laboratory evaluation of Alzheimer's disease
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Laboratory
routine
- thyroid function tests
- erythrocyte sedimentation rate (ESR) or serum C-reactive protein (serum CRP)
- chemistry panel
- urinalysis
- complete blood count (CBC)
- serum vitamin B12 (likely unhelpful[11]) & serum folate
- serologic test for syphilis (not routinely indicated)
- Tropheryma whipplei DNA (if diarrhea)
- HIV1 serology
CSF analysis (lumbar puncture) (not routinely indicated)
- slow virus
- fungal disease
- CSF Abeta42
- earliest marker of AD[12]
- CSF Abeta42 decreased in spontaneous cerebral amyloid angiopathy vs AD[31]
- CSF phospho-tau (microtubule-associated protein tau)
- CSF beta-amyloid & CSF phospho-tau positive characterizes AD
- 73% of CSF beta-amyloid positive & CSF phospho-tau negative patients show pathologic changes of AD[28]
- ratio of CSF Abeta [1-42] / CSF phospho-Thr-181-tau & total CSF tau[3] predicts elderly with MCI likely to progress to AD[10]
- VSNL1 is increased in CSF of AD patients
- CSF neurogranin is elevated in patients with Alzheimer disease & to a lesser extent mild cognitive impairment[22]
- tau in CSF + amyloid-beta 42 in CSF in addition to brain MRI proposed to predict progression of mild cognitive impairment to Alzheimer's disease[16]
- phosphorylated tau in CSF
- N-terminal phospho-tau181 in CSF & N-terminal phospho-tau217 in CSF with concordance of 88.2%, better than mid phospho-tau181 in CSF with either N-terminal measure[25]
serum/plasma biomarkers of Alzheimer's disease
- phosphorylated tau in serum/plasma
- phosphorylated tau181 in serum distingishes AD from FTD[21]
- phosphorylated tau217 in plasma able to discriminate Alzheimer disease from other neurodegenerative diseases[23]
- plasma phospho-tau combined with executive function & memory tests useful for prediction of Alzheimer's disease among older persons with memory complaints[26]
- amyloid-beta in plasma proposed as screening tool[17]
- plasma APP/Abeta [1-42] & plasma Abeta40/42
- plasma Abeta42/40 best predicts brain amyloidosis in blacks & non-Hispanic whites[29]
- neurofilament light chain in serum/plasma levels (plasma NfL) correspond with hallmarks of Alzheimer's disease progression
- plasma GFAP
- outperforms CSF GFAP in predicting amyloid-beta pathology in early Alzheimer's disease[27]
- appears earlier in plasma than plasma phosphorylated tau181 or plasma neurofilament light chain[30]
- higher plasma Abeta40/42, ptau181, plasma NfL, & plasma GFAP are associated with higher risk for cardiovascular disease, mortality from heart failure & kidney disease
- plasma biomarkers of Alzheimer's disease differ by sex & comorbidities[34]
- phosphorylated plasma amyloid-beta 42/40
- plasma phosphorylated tau181 (plasma p-tau181) M > F
- chronic kidney disease associated with higher plasma p-tau181
- higher plasma p-tau181 associated with lower MMSE scores
- plasma glial fibrillary acidic protein (plasma GFAP) F > M,
- diabetes & higher BMI associated with lower plasma GFAP
- higher plasma GFAP associated with lower MMSE scores
- plasma neurofilament light chain (plasma NfL)
- higher BMI associated with lower plasma NfL
- stroke associated with higher plasma NfL[34]
- plasma exosome neurogranin is diminished in patients with Alzheimer disease & mild cognitive impairment[22]
- serum antibodies to beta amyloid & RAGE may be increased in patients with Alzheimer's disease[5]
- serum IL6 may be increased[11]
- biomarkers not cost effective in the absence of disease modifying therapy[14]
proteomics
- battery of 18 plasma proteins[9] including:
- 32 dementia-associated plasma proteins are involved in proteostasis, immunity, synaptic function, & extracellular matrix organization[33]
- 12 of these 32 are associated with CSF biomarkers of AD, neurodegeneration, or neuroinflammation - SERPINA3
- some of the proteins most strongly associated with risk of dementia, are not detected in brain tissue - GDF15
- five different subtypes of AD identified by CSF proteomics of 1038 proteins[37]
- type 1: characterized by proteins related to neuronal hyperplasticity
- enriched with TREM2 R47H
- longest average survival time 8.9 years
- increased CSF total-tau & CSF p-tau
- type 2: characterized by innate immune activation
- increased CSF total-tau & CSF p-tau
- along with subtype 5, highest risk of MCI progression to dementia
- type 3: characterized by RNA dysregulation
- shortest average survival time 5.6 years
- increased CSF total-tau & CSF p-tau
- type 4: characterized by choroid plexus dysfunction
- normal CSF total-tau & CSF p-tau (relative to controls)
- lowest risk of MCI progression to dementia
- type 5: characterized by blood-brain barrier dysfunction[37]
- normal CSF total-tau & CSF p-tau (relative to controls)
- along with subtype 2, highest risk of MCI progression to dementia
- type 1: characterized by proteins related to neuronal hyperplasticity
lipids
- serum cholesterol, serum LDL, serum HDL NOT risk factors[1]
- serum cholesterol-ester DHA levels may correlate with severity of dementia[2]
- a set of ten lipids depleted in peripheral blood predict mild cognitive impairment or Alzheimer's disease within a 2-3 year period (90% accuracy)[13]
- set includes 8 phosphatidylcholines & 2 acylcarnitines
- set of 10 relects membrane integrity[13]
other body fluids
- salivary/buccal specimens
- phosphorylated tau in buccal swab (AAD meeting abstract)
- salivary Abeta42 proposed as a screening test
- soluble Abeta oligomers, a 12-mer Abeta*56 & a 15-mer AbetaO are elevated in nasal secretions of patients with Alzheimer's disease[24]
- urine tests for neural thread protein* & for isoprostane 8,12-iso-iPf2alpha-VI may possibly be useful[6]
genetic testing
- presenilin 1 mutation[4]
- apo-E4 genotype more common in blacks than whites[34]
- do not order apoE genotyping in patients with suspected AD[14]
investigational
- attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) may eventually have a role in diagnosis[15]
- DNA aptamer-attached portable graphene biosensor
- detects beta-amyloid, microtubule-associated protein tau, & alpha-synuclein in easily accessible biofluids[35]
direct-to-consumer Alzheimer testing
- also see direct-to-consumer Alzheimer testing
More general terms
More specific terms
Additional terms
- Alzheimer's disease (ADD)
- clinical laboratory test
- direct-to-consumer Alzheimer testing (Quest AD-Detect test)
- intestinal lipodystrophy (Whipple's disease)
References
- ↑ 1.0 1.1 Journal Watch 23(12):93, 2003 Total plasma cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Tan Zs et al, Arch Intern Med 163(May12):1053, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12742802
- ↑ 2.0 2.1 Tully AM et al, Br J Nutr 89(4):483, 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd-Retrieve&db=Pubmed&list_uids=126541&dopt-Abstract PMID: https://www.ncbi.nlm.nih.gov/pubmed/12654166
- ↑ 3.0 3.1 Lab Tests Online http://www.labtestsonline.org/understanding/analytes/tau/test.html
- ↑ 4.0 4.1 Lab Tests Online http://www.labtestsonline.org/understanding/analytes/psen1/test.html
- ↑ 5.0 5.1 United Press International http://www.nlm.nih.gov/medlineplus/news/fullstory_18187.html
- ↑ 6.0 6.1 Urine Testing for Alzheimer's Disease Lab Tests Online http://www.labtestsonline.org/news/alzheimer020717.html
- ↑ Alzheimer's Disease (Lab Tests Online) http://www.labtestsonline.org/understanding/conditions/alzheimers.html
- ↑ 8.0 8.1 Internal Medicine News 38(16) August 2005
- ↑ 9.0 9.1 Ray S et al, Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 2007 Nov; 13:1359. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17934472
- ↑ 10.0 10.1 Mattsson N et al. CSF Biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009 Jul 22/29; 302:385. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19622817
Petersen RC and Trojanowski JQ. Use of Alzheimer disease biomarkers: Potentially yes for clinical trials but not yet for clinical practice. JAMA 2009 Jul 22/29; 302:436. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19622825
De Meyer G et al Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People Arch Neurol. 2010;67(8):949-956 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20697045 <Internet> http://archneur.ama-assn.org/cgi/content/abstract/67/8/949 - ↑ 11.0 11.1 11.2 Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 12.0 12.1 Jack CR Jr et al. Evidence for ordering of Alzheimer disease biomarkers. Arch Neurol 2011 Dec; 68:1526. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21825215
- ↑ 13.0 13.1 13.2 Mapstone M et al Plasma phospholipids identify antecedent memory impairment in older adults. Nature Medicine. 09 March 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24608097 <Internet> http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3466.html
- ↑ 14.0 14.1 14.2 Medical Knowledge Self Assessment Program (MKSAP) 17, 18. American College of Physicians, Philadelphia 2015, 2018,
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 15.0 15.1 Paraskevaidi M, Morais CLM, Lima KMG et al. Differential diagnosis of Alzheimer's disease using spectrochemical analysis of blood. Proc Natl Acad Sci U S A 2017 Sep 19; 114:E7929. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28874525 Free Article
- ↑ 16.0 16.1 van Maurik IS, Zwan MD, Tijms BM et al Interpreting Biomarker Results in Individual Patients With Mild Cognitive Impairment in the Alzheimer's Biomarkers in Daily Practice (ABIDE) Project. JAMA Neurol. Published online October 16, 2017. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29049480 https://jamanetwork.com/journals/jamaneurology/fullarticle/2657326
- ↑ 17.0 17.1 Nakamura A, Kaneko N, Villemagne VL et al High performance plasma amyloid-beta biomarkers for Alzheimer's disease. Nature. 2018 Feb 8;554(7691):249-254 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29420472 https://www.nature.com/articles/nature25456
- ↑ Blennow K, Zetterberg H. Cerebrospinal fluid biomarkers for Alzheimer's disease. J Alzheimers Dis. 2009;18(2):413-7. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19661632
- ↑ van Maurik IS et al. Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): A modelling study. Lancet Neurol 2019 Nov; 18:1034 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31526625 https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30283-2/fulltext
- ↑ Early-Onset Alzheimer's Panel, Sequencing Laboratory Test Directory ARUP: http://www.aruplab.com/guides/ug/tests/0000000.jsp
- ↑ 21.0 21.1 Thijssen EH, La Joie R, Wolf A et al Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nature Medicine 2020. March 2 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32123386 https://www.nature.com/articles/s41591-020-0762-2
Morrison MS et al. Antemortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy. Brain 2022 May 13; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/35554506 https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awac175/6585495 - ↑ 22.0 22.1 22.2 Liu W, Lin H, He X et al Neurogranin as a cognitive biomarker in cerebrospinal fluid and blood exosomes for Alzheimer;s disease and mild cognitive impairment. Translational Psychiatry April 29, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32350238 Free PMC Article https://www.nature.com/articles/s41398-020-0801-2
- ↑ 23.0 23.1 Palmqvist S, Janelidze S, Quiroz YT et al Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020;324(8):772-781. Published online July 28, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32722745 https://jamanetwork.com/journals/jama/fullarticle/2768841
- ↑ 24.0 24.1 Yoo SJ, Son G, Bae J et al. Longitudinal profiling of oligomeric Abeta in human nasal discharge reflecting cognitive decline in probable Alzheimer's disease. Nature. Sci Rep 2020 Jul 8; 10:11234 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32641719 PMCID: PMC7343787 Free PMC article https://www.nature.com/articles/s41598-020-68148-2
- ↑ 25.0 25.1 Karikari TK et al Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis. Alzheimers & Dementia 2020. Nov 30 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33252199 https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12236
- ↑ 26.0 26.1 Palmqvist S, Tideman P, Cullen N et al Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 2021. May 24 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34031605 https://www.nature.com/articles/s41591-021-01348-z
- ↑ 27.0 27.1 Benedet AL, Mila-Aloma M, Vrillon A et al Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum. JAMA Neurol. Published online October 18, 2021. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34661615 https://jamanetwork.com/journals/jamaneurology/fullarticle/2784931
- ↑ 28.0 28.1 Vromen EM et al. Biomarker A+T-: Is this Alzheimer's disease or not? A combined CSF and pathology study. Brain 2022 May 2; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35511164 https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac158/6576655
- ↑ 29.0 29.1 Schindler SE et al. Effect of race on prediction of brain amyloidosis by plasma Abeta42/Abeta40, phosphorylated tau, & neurofilament light. Neurology 2022. April 22 https://n.neurology.org/content/early/2022/04/22/WNL.0000000000200358
- ↑ 30.0 30.1 George J Alzheimer's Disease Detected in Blood a Decade Before Clinical Symptoms. GFAP levels change before tau, neurodegeneration biomarkers. MedPage Today January 11, 2023 https://www.medpagetoday.com/neurology/alzheimersdisease/102600
Johansson C, Thordardottir S, Laffita-Mesa J et al Plasma biomarker profiles in autosomal dominant Alzheimer's disease. Brain. Jan 11, 2023 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36626935 https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac399/6979878 - ↑ 31.0 31.1 De Kort AM et al. Decreased cerebrospinal fluid amyloid beta 38, 40, 42, and 43 levels in sporadic and hereditary cerebral amyloid angiopathy. Ann Neurol 2023 Jan 27; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/36707720 https://onlinelibrary.wiley.com/doi/10.1002/ana.26610
- ↑ George J Alzheimer's Blood Tests May Improve Primary Care Diagnoses. Without biomarkers, primary care doctors correctly identified Alzheimer's in about 55% of cases. MedPage Today July 21, 2023 https://www.medpagetoday.com/meetingcoverage/aaic/105596
- ↑ 33.0 33.1 Walker KA, Chen J, Shi L et al Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci Transl Med. 2023. July 19. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37467317 https://www.science.org/doi/10.1126/scitranslmed.adf5681
- ↑ 34.0 34.1 34.2 34.3 Ramanan VK et al. Association of plasma biomarkers of Alzheimer disease with cognition and medical comorbidities in a biracial cohort. Neurology 2023 Aug 14; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37580163
- ↑ 35.0 35.1 Bodily TA, Ramanathan A, Wei S et al In pursuit of degenerative brain disease diagnosis: Dementia biomarkers detected by DNA aptamer-attached portable graphene biosensor. Proc Natl Acad Sci. U.S.A. 2023 Nov 21;120(47):e2311565120. Online Nov 13. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37956285 https://www.pnas.org/doi/10.1073/pnas.2311565120
- ↑ Dark HE, Paterson C, Daya GN et al Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk. Ann Neurol. 2023. Oct 6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37801487 https://onlinelibrary.wiley.com/doi/full/10.1002/ana.26817
- ↑ 37.0 37.1 37.2 Tims BM, Vromen EM, Mjaavatten O et al Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging. 2024 Jan;4(1):33-47. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38195725 PMCID: PMC10798889 Free PMC article. https://www.nature.com/articles/s43587-023-00550-7