In 1993, scientists reported the landmark discovery that the apolipoprotein () ɛ4 allele on chromosome 19 was a significant risk factor for late-onset Alzheimer’s disease. This finding   substantially advanced the understanding of Alzheimer’s disease by associating the disease with an identifiable genetic risk factor. The discovery of APOE influenced a new direction in research and continues to be foundational to the development of diagnostics and therapies.

REFERENCES

1. A study published in the Proceedings of the National Academy of Sciences (PNAS) confirmed the association between APOE ɛ4 and Alzheimer’s disease and showed evidence of high avidity binding between APOE and beta-amyloid—the peptide associated with plaques.

Strittmatter, WJ, Saunders, AM, Schmechel, D, Pericak-Vance, M, Enghild, J, Salvesen, GS, & Roses, AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA. 1993;90(5)1977–1981. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46003/

2. A groundbreaking study published in Nature in 1993 showed that the APOE ɛ4 allele was a significant genetic risk factor associated with late-onset Alzheimer’s disease.

Corder, EH, Saunders, AM, Strittmatter, WJ, Schmechel, DE, Gaskell, PC, Small, GW, Roses, AD, Haines, JL, & Pericak-Vance, MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123)921–923. https://doi.org/10.1126/science.8346443

3. A study published in Neurology expanded on the original study, showing that the APOE ɛ4 allele was associated with both familial and sporadic Alzheimer’s disease.

Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hyslop, PH, Pericak-Vance, MA, Joo, SH, Rosi, BL, Gusella, JF, Crapper-MacLachlan, DR, Alberts, MJ, Hulette, C, Crain, B, Goldgaber, D, Roses, AD. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43(8):1467-1472. https://doi:10.1212/wnl.43.8.1467

4. Another PNAS study further explored the interaction between APOE and beta-amyloid peptide as a potential mechanism for neuronal loss.

Strittmatter WJ, Weisgraber KH, Huang DY, Dong, LM, Salvesen, GS, Pericak-Vance, M, Schmechel, D, Saunders, AM, Goldgaber, D, and Roses, AD. Binding of human apolipoprotein E to synthetic amyloid β peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA. 1993;90(17):8098-8102. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC47295/

Penn: Alzheimers Association points to its own QC Program (2009) as the milestone for standardizing CSF biomarkers.

Alzheimer’s Disease Biomarker Advances: Imaging

The mid-2000s marked a period of significant advances in the development of biomarkers for Alzheimer’s disease (AD). Prior to this, research with living patients was limited to cognitive assessment and observation, and misclassification of AD contributed to inconsistent findings. Researchers and clinicians needed an accurate method to confirm diagnoses, explore their relationship with genetic risk factors, detect pathology in genetically high-risk individuals before clinical signs appeared, and act as intermediate phenotypes. One critical breakthrough was the development of the Pittsburgh-B (PiB) compound for positron emission tomography (PET) imaging in 2004. PiB-PET imaging allowed scientists to visualize amyloid-beta plaques in the brains of living patients, offering an unprecedented view of pathology that previously could only be seen post-mortem.

REFERENCES

1. A landmark study published in the Annals of Neurology introduced the use of PiB-Pet imaging that enabled the visualization of amyloid-beta plaques—a hallmark of AlD—in living patients.

Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306-319. https://doi.org/10.1002/ana.20009

2. A comprehensive meta-analysis published in the Journal of the American Medical Association confirmed the relationship between APOE ɛ4 and cerebral amyloid pathology using PET imaging and described a 20- to 30-year interval between the first sign of amyloid and disease onset.

Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313(19):1924–1938. https://doi.org/10.1001/jama.2015.4668

Alzheimer’s Disease Biomarker Advances: Cerebrospinal Fluid

Specific proteins in cerebrospinal fluid (CSF), such as amyloid-beta and tau, also became increasingly recognized and validated as biomarkers for disease progression. Although these CSF biomarkers for Alzheimer’s disease were identified in the early 2000s, it was not until the mid-2000s that they became widely used in large clinical studies. In 2007, researchers demonstrated that CSF levels of tau and beta-amyloid42 could predict future Alzheimer’s disease in older adults with few or no cognitive symptoms.

These biomarkers were crucial for genetics studies—they could be used not only to confirm diagnosis, but also to explore their relationship with genetic risk factors, detect pathology in genetically high-risk individuals years before clinical signs appeared, and act as intermediate phenotypes. Subsequent research used these CSF biomarkers in combination with genetics to better understand gene-environment interactions and mechanisms for disease.

REFERENCES

1. In 2007, a study published in Archives of Neurology demonstrated the power of CSF biomarker ratios for predicting future Alzheimer’s disease in older adults with preclinical cognitive decline.

Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64(3):343–349. https://doi.org/10.1001/archneur.64.3.noc60123

2. In 2023, a study published in Alzheimer’s Research & Therapy showed that DNA methylation in blood was associated with CSF biomarkers for Alzheimer’s disease, even in preclinical cases. This furthered the understanding of preclinical neuropathology and the underlying mechanisms of the disease.

Zhang W, Young JI, Gomez L, Schmidt MA, Lukacsovich D, Varma A, Chen XS, Martin ER, Wang L. Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects. Alzheimers Res Ther. 2023 Apr 10;15(1):78. https://doi.org/10.1186/s13195-023-01216-7

NOTE

Penn: A related milestone in 2001 was reported by another source. A related milestone is reported in 2011. Should only one be retained? If so, which one?

Alzheimer’s Disease Biomarker Advances: Plasma

Although PET and CSF biomarkers were accurate in detecting amyloid pathology, the technology was expensive, invasive, and not widely available. In the late 2010s, researchers found that phosphorylated tau from blood plasma (specifically p-tau181) could accurately predict amyloid pathology and identify Alzheimer’s disease. In 2019, researchers also found that neurofilament light (NfL) in blood samples was associated with neurodegeneration and could be used to monitor both the effects of drug interventions and further neurodegeneration.

Blood draws are routine in clinical care and there are established processes for collecting, storing, and handling blood samples. The introduction of a blood plasma based biomarker for Alzheimer’s disease not only increased the accessibility of screening, diagnosis, and treatment monitoring, but it also helped facilitate the large-scale studies and longitudinal monitoring needed to identify rare genetic variants, refine phenotypes, observe gene-environment interactions, and validate previous genetic findings.

REFERENCES

1. In 2018, an international working group published an overview of their assessment of blood-based biomarkers for Alzheimer’s disease in Nature Reviews Neurology. The working group considered the importance of a more accessible biomarker for clinical and research settings, the validation process needed to determine its efficacy, and the research priorities that would further evaluate its widespread use.

Hampel H, O’Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S, Kiddle SJ, Batrla R, Blennow K. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018 Nov;14(11):639-652. https://doi.org/10.1038/s41582-018-0079-7

2. In 2020, a study published in JAMA Neurology demonstrated that plasma p-tau181 could be reliably measured in blood plasma and was associated with amyloid positivity and the likelihood of Alzheimer’s disease. The study also highlighted the potential use of plasma p-tau181 in primary care settings.

Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, Chamoun M, Savard M, Kang MS, Therriault J, Schöll M, Massarweh G, Soucy JP, Höglund K, Brinkmalm G, Mattsson N, Palmqvist S, Gauthier S, Stomrud E, Zetterberg H, Hansson O, Rosa-Neto P, Blennow K. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020 May;19(5):422-433. https://doi.org/10.1016/S1474-4422(20)30071-5

3. A 2019 study in Nature Medicine showed that NfL in blood plasma could be an effective biomarker for the presence and progression of neurodegeneration associated with Alzheimer’s disease.

Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2019 Jul 1;76(7):791-799. https://doi.org/10.1001/jamaneurol.2019.0765Bottom of Form