Cognitively healthy ageing and its conceptual counterpart, dementia, have long garnered much interest in the research community, the broader public and regulatory bodies alike. Although β-amyloid deposition is widely regarded as the principal neuropathological hallmark of Alzheimer's disease, its precise role in the causal chain of cognitive decline remains under debate. Applying strict criteria to define neurocognitive health, a selection of 35 participants aged over 60 years was drawn from the Human Connectome Project-Ageing. The evaluation of both cognitive and physical fitness, and comprehensive magnetic resonance imaging (MRI) protocol, encompassing diffusion-weighted imaging, T1w/T2w ratio, resting-state functional MRI and arterial spin labelling, were combined with an additional 18F-florbetaben scan to evaluate β-amyloid load. Strikingly, β-amyloid load failed to adhere to the transcription patterns of amyloid precursor protein in all surveyed areas but the entorhinal cortex. Moreover, it was associated with either higher cognitive performance, general fitness, cerebral tissue integrity and cerebral perfusion, or had no discernible impact. This pilot study adds to the growing body of evidence that questions the significance attributed to β-amyloid build-up and the mechanisms of its accumulation in the ageing brain. The results invite a re-evaluation of established theories on β-amyloid build-up neurotoxicity at low concentrations as observed in this cohort. Future investigations should focus on recruiting larger populations to ascertain whether a specific threshold of β-amyloid build-up precipitates cognitive decline or whether β-amyloid accumulation, in fact, serves as a protective mechanism that ultimately fails.

Center for Magnetic Resonance Research University of Minnesota Minneapolis Minnesota USA

Department of Cybernetics Czech Technical University Prague Prague Czech Republic

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology University of Minnesota Medical School Minneapolis Minnesota USA

Department of Psychiatry University of Minnesota Medical School Minneapolis Minnesota USA

Department of Radiology University of Minnesota Minneapolis Minnesota USA

Geriatric Research Education and Clinical Center Veterans Affairs Medical Center Minneapolis Minnesota USA

Zobrazit více v PubMed

Abanto, J. , Dwivedi A. K., Imbimbo B. P., and Espay A. J.. 2024. “Increases in Amyloid‐β42 Slow Cognitive and Clinical Decline in Alzheimer's Disease Trials.” Brain 147: 3513–3521. PubMed

Anstey, K. J. , Cherbuin N., Budge M., and Young J.. 2011. “Body Mass Index in Midlife and Late‐Life as a Risk Factor for Dementia: A Meta‐Analysis of Prospective Studies.” Obesity Reviews 12: e426–e437. PubMed

Beaulieu, C. 2014. “The Biological Basis of Diffusion Anisotropy.” In Diffusion MRI, 155–183. Elsevier.

Bookheimer, S. Y. , Salat D. H., Terpstra M., et al. 2019. “The Lifespan Human Connectome Project in Aging: An Overview.” NeuroImage 185: 335–348. PubMed PMC

Borland, E. , Edgar C., Stomrud E., Cullen N., Hansson O., and Palmqvist S.. 2022. “Clinically Relevant Changes for Cognitive Outcomes in Preclinical and Prodromal Cognitive Stages.” Neurology 99: e1142–e1153. PubMed PMC

Braak, H. , Braak E., and Bohl J.. 1993. “Staging of Alzheimer‐Related Cortical Destruction.” European Neurology 33: 403–408. PubMed

Brydges, C. R. 2019. “Effect Size Guidelines, Sample Size Calculations, and Statistical Power in Gerontology.” Innovation in Aging 3: igz036. PubMed PMC

Christensen, K. J. , Moye J., Armson R. R., and Kern T. M.. 1992. “Health Screening and Random Recruitment for Cognitive Aging Research.” Psychology and Aging 7: 204–208. PubMed PMC

Cohen, J. 1988. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Lawrence Erlbaum Associates.

Cohen, S. I. A. , Linse S., Luheshi L. M., et al. 2013. “Proliferation of Amyloid‐β42 Aggregates Occurs Through a Secondary Nucleation Mechanism.” Proceedings of the National Academy of Sciences 110: 9758–9763. PubMed PMC

Craddock, R. C. , and Clark D. J.. 2016. “Optimized Implementations of Voxel‐Wise Degree Centrality and Local Functional Connectivity Density Mapping in AFNI.” GigaScience 5: 2695209. https://academic.oup.com/gigascience/article/5/suppl_1/s13742‐016‐0147‐0‐d/2965209.

Daneshpour, A. , Nasiri H., Motamed A. K., et al. 2025. “Uncovering Cerebral Blood Flow Patterns Corresponding to Amyloid‐Beta Accumulations in Patients Across the Alzheimer's Disease Continuum Using the Arterial Spin Labeling.” Neurological Sciences 46: 1–10. PubMed

Donohue, M. C. , Sperling R. A., Petersen R., et al. 2017. “Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons.” JAMA 317: 2305–2316. PubMed PMC

Driscoll, I. , and Troncoso J.. 2011. “Asymptomatic Alzheimer's Disease: A Prodrome or a State of Resilience?” Current Alzheimer Research 8: 330–335. PubMed PMC

Dubois, B. , Villain N., Frisoni G. B., et al. 2021. “Clinical Diagnosis of Alzheimer's Disease: Recommendations of the International Working Group.” Lancet Neurology 20: 484–496. PubMed PMC

Filip, P. , Kokošová V., Valenta Z., et al. 2023. “Utility of Quantitative MRI Metrics in Brain Ageing Research.” Frontiers in Aging Neuroscience 15: 1099499. PubMed PMC

Filip, P. , McCarten J. R., Hemmy L., et al. 2025. “Different Grey Matter Microstructural Patterns in Cognitively Healthy Versus Typical Ageing.” NMR in Biomedicine 38: e5305. PubMed PMC

Filip, P. , Svatkova A., Carpenter A. F., et al. 2020. “Rotating Frame MRI Relaxations as Markers of Diffuse White Matter Abnormalities in Multiple Sclerosis.” NeuroImage: Clinical 26: 102234. PubMed PMC

Glasser, M. F. , Coalson T. S., Robinson E. C., et al. 2016. “A Multi‐Modal Parcellation of Human Cerebral Cortex.” Nature 536: 171–178. PubMed PMC

Glasser, M. F. , Sotiropoulos S. N., Wilson J. A., et al. 2013. “The Minimal Preprocessing Pipelines for the Human Connectome Project.” NeuroImage 80: 105–124. PubMed PMC

Glasser, M. F. , and Van Essen D. C.. 2011. “Mapping Human Cortical Areas In Vivo Based on Myelin Content as Revealed by T1‐ and T2‐Weighted MRI.” Journal of Neuroscience 31: 11597–11616. PubMed PMC

Gryglewski, G. , Seiger R., James G. M., et al. 2018. “Spatial Analysis and High Resolution Mapping of the Human Whole‐Brain Transcriptome for Integrative Analysis in Neuroimaging.” NeuroImage 176: 259–267. PubMed

Harms, M. P. , Somerville L. H., Ances B. M., et al. 2018. “Extending the Human Connectome Project Across Ages: Imaging Protocols for the Lifespan Development and Aging Projects.” NeuroImage 183: 972–984. PubMed PMC

Jansen, W. J. , Janssen O., Tijms B. M., et al. 2022. “Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.” JAMA Neurology 79: 228–243. PubMed PMC

Jansen, W. J. , Ossenkoppele R., Knol D. L., et al. 2015. “Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia.” JAMA 313: 1924–1938. PubMed PMC

Juttukonda, M. R. , Li B., Almaktoum R., et al. 2021. “Characterizing Cerebral Hemodynamics Across the Adult Lifespan With Arterial Spin Labeling MRI Data From the Human Connectome Project‐Aging.” NeuroImage 230: 117807. PubMed PMC

Kamiya, K. , Hori M., and Aoki S.. 2020. “NODDI in Clinical Research.” Journal of Neuroscience Methods 346: 108908. PubMed

Krivanek, T. J. , Gale S. A., McFeeley B. M., Nicastri C. M., and Daffner K. R.. 2021. “Promoting Successful Cognitive Aging: A Ten‐Year Update.” Journal of Alzheimer's Disease 81: 871–920. PubMed PMC

Kulmala, J. , Solomon A., Kåreholt I., et al. 2014. “Association Between Mid‐ to Late Life Physical Fitness and Dementia: Evidence From the CAIDE Study.” Journal of Internal Medicine 276: 296–307. PubMed

Kurl, S. , Laukkanen J. A., Lonnroos E., Remes A. M., and Soininen H.. 2018. “Cardiorespiratory Fitness and Risk of Dementia: A Prospective Population‐Based Cohort Study.” Age and Ageing 47: 611–614. PubMed

Martin, C. R. , Preedy V. R., and Rajendram R.. 2021. Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and Diet. Academic Press.

Maschio, C. , and Ni R.. 2022. “Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer's Disease and Other Tauopathies.” Frontiers in Aging Neuroscience 14: 838034. PubMed PMC

McCarten, J. R. 2013. “Clinical Evaluation of Early Cognitive Symptoms.” Clinics in Geriatric Medicine 29: 791–807. PubMed

Möller, H. E. , Bossoni L., Connor J. R., et al. 2019. “Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology.” Trends in Neurosciences 42: 384–401. PubMed

Mucke, L. , and Selkoe D. J.. 2012. “Neurotoxicity of Amyloid β‐Protein: Synaptic and Network Dysfunction.” Cold Spring Harbor Perspectives in Medicine 2: a006338. PubMed PMC

Nelson, M. E. , Jester D. J., Petkus A. J., and Andel R.. 2021. “Cognitive Reserve, Alzheimer's Neuropathology, and Risk of Dementia: A Systematic Review and Meta‐Analysis.” Neuropsychology Review 31: 233–250. PubMed PMC

Ossenkoppele, R. , Pichet Binette A., Groot C., et al. 2022. “Amyloid and Tau PET‐Positive Cognitively Unimpaired Individuals Are at High Risk for Future Cognitive Decline.” Nature Medicine 28: 2381–2387. PubMed PMC

Palombo, M. , Ianus A., Guerreri M., et al. 2020. “SANDI: A Compartment‐Based Model for Non‐Invasive Apparent Soma and Neurite Imaging by Diffusion MRI.” NeuroImage 215: 116835. PubMed PMC

Petersen, R. C. , Wiste H. J., Weigand S. D., et al. 2021. “NIA‐AA Alzheimer's Disease Framework: Clinical Characterization of Stages.” Annals of Neurology 89: 1145–1156. PubMed PMC

Reveley, C. , Ye F. Q., Mars R. B., Matrov D., Chudasama Y., and Leopold D. A.. 2022. “Diffusion MRI Anisotropy in the Cerebral Cortex Is Determined by Unmyelinated Tissue Features.” Nature Communications 13: 6702. PubMed PMC

Rischel, E. B. , Gejl M., Brock B., Rungby J., and Gjedde A.. 2023. “In Alzheimer's Disease, Amyloid Beta Accumulation Is a Protective Mechanism That Ultimately Fails.” Alzheimer's & Dementia 19: 771–783. PubMed

Rosen, R. F. , Tomidokoro Y., Farberg A. S., et al. 2016. “Comparative Pathobiology of β‐Amyloid and the Unique Susceptibility of Humans to Alzheimer's Disease.” Neurobiology of Aging 44: 185–196. PubMed PMC

Selkoe, D. J. , and Hardy J.. 2016. “The Amyloid Hypothesis of Alzheimer's Disease at 25 Years.” EMBO Molecular Medicine 8: 595–608. PubMed PMC

Smith, S. M. , Beckmann C. F., Andersson J., et al. 2013. “Resting‐State fMRI in the Human Connectome Project.” NeuroImage 80: 144–168. PubMed PMC

Sperling, R. A. , Aisen P. S., Beckett L. A., et al. 2011. “Toward Defining the Preclinical Stages of Alzheimer's Disease: Recommendations From the National Institute on Aging‐Alzheimer's Association Workgroups on Diagnostic Guidelines for Alzheimer's Disease.” Alzheimer's & Dementia 7: 280–292. PubMed PMC

Sperling, R. A. , Donohue M. C., Raman R., et al. 2020. “Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals.” JAMA Neurology 77: 735–745. PubMed PMC

Storey, J. D. 2002. “A Direct Approach to False Discovery Rates.” Journal of the Royal Statistical Society. Series B, Statistical Methodology 64: 479–498.

Stüber, C. , Morawski M., Schäfer A., et al. 2014. “Myelin and Iron Concentration in the Human Brain: A Quantitative Study of MRI Contrast.” NeuroImage 93: 95–106. PubMed

Sweeney, M. D. , Sagare A. P., and Zlokovic B. V.. 2018. “Blood–Brain Barrier Breakdown in Alzheimer Disease and Other Neurodegenerative Disorders.” Nature Reviews. Neurology 14: 133–150. PubMed PMC

Veraart, J. , Sijbers J., Sunaert S., Leemans A., and Jeurissen B.. 2013. “Weighted Linear Least Squares Estimation of Diffusion MRI Parameters: Strengths, Limitations, and Pitfalls.” NeuroImage 81: 335–346. PubMed

Walker, L. C. , Schelle J., and Jucker M.. 2016. “The Prion‐Like Properties of Amyloid‐β Assemblies: Implications for Alzheimer's Disease.” Cold Spring Harbor Perspectives in Medicine 6: a024398. PubMed PMC

Wang, H.‐X. , MacDonald S. W. S., Dekhtyar S., and Fratiglioni L.. 2017. “Association of Lifelong Exposure to Cognitive Reserve‐Enhancing Factors With Dementia Risk: A Community‐Based Cohort Study.” PLoS Medicine 14: e1002251. PubMed PMC

Winkler, A. M. , Ridgway G. R., Webster M. A., Smith S. M., and Nichols T. E.. 2014. “Permutation Inference for the General Linear Model.” NeuroImage 92: 381–397. PubMed PMC

Xu, W. L. , Atti A. R., Gatz M., Pedersen N. L., Johansson B., and Fratiglioni L.. 2011. “Midlife Overweight and Obesity Increase Late‐Life Dementia Risk: A Population‐Based Twin Study.” Neurology 76: 1568–1574. PubMed PMC

Zang, Y. , Jiang T., Lu Y., He Y., and Tian L.. 2004. “Regional Homogeneity Approach to fMRI Data Analysis.” NeuroImage 22: 394–400. PubMed

Zang, Y.‐F. , He Y., Zhu C.‐Z., et al. 2007. “Altered Baseline Brain Activity in Children With ADHD Revealed by Resting‐State Functional MRI.” Brain & Development 29: 83–91. PubMed

Zhang, H. , Wang Y., Lyu D., et al. 2021. “Cerebral Blood Flow in Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta‐Analysis.” Ageing Research Reviews 71: 101450. PubMed

Zlokovic, B. V. 2011. “Neurovascular Pathways to Neurodegeneration in Alzheimer's Disease and Other Disorders.” Nature Reviews. Neuroscience 12: 723–738. PubMed PMC