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. 2025 Jun;21(6):e70328.
doi: 10.1002/alz.70328.

Alzheimer's disease plasma biomarkers in the Midwestern Amish

Ping Wang  1 , Yeunjoo E Song  1 , Audrey Lynn  1   2 , Kristy Miskimen  1 , Alex Gulyayev  3   4 , Michael B Prough  3   4 , Daniel A Dorfsman  3   4 , Renee A Laux  1 , Sarada L Fuzzell  1 , Sherri D Hochstetler  1 , Andrew F Zaman  3 , Larry D Adams  3 , Laura J Caywood  3 , Jason E Clouse  3 , Sharlene D Herington  3 , Patrice Whitehead  3 , Yining Liu  5 , Noel Moore  5 , Paula Ogrocki  6   7 , Alan J Lerner  6   7 , Anthony J Griswold  3   4 , Jeffery M Vance  3   4 , Michael L Cuccaro  3   4 , William K Scott  3   4 , Margaret A Pericak-Vance  3   4 , Jonathan L Haines  1   2
Affiliations

Alzheimer's disease plasma biomarkers in the Midwestern Amish

Ping Wang et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: Alzheimer's disease (AD) plasma biomarkers are non-invasive measures of the key amyloid beta (Aβ) and tau pathologies. Validation and generalization studies are needed to fully understand their potential for AD prediction and diagnosis in the elderly population.

Methods: In 1067 Amish individuals aged ≥ 65, we measured plasma Aβ and tau to assess their relationships with AD-related outcomes.

Results: Among Amish individuals with AD, plasma phosphorylated tau protein at epitope 181 (p-tau181) was significantly higher (p = 0.04), and plasma Aβ42/p-tau181 ratio was significantly lower (p = 0.01) than cognitively normal individuals. The association of AD with elevated p-tau181 was driven by apolipoprotein E (APOE) ε4 carriers (odds ratio = 6.02, p < 0.001). Cluster analysis identified two subgroups defined by differing Aβ and tau levels, with the high-risk cluster having more APOE ε4 carriers (p < 0.001).

Discussion: Plasma biomarkers, particularly p-tau181, Aβ42/Aβ40, and Aβ42/p-tau181 ratio, are promising surrogate biomarkers for AD-related pathology and clinical outcomes in the Amish.

Keywords: Alzheimer's disease; cluster analysis; cognitive function; founder population; plasma biomarkers.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Plasma p‐tau181, but not Aβ42/Aβ40 ratio, was significantly higher in Amish individuals with AD than CU individuals. Aβ, amyloid beta; AD, Alzheimer's disease; CINAD, cognitively impaired but not Alzheimer's disease; CU, cognitively unimpaired; MCI, mild cognitive impairment; p‐tau181, phosphorylated tau protein at epitope 181.
FIGURE 2
FIGURE 2
Forest plots illustrating the associations between plasma biomarkers and three clinical outcomes: plasma p‐tau181 and the Aβ42/p‐tau181 ratio were significantly associated with cognitive preservation when comparing CU individuals to those with CI (including CINAD and AD). A, Multivariate regression models were applied among AD and CU individuals. B, Multivariate regression models were applied among individuals with CU and CI (MCI, CINAD, and AD). C, Multivariate regression models were applied among individuals with CU and CI (CINAD and AD). Aβ, amyloid beta; AD, Alzheimer's disease; CI, cognitively impaired; CINAD, cognitively impaired but not Alzheimer's disease; CU, cognitively unimpaired; MCI, mild cognitive impairment; p‐tau181, phosphorylated tau protein at epitope 181.
FIGURE 3
FIGURE 3
Clustering analysis based on plasma Aβ42/Aβ40 and p‐tau181 levels categorized Amish individuals into two distinct groups (k = 2) with low risk and high risk profiles for AD. Aβ, amyloid beta; AD, Alzheimer's disease; CINAD, cognitively impaired but not Alzheimer's disease; CU, cognitively unimpaired; MCI, mild cognitive impairment; p‐tau181, phosphorylated tau protein at epitope 181.
See this image and copyright information in PMC

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