Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
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Volume 10 Number 2 2026
REVIEWS (Open Access)
Cross-species comparative genomics in Alzheimer's disease drug discovery
Moushumi Afroza Mou1, Asim Debnath2, Md Sefaut Ullah3, Muhammad Rizki Saputra 4*
Integrative Biomedical Research 10 (2) 1-8 https://doi.org/10.25163/biomedical.10210968
Submitted: 17 September 2026 Revised: 10 November 2026 Accepted: 17 November 2026 Published: 19 November 2026
Abstract
For decades, Alzheimer's disease (AD) research has leaned on animal models that reproduce amyloid plaques convincingly yet seem to say rather little about how the sporadic, late-onset illness actually unfolds in people. That mismatch has, arguably, contributed to one of the highest attrition rates in drug development. Cross-species comparative genomics offers a way to ask a sharper question: not whether a model "has Alzheimer's", but which parts of the human disease it captures, and which it misses. In this review, we synthesise evidence from first-generation transgenic mice, humanized knock-in lines, tree shrews, non-human primates, naturally aging mammals and invertebrate systems, reading them through transcriptomic, epigenetic and network-level comparisons with human brain tissue. A fairly consistent picture emerges. Neuronal programmes for synaptic transmission and vesicle trafficking are well conserved, whereas microglial, astrocytic and oligodendrocyte networks diverge substantially, with notable rewiring of genes such as PSEN1 and the complement cascade. Knock-in models appear to match human late-onset signatures more closely than overexpression models, and tree shrews and primates narrow the evolutionary gap further, though at real practical cost. The evidence remains uneven, however, and much of the newest computational work has yet to pass peer review. Computational frameworks, particularly Translatable Components Regression, network alignment and emerging foundation models, can recover conserved pathways even where gene-level overlap is modest, and have already nominated repurposing candidates such as suvorexant. We argue that the field may gain most by treating models as partial, quantifiable approximations, chosen and interpreted according to the specific biological question at hand.
Keywords: Alzheimer's disease; comparative genomics; animal models; glial divergence; cross-species translation; TransComp-R; drug repurposing
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