Germline mutations in the APP gene are strongly associated with familial Early-Onset Alzheimer’s Disease (EOAD). Similarly, germline mutations in the APC gene are strongly associated with development of familial adenomatous polyposis (FAP); yet GWAS shows that the APC gene is not of importance in the etiology of non-familial, late-onset colorectal cancer (LOCRC). Genome-Wide Etiology Analysis (GWEA) provides a new method to explain GWAS findings (doi.org/10.1111/imm.13700). GWEA requires the formulation of a disease pathway that includes genes with highest significance on GWAS.

Comparison of APP and APC genes for the presence of “dual modality” hotspots: inherited, mutation-prone DNA sequences (somatic hypermutation hotspots and GC-rich DNA) encoding amino acids that are critical for normal protein function. To apply GWEA to GWAS of LOAD.

The main at-risk codons for beta-amyloid were analyzed: twelve of sixteen (75%) beta-amyloid mutations associated with EOAD arose in or adjacent to dual modality hotspots. Similarly, most APC mutations associated with FAP arose in dual modality hotspots. GWEA analysis of LOAD GWAS shows that the most significant genes are APOE, PICALM and BIN1 (p-values ≤10^-48); each is involved in membrane composition, membrane function or transport across membranes, i.e., the underlying infrastructure to allow membrane polarization, depolarization, and synaptic transmission. To the contrary, the APP gene has a significance of 10^-12 (39^th among 84 loci; doi.org/10.1038/s41588-022-01024-z).

Somatic mutations of APP and APC are common in elderly people. Therefore, they are present among those with and without LOAD and LOCRC, respectively, which explains the lack of significance in GWAS. The most significant genes in GWAS of LOAD affect the underlying infrastructure required for normal cognition. This means that beta-amyloid is a marker but not cause of disease and explains why lowering of brain beta-amyloid does not prevent progression of LOAD.