Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish
Liu, Y.; Song, Y. E.; Wang, W.; Lynn, A.; Miskimen, K.; Fuzzell, S. L.; Hochstetler, S. D.; Laux et al.. medRxiv (preprint), 2026-09-20
Topic: Amyloid, tau and blood-test diagnosis
Structured AbstractO_ST_ABSBackgroundC_ST_ABSThe genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease. MethodUsing extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed. ResultsHeritability estimates suggested that common variants explain much of genetic risk among APOE-{varepsilon}4 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed APOE-{varepsilon}4 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified. DiscussionThese findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the APOE-{varepsilon}4 non-carriers.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Liu, Y., Song, Y. E., Wang, W., Lynn, A., Miskimen, K., Fuzzell, S. L., et al. (2026). Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish. medRxiv (preprint). https://doi.org/10.64898/2026.09.17.26363309
Vancouver
Liu Y, Song YE, Wang W, Lynn A, Miskimen K, Fuzzell SL, et al. Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish. medRxiv (preprint). 2026. doi:10.64898/2026.09.17.26363309.
BibTeX
@article{liu2026-cab8ac54,
author = {Liu, Y. and Song, Y. E. and Wang, W. and Lynn, A. and Miskimen, K. and Fuzzell, S. L. and Hochstetler, S. D. and Laux and others},
title = {{Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.17.26363309},
url = {https://doi.org/10.64898/2026.09.17.26363309}
}
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Key findings
- ResultsHeritability estimates suggested that common variants explain much of genetic risk among APOE-{varepsilon}4 carriers, while unexplained heritability remains in non-carriers in the Amish.
- Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified.
Why it matters
This study in Midwestern Amish communities found that common genetic variants explain much of Alzheimer's risk in APOE-e4 carriers, while other factors remain unexplained in non-carriers, and identified RIN3 and PILRA as linked to cognitive impairment risk. It is genetic research that may guide future work but does not offer a treatment or cure.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 22 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 21 of the 94 points we could judge it on, which is 22 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Jonathan L. Haines: h-index 127 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Case Western Reserve University: institution h-index 1,159 (OpenAlex) |
| Multicenter collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 21 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 21 of the 94 points we could judge it on is 22 out of 100. |
| Total | 22 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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