Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study
Open accessAbstract
Background We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease.Methods Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.Findings 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers.Interpretation Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease.Funding Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.
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Changes in brain chemistry begin to occur 20 years or more prior to the onset of noticeable cognitive symptoms in AD.
“Efforts continue to be placed on the early detection of AD as changes in brain chemistry begin to occur 20 years or more prior to the onset of noticeable cognitive symptoms [137,138,139,140].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [139]
The Discussion reports elevated CSF and plasma Aβ measures in cognitively normal PSEN1 E280A mutation carriers more than two decades before the kindred’s median age at mild cognitive impairment onset. The Research in Context interpretation cautions that it is unclear whether these findings are progressive or developmental, or how far they apply to other forms of AD. The claim extends this finding to AD generally and states that chemical changes begin at that time, which this cross-sectional study does not establish. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe brain changes that cause Alzheimer's symptoms are thought to begin 20 years or more before symptoms start.
“Although these symptoms are new to the individual affected, the brain changes that cause them are thought to begin 20 years or more before symptoms start.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [2]
The Introduction and Research in Context interpretation report brain imaging changes in PSEN1 E280A mutation carriers more than two decades before their estimated clinical onset. The Discussion says it remains unclear whether those early changes are progressive or contribute to later Alzheimer’s pathology, so the paper does not establish that they cause symptoms or that the timing applies to Alzheimer’s disease generally. Page numbers are not provided in our copy. (LLM, conf=0.86)
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ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
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“Overt clinical symptoms typically do not appear until the underlying pathology is welldeveloped [8]; however, functional imaging studies suggest that changes in synaptic function occur several years before outward signs of the disease are apparent [9].”
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Dominantly Inherited Alzheimer Network: facilitating research and clinical trials
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Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease
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Self-citationAlzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects
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Self-citationAPOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease
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- Authors
- Reiman, E. M., Quiroz, Y. T., Fleisher, A. S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A. M., Shah, A. R., Alvarez, S., Arbelaez, A., Giraldo, M., Acosta-Baena, N., Sperling, R. A., Dickerson, B., Stern, C. E., Tirado, V., Munoz, C., Reiman, R. A., Huentelman, M. J., Alexander, G. E., Langbaum, J. B., Kosik, K. S., Tariot, P. N., & Lopera, F.
- Affiliations
- Translational Genomics Research Institute (US)
- Boston University (US)
- University of California San Diego (US)
- University of Arizona (US)
- Washington University in St. Louis (US)
- Universidad de Antioquia (CO)
- Brigham and Women's Hospital (US)
- Banner Alzheimer’s Institute (US)
- University of California, Santa Barbara (US)
- Corresponding author
- Reiman, Eric M
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 11
- Issue
- 12
- Pages
- 1048-1056
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC4181671
- OpenAlex
- W2108493635
- Cited by
- 541
- References
- 42
- Citations by year
- 2026: 24 · 2025: 23 · 2024: 33 · 2023: 38 · 2022: 40 · 2021: 48 · 2020: 43 · 2019: 35 · 2018: 34 · 2017: 34 · 2016: 45 · 2015: 37 · 2014: 43 · 2013: 56 · 2012: 7
- FWCI
- 32.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, P30-AG-19610, R01AG025526, RF1AG041705, R01AG031581, P30AG019610)
- National Institute of Neurological Disorders and Stroke (F31NS078786)
- 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
- autosomal dominant Alzheimer's disease, PSEN1 E280A mutation, presenilin 1, early-onset Alzheimer's disease, preclinical Alzheimer's disease, young adults, hippocampal activation, gray matter reduction, cerebrospinal fluid biomarkers, plasma biomarkers, amyloid-beta, tau protein, APOE ε4, functional MRI, structural MRI
- MeSH terms
- Adolescent, Adult, Alzheimer Disease, Brain, Cross-Sectional Studies, Female, Genes, Dominant, Humans, Magnetic Resonance Imaging, Male, Mutation, Peptide Fragments, Risk Factors, Biomarkers, Case-Control Studies, Amyloid beta-Peptides, Genetic Predisposition to Disease, Presenilin-1, Young Adult
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