APOE-ε4 and BIN1 increase risk of Alzheimer’s disease pathology but not specifically of Lewy body pathology

Lewy body (LB) pathology commonly occurs in individuals with Alzheimer’s disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer’s Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB–), sole LB pathology (AD–LB+), or no pathology (AD–LB–). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD–LB–), and compared the AD+LB+ to AD+LB– groups. APOE-ε4 was significantly associated with risk of AD+LB– and AD+LB+ compared to AD–LB–. However, APOE-ε4 was not associated with risk of AD–LB+ compared to AD–LB– or risk of AD+LB+ compared to AD+LB–. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-023-01626-6.


Supplementary Figure
. A candidate genetic model of AD and LB pathology.APOE and BIN1, among other genes (see e.g., Bellenguez et al.), drive AD pathology.AD pathology primes other, unknown genes to drive LB pathology.In a separate mechanism not involving AD pathology, GBA and SCNA, among other genes (see e.g., Chang et al. (2017) and Nalls et al.), drive LB pathology.Notably, the set of genes including APOE and BIN1 drives LB pathology only by way of AD pathology and does not affect the likelihood of LB pathology after the step of AD pathogenesis; this risk is determined by as yet unidentified genes.[52,2,10,14,24,18,46,48,13,28] and ours.For Beecham et al., Robinson et al., and Sabir et al., we consider only analyses of APOE-ε4-associated risk for LB pathology or dementia [2,46,48].For Guerreiro et al., we describe the larger discovery cohort [24].If a study analyzed a cohort both with and without including certain clinically assessed subjects, we consider the analysis with the fewest clinically assessed individuals for which the effect size of APOE-ε4 and/or the top variant on BIN1 is reported.a These columns are populated only if an analysis was performed on a pathologically confirmed LB -or LB + group.In this case the sizes of the corresponding subgroups are marked as unknown (e.g., AD + LB + and AD -LB + if LB + is known).b The given category was subdivided into multiple phenotypes, described in Table 3, and a separate analysis was performed on each subgroup [28,18,46].c The control cohort of 2,928 individuals studied in Kaivola et al. was part of a larger set of controls studied in Chia et al., of whom 605 were pathologically confirmed [28,13].Therefore, at most 605 of the 2,928 controls in Kaivola et al. were pathologically confirmed, and, accordingly, at fewest 2,323 controls were not pathologically confirmed (only clinically evaluated).

Study
Supplementary Table 2. Genome-wide significant loci in our study.
Chr:Pos:Minor:Major is chromosome, position (genome build hg38, GRCh38), minor allele, and major allele.MAF is minor allele frequency.[OR] [CI] (P) is effect size reported as odds ratio with 95% confidence interval and significance.The loci besides BIN1 and APOE are novel.Supplementary Table 3. Association of APOE-ε2 (rs7412) with different pathology contrasts.The first column corresponds to the current study, while the following two columns correspond to results obtained using the current sample using literature criteria to classify participants into pathology groups (Fig. 1a-b) [52,28].The last column corresponds to a result reported in the literature [48].Effect sizes are reported as OR with 95% confidence interval [CI] and significance (P-value).

Table 4 . Association of rs4663105 on the BIN1 locus and APOE-ε4 (rs429358) with different pathology contrasts.
First two columns correspond to the current study (based on a meta-analysis) and are compared to the association in the subsets of NACC and Rush individuals separately.

Table 5 . Associations of known Alzheimer's disease risk loci reported in Bellenguez et al. (2022) and known Parkinson's disease risk loci reported in Chang et al. (2017) and Nalls et al. (2019) with different pathology contrasts
[3, 12, 40].Loci for which the reported variant was missing from our summary statistics are not included.Chr:Pos:Minor:Major is chromosome, position, and minor allele and major allele in our study.Lit.MAF is the frequency reported in the literature of the minor allele in our study.Lit.effect is the effect size reported in the literature.N+R MAF is the minor allele frequency in our study.