Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

Abstract

Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…It is estimated that approximately as much as 80 % of the phenotypic variability in AD is genetically caused (Cruchaga et al 2012). The search for genes involved in AD has been ongoing for over two decades since 1987 (Tanzi 2012).…”

Molecular Mechanisms of Alzheimer Disease Protection by the A673T Allele of Amyloid Precursor Protein

“…Genetic studies of Alzheimer disease (AD) 5 have helped shape our current understanding of disease etiology. For example, mutations in presenilin1 (PSEN1) and presenilin 2 (PSEN2), enzymes involved in the processing of APP, have been found in autosomal dominant familial cases of AD (2)(3)(4).…”

“…For example, mutations in presenilin1 (PSEN1) and presenilin 2 (PSEN2), enzymes involved in the processing of APP, have been found in autosomal dominant familial cases of AD (2)(3)(4). More recently, PSEN1 mutations have also been identified in some sporadic cases of late onset AD (5). Numerous disease-associated mutations in the APP gene itself have also been identified.…”

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

“…Mutations in APP, PSEN1, and PSEN2 and APOE e4 carrier status were identified from DNA extracted from peripheral blood samples using methods described previously. 31,32 Clinical evaluators remained blinded to the mutation status of each participant.…”