Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2025 Feb 3;8(2):e2458149.
doi: 10.1001/jamanetworkopen.2024.58149.

Alzheimer Disease Blood Biomarkers and Cognition Among Individuals With Diabetes and Overweight or Obesity

Michelle M Mielke  1 , Joni K Evans  2 , Rebecca H Neiberg  2 , Doris P Molina-Henry  3   4 , Santica M Marcovina  5 , Karen C Johnson  6 , Owen T Carmichael  7 , Stephen R Rapp  8   9 , Bonnie C Sachs  10   11 , Jingzhong Ding  11 , Heather M Shappell  2 , Jose A Luchsinger  12 , Mark A Espeland  2   11 , Kathleen M Hayden  8
Affiliations
Randomized Controlled Trial

Alzheimer Disease Blood Biomarkers and Cognition Among Individuals With Diabetes and Overweight or Obesity

Michelle M Mielke et al. JAMA Netw Open. .

Abstract

Importance: Blood-based biomarkers (BBMs) are clinically available to aid in the diagnosis of Alzheimer disease (AD) and AD-related dementias (ADRD), but their association with cognition among older adults with specific chronic conditions has not been examined.

Objective: To longitudinally examine associations between baseline AD and ADRD BBMs and change in BBMs with cognition among participants with type 2 diabetes (T2D) and overweight or obesity.

Design, setting, and participants: The Look AHEAD (Action for Health in Diabetes) study was a clinical trial of older adults with T2D and overweight or obesity randomized to a 10-year intensive lifestyle intervention for weight loss or a diabetes support and education condition. Participants were recruited and followed up at 16 clinical sites across the US. Enrollment occurred from January 1, 2001, to December 31, 2004. The primary intervention spanned the first 4 years after participants' enrollment (January 1, 2008, to December 31, 2011). The clinical trial was stopped in September 2012 and was converted to an observational study. Blood samples were drawn at baseline and 8 to 12 years later. Cognitive assessments were performed from January 1, 2013, to December 31, 2014, and from January 1, 2018, to December 31, 2020. Data for the present cohort study were analyzed between January and August 2024.

Exposures: Baseline and 8- to 12-year change in plasma levels of amyloid-β (Aβ)40, Aβ42, Aβ42/40 ratio, phosphorylated tau 181 (pTau-181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

Main outcomes and measures: Cognitive composite z score and adjudicated mild cognitive impairment or probable dementia.

Results: The mean (SD) baseline age of 758 participants was 61.5 (6.1) years, and 424 participants [55.9%] were female. Mean (SD) body mass index was 34.8 (5.3). Of the participants, 373 were randomized to diabetes support and education and 385 to intensive lifestyle intervention. Increasing baseline BBM levels were not associated with any cognitive composite z score. Increasing levels of NfL (β = -0.032 [SE, 0.013]; P = .01) and GFAP (β = -0.087 [SE, 0.025]; P < .001), but not the Aβ42/40 ratio (β = 0.006 [SE, 0.040]; P = .88) or pTau-181 (β = 0.026 [SE, 0.025]; P = .31), were associated with worsening cognitive function and incident mild cognitive impairment or probable dementia. The intervention had no association with 8- to 12-year change in BBM levels.

Conclusions and relevance: In this study of participants with T2D and overweight or obesity, increasing plasma NfL and GFAP levels over time, but not Aβ42/40 or pTau-181 levels, were associated with cognitive decline and incident cognitive impairment. These results suggest that plasma NfL and GFAP may be important biomarkers of cognitive change among this patient population.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mielke reported serving on scientific advisory boards and/or consulting for Althira, Biogen, Eisai, Lilly, Merck, Novo Nordisk, Roche, Siemens and Healthineers and received speaking honorariums from Novo Nordisk, PeerView Institute, and Roche. Dr Molina-Henry reported receiving grants from the Alzheimer’s Association and American Heart Association outside the submitted work. Dr Sachs reported receiving grants and personal fees from the Alzheimer’s Association outside the submitted work. Dr Luchsinger reported serving as a consultant for Merck KGaA and Novo Nordisk, receiving financial support from Wolters Kluwer, and receiving royalties from Springer outside the submitted work. Dr Espeland reported receiving personal fees from Nestle outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Timeline of the Look AHEAD (Action for Health in Diabetes) Study
aAncillary studies with cognitive assessments, including Look AHEAD–Continuation (n = 3750) as well as Look AHEAD–Extension and Look AHEAD MIND (n = 2451).
See this image and copyright information in PMC

References

    1. Rabinovici GD, Gatsonis C, Apgar C, et al. . Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA. 2019;321(13):1286-1294. doi:10.1001/jama.2019.2000 - DOI - PMC - PubMed
    1. Lista S, Mapstone M, Caraci F, et al. . A critical appraisal of blood-based biomarkers for Alzheimer’s disease. Ageing Res Rev. 2024;96:102290. doi:10.1016/j.arr.2024.102290 - DOI - PubMed
    1. Teunissen CE, Verberk IMW, Thijssen EH, et al. . Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol. 2022;21(1):66-77. doi:10.1016/S1474-4422(21)00361-6 - DOI - PubMed
    1. Janelidze S, Mattsson N, Palmqvist S, et al. . Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26(3):379-386. doi:10.1038/s41591-020-0755-1 - DOI - PubMed
    1. Karikari TK, Pascoal TA, Ashton NJ, et al. . 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;19(5):422-433. doi:10.1016/S1474-4422(20)30071-5 - DOI - PubMed

Publication types

MeSH terms