Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study
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IMPORTANCE: Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE: To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES: We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS: Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40. CONCLUSIONS AND RELEVANCE: This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.
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Progression of biomarker measures in Alzheimer's disease is a continuous process that begins before symptoms.
“and that progression of biomarker measures is also a continuous process that begins before symptoms [9–14]”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [11]
The Results (Age-Related Biomarker Changes; page unavailable) show biomarker differences emerging before notable cognitive changes, and the Discussion describes progressive preclinical changes. However, the study examines one autosomal dominant Alzheimer disease kindred using cross-sectional data; its Discussion says these data provide only rough estimates of longitudinal trajectories and cautions against generalizing to late-onset Alzheimer disease. It therefore supports presymptomatic progression, but not an unqualified claim of a continuous process across Alzheimer disease. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn the Paisa kindred, plasma alterations such as elevated Aβ1-42, altered Aβ1-42/Aβ1-40 ratios, and increased p-tau217 appear before clinical symptom onset.
“In the Paisa kindred, plasma alterations such as elevated amyloid beta (Aβ)1‐42, altered Aβ1‐42/Aβ1‐40 ratios, and increased tau phosphorylated at threonine 217 (p‐tau217) appear before clinical symptom onset. 16 , 17”
From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [16]
The Results (CSF and Plasma Biomarkers; page unavailable) report higher plasma Aβ1-42 in mutation carriers than noncarriers, and the Discussion says this was also true in cognitively unimpaired carriers. The paper does not report an altered plasma Aβ1-42/Aβ1-40 ratio or measure plasma p-tau217; its phosphorylated-tau findings concern CSF p-tau181. It also found no age-associated change in plasma Aβ1-42, so it does not establish when that plasma difference first appears. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe first biomarkers to become abnormal in carriers of deterministic AD mutations are those of Aβ.
“The first biomarkers to become abnormal in carriers of deterministic AD mutations are those of Aβ [9–11,14].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [11]
A widely held view is that amyloid biomarkers represent the earliest evidence of AD neuropathologic change currently detectable in living persons.
“Consequently, a widely held view is that amyloid biomarkers represent the earliest evidence of AD neuropathologic change currently detectable in living persons [9,11,72,103,104].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [11]
ADAD work has revealed a temporal ordering of biomarkers consistent with theoretical models, and indications that pathology progressively appears in new regions of the brain as the disease worsens.
“ADAD work has revealed a temporal ordering of biomarkers consistent with theoretical models,6–8 and indications that pathology progressively appears in new regions of the brain as the disease worsens7.”
From Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study (2018) · cites this paper as [8]
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Self-citationAnti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer’s Disease
Gomar, J. J., Conejero-Goldberg, C., Davies, P., Goldberg, T. E., & Initiative, F. T. A. D. N. (2016) · Journal of Alzheimer’s Disease · doi:10.3233/jad-150937 · Cited by 13 · see citing works
Pineda‐Lopez, L., Aguillon, D., Villar‐Vesga, J., Valderrama‐Carmona, P., Guerrero, A., Upreti, A., Arevalo‐Alquichire, S., Correa, L., Mendez‐Castellanos, K., Castaño, D., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71148 · Cited by 4 · see citing works
- Authors
- Fleisher, A. S., Chen, K., Quiroz, Y. T., Jakimovich, L. J., Gutierrez Gomez, M., Langois, C. M., Langbaum, J. B. S., Roontiva, A., Thiyyagura, P., Lee, W., Ayutyanont, N., Lopez, L., Moreno, S., Muñoz, C., Tirado, V., Acosta-Baena, N., Fagan, A. M., Giraldo, M., Garcia, G., Huentelman, M. J., Tariot, P. N., Lopera, F., & Reiman, E. M.
- Affiliations
- Eli Lilly (United States) (US)
- Arizona Alzheimer’s Consortium (US)
- Harvard University (US)
- Banner Alzheimer’s Institute (US)
- Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia
- Universidad de Antioquia (CO)
- Washington University in St. Louis (US)
- University of Arizona (US)
- Translational Genomics Research Institute (US)
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-03-01
- Volume
- 72
- Issue
- 3
- Pages
- 316
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4355261
- OpenAlex
- W2019528205
- Cited by
- 177
- References
- 41
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 11 · 2023: 13 · 2022: 15 · 2021: 22 · 2020: 20 · 2019: 15 · 2018: 19 · 2017: 13 · 2016: 16 · 2015: 12
- FWCI
- 16.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repository University of Antioquia (University of Antioquia) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Aging (RF1AG041705, R01AG055444, R01AG041232, R01AG031581, U19 AG03243806, P30AG019610, P50AG005134, U19AG032438, P01AG026276, P30AG062421)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- presenilin-1 E280A mutation, autosomal dominant Alzheimer's disease, mutation carriers, amyloid-beta, tau protein, cerebrospinal fluid biomarkers, plasma amyloid-beta, 18F-florbetapir PET, cerebral metabolic rate of glucose, hippocampal volume, precuneus, gray matter volume, age of onset
- MeSH terms
- Adult, Aging, Alzheimer Disease, Cross-Sectional Studies, Female, Heterozygote, Humans, Male, Middle Aged, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, Presenilin-1, Young Adult
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