nocturnin |
220671_at |
(D) AP/4 69.5% |
6 |
Gender Dx F-PTSD C: (3/9) 1/1.01E−02 |
PTSD Post-Deployment PTSD |
12 | ||
|
CEP350 centrosomal protein 350 kDa |
204373_s_at |
(D) DE/4 67.1% |
6 |
Gender Dx M-PSYCHOSIS L: (2/22) 54.6/3.77E−02 |
Autism BP Cocaine Depression PTSD Stress Suicide SZ |
Antidepressants, Fluoxetine | 12 | |
|
PPP2R2B protein phosphatase 2, regulatory subunit B, beta |
205643_s_at |
(I) DE/4 63.5% |
6 |
Gender Dx F-BP L: (2/9) 1/2.02E−02 |
ADHD Aging Alcohol ASD Circadian abnormalities Longevity PTSD Suicide SZ |
12 | ||
|
NRP2 neuropilin 2 |
222877_at |
(I) DE/4 61.3% |
6 |
Gender Dx M-MDD L:(3/18) 0.98/5.43E−03 |
Longevity MDD Phencyclidine Stress |
Clozapine | 12 | |
|
CTSS cathepsin S |
232617_at |
(D) DE/4 56.9% |
8 |
Aging Alcohol ASD BP Brain arousal Pain Suicide |
Omega-3 fatty acids | 12 | ||
|
VEGFA vascular endothelial growth factor A |
211527_x_at |
(I) DE/2 45.3% |
8 |
Gender Dx M-MDD C: (11/38) 0.7/2.57E−02 |
Alcohol Anxiety BP Chronic Stress Depression Hallucinations Intellect MDD Pain MSK Stress Suicide SZ |
Antipsychotics Fluoxetine Steroids |
12 | |
|
MAPT microtubule associated protein tau |
233117_at |
(I) DE/2 44.2% |
10 |
Aging Alcohol Intellect MDD Methamphetamine Phencyclidine Stress Suicide SZ |
Lithium Omega-3 fatty acids |
12 | ||
|
GSK3B glycogen synthase kinase 3 beta |
240562_at |
(I) DE/2 39.2% |
10 |
Aging Alcohol ASD BP MDD Methamphetamine Psychological Stress Stress Suicide SZ Yohimbine |
Antipsychotics Antipsychotics Pregnenolone sulfate Fluoxetine (SSRI) Lithium mood stabilizing drugs Valproate |
12 | ||
|
GSK3B glycogen synthase kinase 3 beta |
242336_at |
(D) AP/2 34.1% |
10 |
Aging Alcohol ASD BP BP,SZ MDD Stress Suicide SZ |
Astaxanthin-DHA Antipsychotics Lithium Omega-3 fatty acids Ketamine lipoteichoic acid Valproate enzastaurin, glycogen synthase kinase-3beta inhibitor |
12 | ||
|
BACE1 Beta-Secretase 1 |
224335_s_at |
(I) DE/2 43.1% |
8 |
MDD Stress Suicide |
10 |
Bold—top biomarkers after discovery and prioritization (n = 23, CFG ≥ 12)). Underlined—best predictor in a category after testing of the longer list candidate biomarkers after discovery and prioritization (n = 138, CFG ≥ 10), as depicted in Fig. 2. We tabulated into a convergent functional evidence (CFE) score all the evidence from discovery (up to six points), prioritization (up to 12 points), testing (State Memory Retention State and Trait Future Positive Neuropsychological Testing (up to six points each if significantly predicts in all subjects, four points if predicts by gender, two points if predicts in gender/diagnosis subgroups). The goal is to highlight, based on the totality of our data and of the evidence in the field to date, biomarkers that have all around evidence: track memory, are implicated in AD, and predict memory state and future dementia. Such biomarkers merit priority evaluation in future clinical trials. Red—increased in expression (I) in high memory states, blue—decreased in expression (D). DE—differential expression, AP—absent/present. C—cross-sectional analyses; L—longitudinal analyses, using levels and slopes from multiple visits. In all, by gender, and personalized by gender and diagnosis (gender/Dx), DE—differential expression, AP—absent/present. For Step 3 predictions, C-cross-sectional (using levels from one visit), L-longitudinal, M-males, F-females. MDD-depression, BP-bipolar, SZ-schizophrenia, SZA-schizoaffective, PSYCHOSIS- schizophrenia and schizoaffective combined, PTSD-post-traumatic stress disorder. This is a summary table—the Supplementary Information contains 336 references related to the data summarized here