Table 5.

Studies of genetic associations

Category		# Of papers	Example paper
Genotype	APOE alone	6 [175–180]	Sampedro et al. 2015, Oncotarget	Female carriers of the APOE ε4 allele had widespread hypometabolism and cortical thinning compared with female noncarriers, whereas male carriers had a higher risk of cerebral microbleeds, suggesting a differential sex bias of the APOE ε4 allele.
	Candidate SNPs and genes	16 [181–195]	Lazaris et al. 2015, Neurology Genetics	SNPs in BIN1, CD2AP, and CR1 modulated the association between plasma ApoE and Aβ load, independent of APOE4 status.
	Candidate pathways	1 [196]	Biffi et al. 2014, Neurobiol Aging	Variants in oxidative phosphorylation genes, summarized as a genetic risk score, were associated with clinical status, and hippocampal and entorhinal cortex volumes, suggesting an overlap of the genetic structure of AD and stroke.
	Epistatic interactions	3 [197–199]	Hohman et al. 2014, Neurobiol Aging	Found epistatic interactions between GSK3β (tau protein kinase 1) and Aβ-related genes such as APP. Combined interactions explained up to 1.5% of the variance in Aβ deposition.
Phenotype	Case-control	12 [200–211]	Escott-Price et al. 2014, PLoS One	A novel gene-wide statistical approach in a mega meta-analysis of genome-wide data sets identified two novel loci, TP53INP1 and IGHV1 associated with AD, and found evidence of a gene-wide association for loci previously identified by SNP analysis.
	Structural imaging	6 [212–217]	Xu et al. 2014, PLoS One	Used longitudinal structural MRI data as phenotypes in a GWAS and identified a larger number of SNP-phenotypes associations than from baseline data. APOE and TOMM40 were top hits; this is a novel SNP that was identified in APOE.
	Aβ deposition (PET, CSF)	6 [218–223]	Ramanan et al. 2015, Brain	Used longitudinal florbetapir PET data in a GWAS and identified an intronic SNP in IL1RAP, rs12053868, significant in the absence of APOE ε4 allele. The minor allele was associated with greater cortical Aβ burden, atrophy, rate of MCI to AD progression, and cognitive decline. IL1RAP is involved in microglial activation.
	Fluid (CSF, blood)	3 [224,225]	Kauwe et al. 2014, PLoS Genet	GWAS of panel of CSF analytes involved in a range of imported AD processes such as endocytosis, cholesterol metabolism, inflammatory and immune response, identified associations with proteins involved in Aβ processing or proinflammatory signaling.
	Neuropsychological assessments	2 [226,227]	Sherva et al. 2014, Alz Dem	Used longitudinal changes in ADAS-cog to identified variants in the SPON1 gene whose minor alleles were associated with more rapid cognitive decline. Spondin 1 inhibits APP cleavage by BACE.
Other studies		3 [228–230]	Chen et al. 2015, Nat Commun	ADNI one of six cohorts identifying polygenic architecture of human cortex. Variability of cortex surface area explained by additive effects of genome-wide SNPs with those in evolutionary conserved areas contributing more to medial and temporal cortices.

Abbreviations: APOE, apolipoprotein E; SNP, small nucleotide polymorphism; AD, Alzheimer’s disease; APP, Aβ precursor protein; PET, positron emission tomography; CSF, cerebrospinal fluid; GWAS, genome-wide association study; MCI, mild cognitive impairment; ADAS-cog, Alzheimer’s Disease Assessment Scale–cognitive subscale; BACE, beta-secretase 1.