Genetics of Neurodegeneration

MAF (x-axis) is the frequency at which a non-reference (variant) allele occurs in the population. Variant carriers with OR=1 and non-carriers have the same odds of developing Alzheimer’s disease, variants with OR >1 are associated with an increased risk of Alzheimer’s disease, and variants with OR <1 are associated with a protective effect (y-axis). (A) Causative or strong risk increasing variants. A schematic representation of individual rare variants for which ORs cannot be estimated due to extreme variant rareness. Linkage studies in large pedigrees indicate that specific rare variants in PSEN1, PSEN2, and APP cause autosomal dominant Alzheimer’s disease, in some cases with age at onsets as early as 40 years old. Note that not all variants in these three genes give rise to autosomal dominant Alzheimer’s disease; some might be risk-modifiers or non-pathogenic. Further, evidence is accumulating that certain variants in the SORL1 gene are causative of Alzheimer’s disease before the age of 70 years. The Alzheimer’s disease-association of variants in the SORL1, ABCA7, and TREM2 genes was found in gene-based tests; carriers may come from small pedigrees with inheritance patterns of Alzheimer’s disease suggestive of autosomal dominant inheritance. (B) GWAS hits are common (by convention, MAF >1%) variants that represent risk alleles that occur with significantly different frequency in patients with Alzheimer’s disease and controls. Each variant is represented by the gene in which it occurs, or when the variant is non-coding, by the gene that maps closest to the variant (depicted in dark grey). (C) Protective variants are (very) rare variants suggested to confer resistance against age-associated or disease-associated risk factors of cognitive decline. GWAS=genome-wide association studies. MAF=minor allele frequency. OR=odds ratio. PRS=polygenic risk scores.