Genetic architecture of Alzheimer's disease

In the paper

“common polymorphisms in the gene apolipoprotein E (APOE) are the most significant genetic risk factor for AD [52–54].”

What the sources say

• Not checked yetcites [52] Pericak-Vance MA, Bebout JL, Gaskell PC Jr., Yamaoka LH, Hung WY, Alberts MJ, … (1991). Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. American journal of human genetics, 48(6), 1034– 1050. 2035524 PMC1683100
• Not checked yetcites [53] Roses AD, & Saunders AM (1994). APOE is a major susceptibility gene for Alzheimer’s disease. Current opinion in biotechnology, 5(6), 663– 667. 7765750 source
• Not checked yetcites [54] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, … Pericak-Vance MA (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921– 923. 8346443 source

In the paper

“the effect of APOEε4 has been reported to differ across ethnicities [58–61]”

What the sources say

• Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467 source
• Not checked yetcites [59] Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, … Kuwano R (2013). SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PloS one, 8(4), e58618. 23565137 PMC3614978 source
• Not checked yetcites [60] Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, … Farrer LA (2017). Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 13(7), 727– 738. PMC5496797 28183528 source
• Not checked yetcites [61] Murrell JR, Price B, Lane KA, Baiyewu O, Gureje O, Ogunniyi A, … Hall KS (2006). Association of apolipoprotein E genotype and Alzheimer disease in African Americans. Archives of neurology, 63(3), 431– 434. 16533971 PMC3203415 source

In the paper

“A majority of ADAD families carry a pathogenic mutation in one of three genes: APP, presenilin 1 (PSEN1), or presenilin 2 (PSEN2) [2, 33].”

What the sources say

• Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source
• Not checked yetcites [33] Bekris LM, Yu CE, Bird TD, & Tsuang DW (2010). Genetics of Alzheimer disease. Journal of geriatric psychiatry and neurology, 23(4), 213– 227. 21045163 PMC3044597 source

In the paper

“PSEN2 mutations are much rarer, with only around 30 mutations identified in ADAD families [2].”

What the sources say

• Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source

In the paper

“To date, more than 50 highly penetrant mutations have been identified in APP [2].”

What the sources say

• Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source

In the paper

“Mutations in the Aβ domain itself alter the hydrophobicity and downstream aggregation propensity of Aβ peptides, leading to an increase in plaque load [36].”

What the sources say

• Not checked yetcites [36] Tcw J, & Goate AM (2017). Genetics of beta-Amyloid Precursor Protein in Alzheimer’s Disease. Cold Spring Harbor perspectives in medicine, 7(6). 10.1101/cshperspect.a024539 PMC5453386 28003277 source

In the paper

“Estimates of heritability for EOAD are as high as 90–100% [24]”

What the sources say

• Not checked yetcites [24] Wingo TS, Lah JJ, Levey AI, & Cutler DJ (2012). Autosomal recessive causes likely in early-onset Alzheimer disease. Archives of neurology, 69(1), 59– 64. 21911656 PMC3332307 source

In the paper

“familial EOAD mutations in PSEN1 and PSEN2 typically result in an increased production of longer and more aggregation-prone derivatives of APP such as Aβ1–42 [47–49].”

What the sources say

• Not checked yetcites [47] Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, … Selkoe DJ (1997). Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature medicine, 3(1), 67– 72. 8986743 source
• Not checked yetcites [48] Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, … Hutton M (1998). Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Annals of neurology, 43(2), 256– 258. 9485068 source
• Not checked yetcites [49] Cacquevel M, Aeschbach L, Houacine J, & Fraering PC (2012). Alzheimer’s disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified gamma-secretase complexes. PloS one, 7(4), e35133. 22529981 PMC3329438 source

In the paper

“heritability estimates for LOAD are slightly lower, in the range of 60–80% [25]”

What the sources say

• Not checked yetcites [25] Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K, Mortimer JA, … Ahlbom A (1997). Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. The journals of gerontology. Series A, Biological sciences and medical sciences, 52(2), M117– 25. 9060980 source

In the paper

“mutations occurring near the βsecretase cleavage site, such as the Swedish mutation (K670N/M671L), appear to result in increased production of total Aβ [34, 35].”

What the sources say

• Not checked yetcites [34] Busciglio J, Gabuzda DH, Matsudaira P, & Yankner BA (1993). Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proceedings of the National Academy of Sciences of the United States of America, 90(5), 2092– 2096. 8446635 PMC46027 source
• Not checked yetcites [35] Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, … Selkoe DJ (1994). Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proceedings of the National Academy of Sciences of the United States of America, 91(25), 11993– 11997. 7991571 PMC45362 source

In the paper

“a protective mutation in APP (A673T) identified in the Icelandic population [38] results in approximately a 40% reduction in the formation of amyloidogenic peptides.”

What the sources say

• Not checked yetcites [38] Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, … Stefansson K (2012). A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature, 488(7409), 96– 99. 22801501 source

In the paper

“PSEN1 mutations are estimated to contribute to around 80% of monogenic AD.”

In the paper

“The effects of these loci were attributed to nearby genes, clusterin (CLU) and phosphatidylinositol binding clathrin assembly protein (PICALM), respectively.”

In the paper

“the findings here provide a putative mechanism by which regulation of MAPT splicing and exclusion of exon 3 may promote AD independently of APOEε4 genotype.”

In the paper

“a large transethnic GWAS utilizing samples from Caucasians, African Americans, Japanese, and Israeli-Arabs identified several loci contributing to disease risk in all populations [101].”

What the sources say

• Not checked yetcites [101] Li YR, & Keating BJ (2014). Trans-ethnic genome-wide association studies: advantages and challenges of mapping in diverse populations. Genome medicine, 6(10), 91. 25473427 PMC4254423 source

In the paper

“Several genome-wide significant loci not previously detected at the SNP level have been identified using gene-based approaches, including those assigned to TP53INP [115] and PPARGC1A [116].”

What the sources say

• Not checked yetcites [115] Escott-Price V, Bellenguez C, Wang L-S, Choi S-H, Harold D, Jones L, … Cardiovascular Health Study (CHS). (2014). Gene-wide analysis detects two new susceptibility genes for Alzheimer’s disease. PloS one, 9(6), e94661. 24922517 PMC4055488 source
• Not checked yetcites [116] Baker E, Sims R, Leonenko G, Frizzati A, Harwood J, Grozeva D, … EADI Consortium. (n.d.). Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease. 10.1101/374876 PMC6613773 31283791 source

In the paper

“APOEε4 has been shown to modify the age at onset in both EOAD and LOAD [64–66].”

What the sources say

• Not checked yetcites [64] Houlden H, Crook R, Hardy J, Roques P, Collinge J, & Rossor M (1994). Confirmation that familial clustering and age of onset in late onset Alzheimer’s disease are determined at the apolipoprotein E locus. Neuroscience letters, 174(2), 222– 224. 7970184 source
• Not checked yetcites [65] Olarte L, Schupf N, Lee JH, Tang MX, Santana V, Williamson J, … Mayeux R (2006). Apolipoprotein E epsilon4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics. Archives of neurology, 63(11), 1586– 1590. 17101827 source
• Not checked yetcites [66] Locke PA, Conneally PM, Tanzi RE, Gusella JF, & Haines JL (1995). Apolipoprotein E4 allele and Alzheimer disease: examination of allelic association and effect on age at onset in both early- and late-onset cases. Genetic epidemiology, 12(1), 83– 92. 7713402 source

In the paper

“Utilizing multiple ethnic groups in GWAS also enhances the ability of researchers to identify putative causal variants in associated loci due to variations in LD structure across populations [101].”

What the sources say

• Not checked yetcites [101] Li YR, & Keating BJ (2014). Trans-ethnic genome-wide association studies: advantages and challenges of mapping in diverse populations. Genome medicine, 6(10), 91. 25473427 PMC4254423 source

In the paper

“Among APOEε4− subjects, several novel associations between AD risk and SNPs near the MAPT locus were identified.”

What the sources say

• Not checked yetcites [107] Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert J-C, Chung J, Naj AC, … Farrer LA (2016). A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular psychiatry, 21(1), 108– 117. 25778476 PMC4573764 source

In the paper

“seven of the earliest GWAS, each of which used less than 2,000 cases, identified only APOE as significantly associated with AD [84–90].”

What the sources say

• Not checked yetcites [84] Feulner TM, Laws SM, Friedrich P, Wagenpfeil S, Wurst SH, Riehle C, … Riemenschneider M (2010). Examination of the current top candidate genes for AD in a genome-wide association study. Molecular psychiatry, 15(7), 756– 766. 19125160 source
• Not checked yetcites [85] Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, … Younkin SG (2009). Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nature genetics, 41(2), 192– 198. 19136949 PMC2873177 source
• Not checked yetcites [86] Beecham GW, Martin ER, Li YJ, Slifer MA, Gilbert JR, Haines JL, & Pericak-Vance MA (2009). Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. American journal of human genetics, 84(1), 35– 43. 19118814 PMC2668056 source
• Not checked yetcites [87] Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, … Tanzi RE (2008). Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. American journal of human genetics, 83(5), 623– 632. 18976728 PMC2668052 source
• Not checked yetcites [88] Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, … Roses AD (2008). Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Archives of neurology, 65(1), 45– 53. 17998437 source
• Not checked yetcites [89] Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, … Kirov G (2008). A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC medical genomics, 1, 44. 18823527 PMC2570675 source
• Not checked yetcites [90] Liu F, Arias-Vasquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, … van Duijn CM (2007). A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. American journal of human genetics, 81(1), 17– 31. 17564960 PMC1950931 source

In the paper

“APOEε2/APOEε4 individuals are still at increased risk for AD, suggesting the APOEε4 isoform exhibits some dominant effect over the APOEε2 isoform [58].”

What the sources say

• Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467 source

In the paper

“individuals that inherited the APOEε4 allele (and surrounding region) from an African ancestor had a lower risk of developing AD than an individual who inherited APOEε4 from a European ancestor [62, 102].”

What the sources say

• Not checked yetcites [62] Rajabli F, Feliciano BE, Celis K, Hamilton-Nelson KL, Whitehead PL, Adams LD, … Pericak-Vance MA (2018). Ancestral origin of ApoE epsilon4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS genetics, 14(12), e1007791. 30517106 PMC6281216 source
• Not checked yetcites [102] Blue EE, Horimoto ARVR, Mukherjee S, Wijsman EM, & Thornton TA (2019). Local ancestry at APOE modifies Alzheimer’s disease risk in Caribbean Hispanics. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 15(12), 1524– 1532. PMC6925639 31606368 source

In the paper

“variation at this locus is estimated to explain only a portion of the heritability of LOAD [76]”

What the sources say

• Not checked yetcites [76] Ridge PG, Mukherjee S, Crane PK, Kauwe JS, & Alzheimer’s Disease Genetics, Consortium. (2013). Alzheimer’s disease: analyzing the missing heritability. PloS one, 8(11), e79771. 24244562 PMC3820606 source

In the paper

“these approaches when applied to the ABCA7 locus identified a deleterious frameshift deletion in ABCA7 present in African Americans with AD at a higher frequency than either control African Americans or Caucasians [103].”

What the sources say

• Not checked yetcites [103] Cukier HN, Kunkle BW, Vardarajan BN, Rolati S, Hamilton-Nelson KL, Kohli MA, … Alzheimer’s Disease Genetics Consortium. (2016). ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurology. Genetics, 2(3), e79. 27231719 PMC4871806 source

In the paper

“suggesting additional genetic variants play a significant role in determining an individual’s risk for disease.”

In the paper

“only 2% of variants identified as associated with LOAD in the latest meta-analysis fell within exons [97].”

What the sources say

• Not checked yetcites [97] Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, … Environmental Risk for Alzheimer’s Disease, Consortium. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics, 51(3), 414– 430. 30820047 PMC6463297 source

In the paper

“The larger of these, involving over 16,000 individuals, identified SNPs on chromosomes 8 and 11 as significantly associated with disease risk [91].”

What the sources say

• Not checked yetcites [91] Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, … Williams J (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nature genetics, 41(10), 1088– 1093. 19734902 PMC2845877 source

In the paper

“The first association studies covering most of the genome were published in 2007 [81, 82].”

What the sources say

• Not checked yetcites [81] Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, … Stephan DA (2007). A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. The Journal of clinical psychiatry, 68(4), 613– 618. 17474819 source
• Not checked yetcites [82] Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, … Stephan DA (2007). GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron, 54(5), 713– 720. 17553421 PMC2587162 source

In the paper

“loss-of-function mutations in ABCA7 have been identified as associated with disease risk in European populations [104–106]”

What the sources say

• Not checked yetcites [104] Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, … Stefansson K (2015). Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics, 47(5), 445– 447. 25807283 source
• Not checked yetcites [105] Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S, … Sleegers K (2015). Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet neurology, 14(8), 814– 822. 26141617 source
• Not checked yetcites [106] Vardarajan BN, Ghani M, Kahn A, Sheikh S, Sato C, Barral S, … Others. (2015). Rare coding mutations identified by sequencing of A lzheimer disease genome-wide association studies loci. Annals of neurology, 78(3), 487– 498. 26101835 PMC4546546 source

In the paper

“Missense variants with predicted deleterious effects on protein function have been identified by GWAS in TREM2, CR1, MS4A2, MS4A6A, TOMM40, IQCK, and CD33, among others [97, 113]”

What the sources say

• Not checked yetcites [97] Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, … Environmental Risk for Alzheimer’s Disease, Consortium. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics, 51(3), 414– 430. 30820047 PMC6463297 source
• Not checked yetcites [113] Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, … Posthuma D (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature genetics, 51(3), 404– 413. 30617256 PMC6836675 source

In the paper

“However, evidence suggests the most accurate prediction results from a combined consideration of the PRS as well as these additional predictors (APOE genotype, age, and sex) [123].”

What the sources say

• Not checked yetcites [123] Escott-Price V, Shoai M, Pither R, Williams J, & Hardy J (2017). Polygenic score prediction captures nearly all common genetic risk for Alzheimer’s disease. Neurobiology of aging, 49, 214 e7– 214 e11. 27595457 source

In the paper

“Interestingly, estimates suggest common variants identified by GWAS explain only 30% of the heritability of AD [76]”

What the sources say

• Not checked yetcites [76] Ridge PG, Mukherjee S, Crane PK, Kauwe JS, & Alzheimer’s Disease Genetics, Consortium. (2013). Alzheimer’s disease: analyzing the missing heritability. PloS one, 8(11), e79771. 24244562 PMC3820606 source

In the paper

“Overlap in the genetic architecture between AD and other diseases has also been reported, including type 2 diabetes [124] and immune-mediated diseases such as Crohn’s disease [125, 126], although the precise mechanisms underlying this overlap remain to be elucidated.”

What the sources say

• Not checked yetcites [124] Hao K, Di Narzo AF, Ho L, Luo W, Li S, Chen R, … Pasinetti GM (2015). Shared genetic etiology underlying Alzheimer’s disease and type 2 diabetes. Molecular aspects of medicine, 43–44, 66– 76. PMC6021176 26116273 source
• Not checked yetcites [125] Yokoyama JS, Wang Y, Schork AJ, Thompson WK, Karch CM, Cruchaga C, … Alzheimer’s Disease Neuroimaging, Initiative. (2016). Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. JAMA neurology, 73(6), 691– 697. 27088644 PMC4905783 source
• Not checked yetcites [126] Potter H (2016). New Genetic Links Between Alzheimer Disease and Immune-Mediated Diseases Revealed by Overlapping Genome-wide Association Study Hits. JAMA neurology, 73(6), 638– 640. 27088554 source

In the paper

“Given the small effect sizes of loci other than APOE identified by GWAS, it is likely an individual’s risk for AD is determined by the combinatorial effect of multiple variants acting together across the genome.”

In the paper

“Since the identification of R47H, additional rare variants in TREM2 have been associated with AD risk [138–140]”

What the sources say

• Not checked yetcites [138] Benitez BA, Cooper B, Pastor P, Jin S-C, Lorenzo E, Cervantes S, & Cruchaga C (2013). TREM2 is associated with the risk of Alzheimer’s disease in Spanish population. Neurobiology of aging, 34(6), 1711.e15– 7. PMC3596468 23391427 source
• Not checked yetcites [139] Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, … Cruchaga C (2014). Coding variants in TREM2 increase risk for Alzheimer’s disease. Human molecular genetics, 23(21), 5838– 5846. 24899047 PMC4189899 source
• Not checked yetcites [140] Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, … Ertekin-Taner N (2015). TREM2 is associated with increased risk for Alzheimer’s disease in African Americans. Molecular neurodegeneration, 10, 19. 25886450 PMC4426167 source

In the paper

“Although GWAS variants were not associated with risk for familial EOAD inherited in an autosomal dominant fashion, the researchers noted that the sample size was small and that variant burden may have been associated with age at symptom onset in these families [26].”

What the sources say

• Not checked yetcites [26] Cruchaga C, Del-Aguila JL, Saef B, Black K, Fernandez MV, Budde J, … Harari O (2018). Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 14(2), 205– 214. PMC5803427 28943286 source

In the paper

“highlighting the critical role of this protein in the etiology of AD.”

In the paper

“PRS incorporating only genome-wide significant SNPs have showed only a modest improvement in disease prediction over known risk factors such as APOEε4, age, and sex [119–121].”

What the sources say

• Not checked yetcites [119] Sleegers K, Bettens K, De Roeck A, Van Cauwenberghe C, Cuyvers E, Verheijen J, … Belneu consortium. (2015). A 22-single nucleotide polymorphism Alzheimer’s disease risk score correlates with family history, onset age, and cerebrospinal fluid Abeta42. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 11(12), 1452– 1460. 26086184 source
• Not checked yetcites [120] Chouraki V, Reitz C, Maury F, Bis JC, Bellenguez C, Yu L, … International Genomics of Alzheimer’s, Project. (2016). Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer’s Disease. Journal of Alzheimer’s disease: JAD, 53(3), 921– 932. 27340842 PMC5036102 source
• Not checked yetcites [121] Yokoyama JS, Bonham LW, Sears RL, Klein E, Karydas A, Kramer JH, … Coppola G (2015). Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer’s disease. BMC neurology, 15, 47. 25880661 PMC4459447 source

In the paper

“suggesting the genetic architecture of AD is more complex than that suggested by the “common disease, common variant” hypothesis GWAS is designed to test [127].”

What the sources say

• Not checked yetcites [127] Guerreiro RJ, Gustafson DR, & Hardy J (2012). The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiology of aging, 33(3), 437– 456. 20594621 PMC2980860 source

In the paper

“Evidence suggests the R47H variant reduces the ability of TREM2 to bind ligands such as lipidated APOE [137]”

What the sources say

• Not checked yetcites [137] Yeh FL, Wang Y, Tom I, Gonzalez LC, & Sheng M (2016). TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron, 91(2), 328– 340. 27477018 source

In the paper

“One of the most well-studied rare variants that confers elevated risk for AD is the R47H variant in TREM2 [131, 132].”

What the sources say

• Not checked yetcites [131] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, … Stefansson K (2013). Variant of TREM2 associated with the risk of Alzheimer’s disease. The New England journal of medicine, 368(2), 107– 116. 23150908 PMC3677583 source
• Not checked yetcites [132] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, … Alzheimer Genetic Analysis, Group. (2013). TREM2 variants in Alzheimer’s disease. The New England journal of medicine, 368(2), 117– 127. 23150934 PMC3631573 source

In the paper

“As mentioned above, the contribution of rare variants to AD cannot be adequately assessed by GWAS, although improved imputation methods are being developed to address this limitation [128].”

What the sources say

• Not checked yetcites [128] Kunkle BW, Jaworski J, Barral S, Vardarajan B, Beecham GW, Martin ER, … Pericak-Vance MA (2016). Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer’s disease. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(1), 2– 10. PMC4717829 26365416 source

In the paper

“In addition, the increased power provided by expansion of the PRS beyond GWAS risk variants suggests that there are still unidentified common variants that could contribute to disease.”

In the paper

“This approach likely better captures the underlying genetic architecture of AD, since as discussed above GWAS SNPs simply act as tagging variants for a given risk locus and are often not themselves the causal variants.”

In the paper

“For example, rare variants in PLCG2 and ABI3 have been associated with disease risk [130, 141].”

What the sources say

• Not checked yetcites [130] Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, … Schellenberg GD (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nature genetics, 49(9), 1373– 1384. 28714976 PMC5669039 source
• Not checked yetcites [141] Dalmasso MC, Brusco LI, Olivar N, Muchnik C, Hanses C, Milz E, … Ramirez A (2019). Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease. Translational psychiatry, 9(1), 55. 30705288 PMC6355764 source

In the paper

“Interestingly, several genes harboring rare variants, including ADAM10 [114] and SORL1 (discussed below), also emerge as candidates nominated by GWAS studies due to their proximity to AD-associated SNPs.”

What the sources say

• Not checked yetcites [114] Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, … Visscher PM (2018). GWAS on family history of Alzheimer’s disease. Translational psychiatry, 8(1), 99. 29777097 PMC5959890 source

In the paper

“Targeted sequencing analyses have also provided insight into genetic modifiers of the age at first symptom onset in EOAD families [164, 165].”

What the sources say

• Not checked yetcites [164] Velez JI, Rivera D, Mastronardi CA, Patel HR, Tobon C, Villegas A, … Arcos-Burgos M (2016). A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer’s Disease. Neural plasticity, 2016, 9760314. 26949549 PMC4753688 source
• Not checked yetcites [165] Lee JH, Cheng R, Vardarajan B, Lantigua R, Reyes-Dumeyer D, Ortmann W, … Mayeux R (2015). Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation in PSEN1 With Familial Alzheimer Disease Among Caribbean Hispanics. JAMA neurology, 72(9), 1043– 1051. 26214276 PMC5010776 source

In the paper

“Indeed, there is evidence that alternative APP-derived fragments as well as APP itself play important roles in the modulation of immune cell activation [160], protein clearance [161], and lipid homeostasis [162].”

What the sources say

• Not checked yetcites [160] Sondag CM, & Combs CK (2004). Amyloid precursor protein mediates proinflammatory activation of monocytic lineage cells. The Journal of biological chemistry, 279(14), 14456– 14463. 14732706 source
• Not checked yetcites [161] Lauritzen I, Pardossi-Piquard R, Bourgeois A, Pagnotta S, Biferi MG, Barkats M, … Checler F (2016). Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology. Acta neuropathologica, 132(2), 257– 276. 27138984 PMC4947121 source
• Not checked yetcites [162] Grimm MO, Mett J, Grimm HS, & Hartmann T (2017). APP Function and Lipids: A Bidirectional Link. Frontiers in molecular neuroscience, 10, 63. 28344547 PMC5344993 source

In the paper

“In support, sequencing studies have identified rare variants in APP, PSEN1, and PSEN2 that increase risk for LOAD [157].”

What the sources say

• Not checked yetcites [157] Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD, … Nia-Load Ncrad Family Study Consortium. (2012). Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PloS one, 7(2), e31039. 22312439 PMC3270040 source

In the paper

“A large portion of GWAS variants and even variants in high LD with the lead variant fall within non-coding regions of the genome, making their functional importance difficult to infer [168].”

What the sources say

• Not checked yetcites [168] Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, … Stamatoyannopoulos JA (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science, 337(6099), 1190– 1195. 22955828 PMC3771521 source

In the paper

“This provides further evidence these genes are causally involved in disease etiology and facilitates the interpretation of complex GWAS loci.”

In the paper

“suggesting APP plays a role in disease pathogenesis beyond Aβ.”

In the paper

“Common variants near SORL1 have also been identified as associated with disease through GWAS [96], suggesting the same loci may contribute to both EOAD and LOAD.”

What the sources say

• Not checked yetcites [96] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, … Amouyel P (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nature genetics, 45(12), 1452– 1458. 24162737 PMC3896259 source

In the paper

“Suppression of ABCA7 led to increased β-secretase-mediated processing of APP and subsequent elevation of Aβ species [151].”

What the sources say

• Not checked yetcites [151] Satoh K, Abe-Dohmae S, Yokoyama S, St George-Hyslop P, & Fraser PE (2015). ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing. The Journal of biological chemistry, 290(40), 24152– 24165. 26260791 PMC4591804 source

In the paper

“Although causal variants in these genes are typically thought to be inherited in an autosomal dominant fashion, de novo variants in APP, PSEN1, and PSEN2 have also been identified by sequencing in sporadic cases of EOAD that occur with no family history of disease [158, 159].”

What the sources say

• Not checked yetcites [158] Lanoiselee HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, … collaborators of the, C. N. R. M. A. J. project. (2017). APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS medicine, 14(3), e1002270. 28350801 PMC5370101 source
• Not checked yetcites [159] Rovelet-Lecrux A, CNR-MAJ collaborators, Charbonnier C, Wallon D, Nicolas G, Seaman MNJ, … Campion D (2015). De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease. Molecular Psychiatry. 10.1038/mp.2015.100 26194182 source

In the paper

“ABCA7, an ATP-binding cassette transporter protein, is known to be involved in endocytosis and intracellular trafficking of APP [151].”

What the sources say

• Not checked yetcites [151] Satoh K, Abe-Dohmae S, Yokoyama S, St George-Hyslop P, & Fraser PE (2015). ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing. The Journal of biological chemistry, 290(40), 24152– 24165. 26260791 PMC4591804 source

In the paper

“There has been a growing appreciation in recent years that simply assigning a GWAS-identified SNP to the nearest gene in linear genomic space may lead to false associations [174].”

What the sources say

• Not checked yetcites [174] Brodie A, Azaria JR, & Ofran Y (2016). How far from the SNP may the causative genes be? Nucleic acids research, 44(13), 6046– 6054. 27269582 PMC5291268 source

In the paper

“Besides mutations in SORL1 described above, mutations in NOTCH3 were identified in a Turkish family with AD [163].”

What the sources say

• Not checked yetcites [163] Guerreiro RJ, Lohmann E, Kinsella E, Bras JM, Luu N, Gurunlian N, … Singleton A (2012). Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer’s disease. Neurobiology of aging, 33(5), 1008 e17– 23. PMC3306507 22153900 source

In the paper

“While mutations in these genes are the most well-studied mutations associated with EOAD, it is estimated that a significant portion of EOAD remains unexplained genetically [2].”

What the sources say

• Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source

In the paper

“These data suggest APP, PSEN1, and PSEN2 may play a larger role in the development of AD than previously thought and highlight the need to screen both EOAD and LOAD cases by sequencing to identify pathogenic mutations in these genes.”

In the paper

“for example in the most recent large GWAS of AD, implicated loci contained an average of 16 genes [97].”

What the sources say

• Not checked yetcites [97] Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, … Environmental Risk for Alzheimer’s Disease, Consortium. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics, 51(3), 414– 430. 30820047 PMC6463297 source

In the paper

“For a number of genes including APOE, ABCA7, BIN1, TREM2, SORL1, ADAM10, and SPI1, there exists a number of functional studies and genetic evidence to suggest they are indeed the causal genes in their respective loci [97, 173], although their identification does not preclude the existence of additional pathogenic genes in these loci.”

What the sources say

• Not checked yetcites [97] Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, … Environmental Risk for Alzheimer’s Disease, Consortium. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics, 51(3), 414– 430. 30820047 PMC6463297 source
• Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334 source

In the paper

“Notably, an enrichment for rare disruptive and putatively damaging variants in SORL1 were also identified among EOAD cases [155, 156].”

What the sources say

• Not checked yetcites [155] Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, … Phrc Gmaj Collaborators. (2012). High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular psychiatry, 17(9), 875– 879. 22472873 source
• Not checked yetcites [156] Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, … Cnr-Maj collaborators. (2016). SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Molecular psychiatry, 21(6), 831– 836. 26303663 source

In the paper

“Common variants near SORL1 have also been identified as associated with disease through GWAS [96], suggesting the same loci may contribute to both EOAD and LOAD.”

What the sources say

• Not checked yetcites [96] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, … Amouyel P (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nature genetics, 45(12), 1452– 1458. 24162737 PMC3896259 source

In the paper

“A targeted secondary analysis revealed an enrichment for AD variants in regions of open chromatin as measured by ATAC-seq in microglia [184], suggesting a lack of signal in brain tissue is due to the heterogeneity of the bulk tissue from which it was derived.”

What the sources say

• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245

In the paper

“Targeted studies have revealed methylation alterations at additional loci associated with disease [195–197]”

What the sources say

• Not checked yetcites [195] Lunnon K, & Mill J (2013). Epigenetic studies in Alzheimer’s disease: current findings, caveats, and considerations for future studies. American journal of medical genetics. Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics, 162B(8), 789– 799. PMC3947441 24038819 source
• Not checked yetcites [196] Yu L, Chibnik LB, Srivastava GP, Pochet N, Yang J, Xu J, … Bennett DA (2015). Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA neurology, 72(1), 15– 24. 25365775 PMC4344367 source
• Not checked yetcites [197] Chibnik LB, Yu L, Eaton ML, Srivastava G, Schneider JA, Kellis M, … De Jager PL (2015). Alzheimer’s loci: epigenetic associations and interaction with genetic factors. Ann Clin Transl Neurol, 2(6), 636– 647. 26125039 PMC4479524 source

In the paper

“a major role of APOE is to facilitate the transport of cholesterol from astrocytes to neurons in the CNS [188].”

What the sources say

• Not checked yetcites [188] Mahley RW (2016). Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism. Arteriosclerosis, thrombosis, and vascular biology, 36(7), 1305– 1315. PMC4942259 27174096 source

In the paper

“AD-associated variants were enriched for colocalization with eQTLs specifically regulating gene expression in monocytes, but not in T-cells, demonstrating AD variants have a cell-type specific effect on gene expression.”

What the sources say

• Not checked yetcites [193] Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, … De Jager PL (2014). Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science, 344(6183), 519– 523. 24786080 PMC4910825 source

In the paper

“In support of this hypothesis, regions of open chromatin in human monocytes, macrophages, and microglia [173, 184] containing AD risk variants were shown to be enriched for binding motifs of the transcription factor SPI1, providing a mechanistic explanation by which alterations in SPI1 levels conferred by variants in the SPI1 locus may have widespread effects on cellular function.”

What the sources say

• Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334 source
• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245 source

In the paper

“demonstrating AD variants have a cell-type specific effect on gene expression.”

In the paper

“Using quantitative endophenotypes as the primary endpoint for GWAS instead of a binary classification of presence/absence of disease enables a more precise phenotype measurement, thus increasing the power for identification of genetic variants associated with disease [207]”

What the sources say

• Not checked yetcites [207] Hall MH, & Smoller JW (2010). A new role for endophenotypes in the GWAS era: functional characterization of risk variants. Harvard review of psychiatry, 18(1), 67– 74. 20047462 PMC3586547 source

In the paper

“Similar enrichment for immune and liver cell categories was replicated by a second group utilizing an expanded set of tissue-specific annotations [185].”

What the sources say

• Not checked yetcites [185] Lu Q, Powles RL, Abdallah S, Ou D, Wang Q, Hu Y, … Zhao H (2017). Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer’s disease. PLoS genetics, 13(7), e1006933. 28742084 PMC5546707 source

In the paper

“Together, these studies suggest the genetic architecture of AD primarily impacts regulatory elements active in cells of the immune system.”

In the paper

“Remarkably, immune cell types, specifically hematopoietic stem cells and primary blood monocytes, were again identified as primary cell types containing areas of accessible chromatin in which AD-associated variants were preferentially located [184].”

What the sources say

• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245

In the paper

“This idea is supported by studies showing that alleles associated with AD show an effect on gene expression specifically in monocytes.”

What the sources say

• Not checked yetcites [193] Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, … De Jager PL (2014). Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science, 344(6183), 519– 523. 24786080 PMC4910825 source

In the paper

“Several studies have performed targeted analysis of the impact of identified AD SNPs on brain-specific gene expression [200–202].”

What the sources say

• Not checked yetcites [200] Karch CM, Ezerskiy LA, Bertelsen S, Alzheimer’s Disease Genetics, Consortium, & Goate AM (2016). Alzheimer’s Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PloS one, 11(2), e0148717. 26919393 PMC4769299 source
• Not checked yetcites [201] Katsumata Y, Nelson PT, Estus S, Fardo DW, Weiner MW, Aisen P, … Initia ADN (2019). Translating Alzheimer’s disease-associated polymorphisms into functional candidates: a survey of IGAP genes and SNPs. Neurobiology of aging, 74, 135– 146. 30448613 PMC6331247 source
• Not checked yetcites [202] Allen M, Kachadoorian M, Carrasquillo MM, Karhade A, Manly L, Burgess JD, … Ertekin-Taner N (2015). Late-onset Alzheimer disease risk variants mark brain regulatory loci. Neurol Genet, 1(2), e15. 27066552 PMC4807909 source

In the paper

“and two independent genome-wide studies recently identified a differentially methylated region in the ANK1 gene as associated with the burden of AD pathology [198, 199].”

What the sources say

• Not checked yetcites [198] Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, … Mill J (2014). Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nature neuroscience, 17(9), 1164– 1170. 25129077 PMC4410018 source
• Not checked yetcites [199] De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, … Bennett DA (2014). Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature neuroscience, 17(9), 1156– 1163. 25129075 PMC4292795 source

In the paper

“No enrichment was observed for AD variants in brain-specific DNase sites, although the only two datasets included were generated from fetal tissue, which is likely not reflective of the regulatory chromatin landscape observed in adult or diseased brains.”

What the sources say

• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245

In the paper

“This is supported by a recent identification of the enrichment of AD-associated variants in enhancers active in primary human microglia [192].”

What the sources say

• Not checked yetcites [192] Nott A, Holtman IR, Coufal NG, Schlachetzki JCM, Yu M, Hu R, … Glass CK (2019). Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science, 366(6469), 1134– 1139. 31727856 PMC7028213 source

In the paper

“Together, these findings suggest insights into the localization of genetic risk for AD identifies clinically relevant tissue- and cell-type enrichments.”

In the paper

“Using a similar technique and annotation dataset, Huang et al. found a significant enrichment of AD SNPs in functional annotations attributed to hematopoietic cells, specifically monocytes and B-cells [173].”

What the sources say

• Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334 source

In the paper

“suggesting a lack of signal in brain tissue is due to the heterogeneity of the bulk tissue from which it was derived.”

In the paper

“Interestingly, several genes expressed in the liver including liver X receptors (LXRs) have been suggested as potential therapeutic targets for AD [189–191].”

What the sources say

• Not checked yetcites [189] Sodhi RK, & Singh N (2013). Liver X receptors: emerging therapeutic targets for Alzheimer’s disease. Pharmacological research: the official journal of the Italian Pharmacological Society, 72, 45– 51. 23542729 source
• Not checked yetcites [190] Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, … Tontonoz P (2007). Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proceedings of the National Academy of Sciences of the United States of America, 104(25), 10601– 10606. 17563384 PMC1890560 source
• Not checked yetcites [191] Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, … Lazo JS (2005). The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease. The Journal of biological chemistry, 280(6), 4079– 4088. 15557325 source

In the paper

“Based on data from peripheral cells and select microglia-specific datasets [184, 192], it is likely the regulation of gene expression in microglia will emerge as critical to disease pathogenesis.”

What the sources say

• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245 source
• Not checked yetcites [192] Nott A, Holtman IR, Coufal NG, Schlachetzki JCM, Yu M, Hu R, … Glass CK (2019). Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science, 366(6469), 1134– 1139. 31727856 PMC7028213 source

In the paper

“Combined with cell- and tissue-specific gene expression sets, these annotations can provide a comprehensive picture of how and where variants and associated regulatory elements may be impacting gene expression, and presumably, disease risk.”

In the paper

“Huang et al. [173] leveraged this information to identify SPI1 as the most likely candidate causal gene in the genomic region traditionally annotated as the CELF1 locus due to the proximity of the lead GWAS SNP to the gene CELF1.”

What the sources say

• Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334 source

In the paper

“while several genes previously implicated in AD (including APOE and PICALM [229]) have been associated with imaging endophenotypes”

What the sources say

• Not checked yetcites [229] Furney SJ, Simmons A, Breen G, Pedroso I, Lunnon K, Proitsi P, … AddNeuroMed, Consortium. (2011). Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer’s disease. Molecular psychiatry, 16(11), 1130– 1138. 21116278 PMC5980656 source

In the paper

“Groups are actively working to integrate multiple imaging traits together, providing an even further improved diagnostic classification [232, 233]”

What the sources say

• Not checked yetcites [232] Xu Z, Wu C, Pan W, & Alzheimer’s Disease Neuroimaging, Initiative. (2017). Imaging-wide association study: Integrating imaging endophenotypes in GWAS. NeuroImage, 159, 159– 169. 28736311 PMC5671364 source
• Not checked yetcites [233] Scelsi MA, Khan RR, Lorenzi M, Christopher L, Greicius MD, Schott JM, … Altmann A (2018). Genetic study of multimodal imaging Alzheimer’s disease progression score implicates novel loci. Brain: a journal of neurology, 141(7), 2167– 2180. 29860282 PMC6022660 source

In the paper

“amyloid burden across the brain can be localized and quantified through the combined use of a radiolabeled ligand such as Pittsburgh B and positron emission tomography (PET) imaging [219].”

What the sources say

• Not checked yetcites [219] Suppiah S, Didier MA, & Vinjamuri S (2019). The Who, When, Why, and How of PET Amyloid Imaging in Management of Alzheimer’s Disease-Review of Literature and Interesting Images. Diagnostics (Basel), 9(2). 10.3390/diagnostics9020065 PMC6627350 31242587 source

In the paper

“suggesting improved phenotype definition afforded by quantitative measurements is capable of identifying small-effect loci that may be missed by a case/control GWAS.”

In the paper

“While the majority of loci overlap with GWAS loci, several novel loci not previously associated with AD risk have also been identified through these analyses, including variants located near the genes GLIS3, GLIS1, GEMC1, and within SERPINB1 [23, 211].”

What the sources say

• Not checked yetcites [23] Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, … Goate AM (2013). GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron, 78(2), 256– 268. 23562540 PMC3664945 source
• Not checked yetcites [211] Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, … Cruchaga C (2017). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta neuropathologica, 133(5), 839– 856. 28247064 PMC5613285 source

In the paper

“this measurement can be used to differentiate AD patients from other clinical diagnoses [221]”

What the sources say

• Not checked yetcites [221] Dukart J, Mueller K, Horstmann A, Vogt B, Frisch S, Barthel H, … Schroeter ML (2010). Differential effects of global and cerebellar normalization on detection and differentiation of dementia in FDG-PET studies. NeuroImage, 49(2), 1490– 1495. 19770055 source

In the paper

“the loci identified by imaging studies may contain novel genes contributing to the etiology of AD that may have been missed by traditional approaches.”

In the paper

“suggesting these AD risk variants may act, in part, by regulating neurodegeneration.”

In the paper

“are heritable [223, 224]”

What the sources say

• Not checked yetcites [223] Kremen WS, Panizzon MS, Neale MC, Fennema-Notestine C, Prom-Wormley E, Eyler LT, … Dale AM (2012). Heritability of brain ventricle volume: converging evidence from inconsistent results. Neurobiology of aging, 33(1), 1– 8. 20363053 PMC3221930 source
• Not checked yetcites [224] Lunetta KL, Erlich PM, Cuenco KT, Cupples LA, Green RC, Farrer LA, … Mirage Study Group. (2007). Heritability of magnetic resonance imaging (MRI) traits in Alzheimer disease cases and their siblings in the MIRAGE study. Alzheimer disease and associated disorders, 21(2), 85– 91. 17545732 source

In the paper

“In targeted analyses, it has been shown that genetic variants that increase risk for AD also influence CSF Aβ1–42 levels, including pathogenic mutations in APP, PSEN1, and PSEN2, as well as APOE [208–210].”

What the sources say

• Not checked yetcites [208] Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, … Cummings JL (2008). Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology, 71(2), 85– 92. 18509095 PMC12435649 source
• Not checked yetcites [209] Kauwe JS, Wang J, Mayo K, Morris JC, Fagan AM, Holtzman DM, & Goate AM (2009). Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics, 10(1), 13– 17. 18813964 PMC2726757 source
• Not checked yetcites [210] Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM, … Goate AM (2007). Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer’s disease presenilin 1 mutation. Annals of neurology, 61(5), 446– 453. 17366635 source

In the paper

“suggesting it may be a relevant secondary biomarker of disease progression.”

In the paper

“For example, the levels of soluble TREM2 (sTREM2) have been shown to increase five years before symptom onset in autosomal dominant forms of AD [212].”

What the sources say

• Not checked yetcites [212] Suarez-Calvet M, Araque Caballero MA, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, … Dominantly Inherited Alzheimer, Network. (2016). Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury. Science translational medicine, 8(369), 369ra178. PMC5385711 27974666 source

In the paper

“a large number of novel loci and genes have been nominated by these analyses [222, 229–231]”

What the sources say

• Not checked yetcites [222] Risacher SL, Saykin AJ, West JD, Shen L, Firpi HA, McDonald BC, & Alzheimer’s Disease Neuroimaging, Initiative. (2009). Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Current Alzheimer research, 6(4), 347– 361. 19689234 PMC2764863 source
• Not checked yetcites [229] Furney SJ, Simmons A, Breen G, Pedroso I, Lunnon K, Proitsi P, … AddNeuroMed, Consortium. (2011). Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer’s disease. Molecular psychiatry, 16(11), 1130– 1138. 21116278 PMC5980656 source
• Not checked yetcites [230] Potkin SG, Guffanti G, Lakatos A, Turner JA, Kruggel F, Fallon JH, … Alzheimer’s Disease Neuroimaging, Initiative. (2009). Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease. PloS one, 4(8), e6501. 19668339 PMC2719581 source
• Not checked yetcites [231] Stein JL, Hua X, Morra JH, Lee S, Hibar DP, Ho AJ, … Alzheimer’s Disease Neuroimaging, Initiative. (2010). Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer’s disease. NeuroImage, 51(2), 542– 554. 20197096 PMC2856746 source

In the paper

“AD patients exhibit decreased uptake of FDG on PET [220]”

What the sources say

• Not checked yetcites [220] Ou YN, Xu W, Li JQ, Guo Y, Cui M, Chen KL, … Alzheimer’s Disease Neuroimaging, Initiative. (2019). FDG-PET as an independent biomarker for Alzheimer’s biological diagnosis: a longitudinal study. Alzheimer’s research & therapy, 11(1), 57. PMC6599313 31253185 source

In the paper

“SNPs in and around candidate genes including APOE, BIN1, SORL1, and CR1 have been associated with traits including medial temporal lobe atrophy and cortical thickness [225–228]”

What the sources say

• Not checked yetcites [225] Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Cedarbaum J, … Alzheimer’s Disease Neuroimaging, Initiative. (2015). 2014 Update of the Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 11(6), e1– 120. PMC5469297 26073027 source
• Not checked yetcites [226] Saykin AJ, Shen L, Foroud TM, Potkin SG, Swaminathan S, Kim S, … Alzheimer’s Disease Neuroimaging, Initiative. (2010). Alzheimer’s Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 6(3), 265– 273. PMC2868595 20451875 source
• Not checked yetcites [227] Biffi A, Anderson CD, Desikan RS, Sabuncu M, Cortellini L, Schmansky N, … Alzheimer’s Disease Neuroimaging, Initiative. (2010). Genetic variation and neuroimaging measures in Alzheimer disease. Archives of neurology, 67(6), 677– 685. 20558387 PMC2956757 source
• Not checked yetcites [228] Cuenco K T, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA, … Mirage Study Group. (2008). Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Archives of neurology, 65(12), 1640– 1648. 19064752 PMC2719762 source

In the paper

“demonstrating regulation of this endophenotype is orchestrated by genetic variants that also modify risk for disease.”

In the paper

“they reliably predict cognitive decline [222]”

What the sources say

• Not checked yetcites [222] Risacher SL, Saykin AJ, West JD, Shen L, Firpi HA, McDonald BC, & Alzheimer’s Disease Neuroimaging, Initiative. (2009). Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Current Alzheimer research, 6(4), 347– 361. 19689234 PMC2764863 source

In the paper

“Common variants in the MS4A gene cluster were shown to significantly regulate sTREM2 levels in CSF [134], demonstrating regulation of this endophenotype is orchestrated by genetic variants that also modify risk for disease.”

What the sources say

• Not checked yetcites [134] Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, … Cruchaga C (2019). The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Science translational medicine, 11(505). 10.1126/scitranslmed.aau2291 PMC6697053 31413141 source

In the paper

“suggesting FDG-PET provides an additional reliable endophenotype of AD.”

In the paper

“The identification of distinct loci for Aβ1–42 versus tau traits suggest these endophenotypes are regulated, in part, by distinct genetic mechanisms.”

In the paper

“together the additive risk conferred by all variants was significantly associated with both Aβ1–42 and tau.”

What the sources say

• Not checked yetcites [211] Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, … Cruchaga C (2017). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta neuropathologica, 133(5), 839– 856. 28247064 PMC5613285 source

In the paper

“Under normal conditions, surveillance mechanisms including those associated with DNA repair and chromatin remodeling function to repress TE activity and largely maintain genomic stability [243]”

What the sources say

• Not checked yetcites [243] Levin HL, & Moran JV (2011). Dynamic interactions between transposable elements and their hosts. Nature reviews. Genetics, 12(9), 615– 627. PMC3192332 21850042 source

In the paper

“Although in their analysis the individual GWAS SNPs were not significantly associated with CSF levels of Aβ1–42 or tau”

What the sources say

• Not checked yetcites [211] Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, … Cruchaga C (2017). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta neuropathologica, 133(5), 839– 856. 28247064 PMC5613285 source

In the paper

“the finding of a sporadic AD patient who harbored a disease-causative mutation in PSEN1 only in approximately 14% of brain cells [236]”

What the sources say

• Not checked yetcites [236] Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, … Tabrizi SJ (2004). Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease. Human molecular genetics, 13(12), 1219– 1224. 15115757 source

In the paper

“Rare autosomal CNVs in genes besides APP have been implicated in EOAD [252]”

What the sources say

• Not checked yetcites [252] Hooli BV, Kovacs-Vajna ZM, Mullin K, Blumenthal MA, Mattheisen M, Zhang C, … Tanzi RE (2014). Rare autosomal copy number variations in early-onset familial Alzheimer’s disease. Molecular psychiatry, 19(6), 676– 681. 23752245 source

In the paper

“demonstrating consideration of genetic variation beyond SNPs can improve our understanding of the genetic architecture of AD.”

In the paper

“DNA replication stress and insufficient repair mechanisms may contribute to the development of somatic mutations in neurons [246]”

What the sources say

• Not checked yetcites [246] Yurov YB, Vorsanova SG, & Iourov IY (2011). The DNA replication stress hypothesis of Alzheimer’s disease. TheScientificWorldJournal, 11, 2602– 2612. PMC3254013 22262948 source

In the paper

“suggesting sex-specific effects of APOE genotype emerge downstream of amyloidosis [258]”

In the paper

“a functional CNV in the gene CR1 modifying isoform production was shown to increase risk for LOAD in two populations [253]”

What the sources say

• Not checked yetcites [253] Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert JC, Bettens K, Le Bastard N, … an Broeckhoven C (2012). Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Molecular psychiatry, 17(2), 223– 233. 21403675 PMC3265835 source

In the paper

“neurons from AD patients have been observed to have an enriched number of somatic variations not observed in peripheral DNA [239, 240]”

What the sources say

• Not checked yetcites [239] Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, … De Strooper B (2015). On the identification of low allele frequency mosaic mutations in the brains of Alzheimer’s disease patients. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 11(11), 1265– 1276. 25937274 source
• Not checked yetcites [240] Parcerisas A, Rubio SE, Muhaisen A, Gomez-Ramos A, Pujadas L, Puiggros M, … Soriano E (2014). Somatic signature of brain-specific single nucleotide variations in sporadic Alzheimer’s disease. Journal of Alzheimer’s disease: JAD, 42(4), 1357– 1382. 25024348 source

In the paper

“suggesting the contribution of small-effect GWAS loci to AD risk is, in part, mediated by the effect of these variants on specific neuropathologies, including Aβ1–42 and tau levels as well as neurodegeneration.”

In the paper

“and provide important insight into the mechanisms by which variants modifying disease risk may act.”

In the paper

“Neuropathological examination of patient brains harboring APP duplications show abundant plaque and tangle pathology as well cerebral amyloid angiopathy (CAA)”

What the sources say

• Not checked yetcites [248] Planton M, Raposo N, Albucher JF, & Pariente J (2017). Cerebral amyloid angiopathy-related cognitive impairment: The search for a specific neuropsychological pattern. Revue neurologique, 173(9), 562– 565. 28993004 source
• Not checked yetcites [249] Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, & Heyman A (1996). Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology, 46(6), 1592– 1596. 8649554 source

In the paper

“indicating the degree to which mutations that are expressed throughout the body have a profound effect on disease severity [236]”

In the paper

“Together, this work suggests the genetic architecture of AD may not be completely accurately represented by studies utilizing peripheral blood DNA”

In the paper

“Additional somatic mutations in genes known to confer risk for AD such as APP and SORL1 [237] have been identified in the brains of both EOAD and LOAD patients [238, 239]”

What the sources say

• Not checked yetcites [237] Nicolas G, Acuna-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S, … Hoischen A (2018). Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer’s disease. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 14(12), 1632– 1639. PMC6544509 30114415 source
• Not checked yetcites [238] Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK, … Chun J (2015). Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer’s disease brains. eLife, 4 10.7554/eLife.05116 PMC4337608 25650802 source
• Not checked yetcites [239] Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, … De Strooper B (2015). On the identification of low allele frequency mosaic mutations in the brains of Alzheimer’s disease patients. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 11(11), 1265– 1276. 25937274 source

In the paper

“Neuropathologies such as tau have been observed to promote activation of TEs”

What the sources say

• Not checked yetcites [245] Li W, Prazak L, Chatterjee N, Gruninger S, Krug L, Theodorou D, & Dubnau J (2013). Activation of transposable elements during aging and neuronal decline in Drosophila. Nature neuroscience, 16(5), 529– 531. 23563579 PMC3821974 source

In the paper

“Together, these endophenotype-focused GWAS analyses highlight the overlap in genetic architecture across various aspects of AD”

In the paper

“increased genetic risk for LOAD as defined by a high PRS is associated with several imaging endophenotypes, including decreased cortical thickness in brain regions known to be vulnerable to degeneration in AD, decreased total brain volume, and decreased hippocampal volume [234]”

What the sources say

• Not checked yetcites [234] Harrison TM, & Bookheimer SY (2016). Neuroimaging genetic risk for Alzheimer’s disease in preclinical individuals: From candidate genes to polygenic approaches. Biological psychiatry. Cognitive neuroscience and neuroimaging, 1(1), 14– 23. 26858991 PMC4743051 source

In the paper

“Across studies, the association of GWAS-derived PRS with endophenotypes remained significant even after removal of APOE”

In the paper

“Notable sex differences in the clinical and pathological presentation between the sexes exist, each of which have been extensively reviewed previously [258–261]”

What the sources say

• Not checked yetcites [258] Dumitrescu L, Mayeda ER, Sharman K, Moore AM, & Hohman TJ (2019). Sex Differences in the Genetic Architecture of Alzheimer’s Disease. Current genetic medicine reports, 7(1), 13– 21. 31360619 PMC6662731 source
• Not checked yetcites [259] Mielke MM, Vemuri P, & Rocca WA (2014). Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clinical epidemiology, 6, 37– 48. 24470773 PMC3891487 source
• Not checked yetcites [260] Laws KR, Irvine K, & Gale TM (2018). Sex differences in Alzheimer’s disease. Current opinion in psychiatry, 31(2), 133– 139. 29324460 source
• Not checked yetcites [261] Laws KR, Irvine K, & Gale TM (2016). Sex differences in cognitive impairment in Alzheimer’s disease. World J Psychiatry, 6(1), 54– 65. 27014598 PMC4804268 source

In the paper

“Several studies have demonstrated APOE genotype has an exacerbated effect on disease risk in females [58]”

What the sources say

• Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467 source

In the paper

“suggesting these approaches may be useful in identifying recessive mutations that modify an individual’s risk for AD.”

In the paper

“Since the discovery that genetic variants are enriched within regulatory regions active in myeloid cells [173, 183, 184], a large emphasis in the field has been placed on improving resources to better model the impact of these variants in a disease-relevant context.”

What the sources say

• Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334 source
• Not checked yetcites [183] Gagliano SA, Pouget JG, Hardy J, Knight J, Barnes MR, Ryten M, & Weale ME (2016). Genomics implicates adaptive and innate immunity in Alzheimer’s and Parkinson’s diseases. Ann Clin Transl Neurol, 3(12), 924– 933. 28097204 PMC5224821 source
• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245 source

In the paper

“Analyses aimed at genes which influence disease in a non-additive fashion have identified novel candidate genes for obesity and type 2 diabetes [267]”

What the sources say

• Not checked yetcites [267] Wood AR, Tyrrell J, Beaumont R, Jones SE, Tuke MA, Ruth KS, … Weedon MN (2016). Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively. Diabetologia, 59(6), 1214– 1221. 26961502 PMC4869698 source

In the paper

“this suggests patients diagnosed with clinical AD and included in many GWAS as “cases” may in fact not be pure AD cases but rather be suffering from a type of dementia due to mixed causes.”

In the paper

“an individual’s genetic background has been reported to influence how they respond to environmental exposures or lifestyle factors [269]”

What the sources say

• Not checked yetcites [269] Eid A, Mhatre I, & Richardson JR (2019). Gene-environment interactions in Alzheimer’s disease: A potential path to precision medicine. Pharmacology & therapeutics, 199, 173– 187. 30877021 PMC6827882 source

In the paper

“suggesting gene-gene interactions do indeed contribute to the heritability of AD.”

In the paper

“a PRS derived from human LOAD GWAS [96] showed significant association with cognitive outcomes across genetically diverse AD mice at 14 months of age [288]”

What the sources say

• Not checked yetcites [96] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, … Amouyel P (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nature genetics, 45(12), 1452– 1458. 24162737 PMC3896259 source
• Not checked yetcites [288] Neuner SM, Heuer SE, Huentelman MJ, O’Connell KMS, & Kaczorowski CC (2019). Harnessing Genetic Complexity to Enhance Translatability of Alzheimer’s Disease Mouse Models: A Path toward Precision Medicine. Neuron, 101(3), 399– 411 e5. 30595332 PMC6886697 source

In the paper

“suggesting additional factors such as background genetic modifiers or even non-genetic lifestyle factors play a substantial role in dictating disease risk and severity.”

In the paper

“This highlights the possibility that extensive gene-gene interactions may contribute significantly to the genetic architecture of AD such that the effect of any AD-associated variant may largely depend on surrounding genetic context [268]”

In the paper

“traditional models created by incorporating a highly penetrant mutation in APP, PSEN1, or PSEN2 onto a single inbred background strain have largely failed to yield successful results in human clinical trials [286, 287]”

What the sources say

• Not checked yetcites [286] Onos KD, Sukoff Rizzo SJ, Howell GR, & Sasner M (2016). Toward more predictive genetic mouse models of Alzheimer’s disease. Brain research bulletin, 122, 1– 11. 26708939 PMC4843786 source
• Not checked yetcites [287] Hargis KE, & Blalock EM (2017). Transcriptional signatures of brain aging and Alzheimer’s disease: What are our rodent models telling us? Behavioural brain research, 322(Pt B), 311– 328. 27155503 PMC5533609 source

In the paper

“current evidence points to important differences in the AD genetic architecture across sexes.”

In the paper

“Several modifiable risk factors have been associated with AD risk across populations, including educational attainment, obesity, cholesterol levels, social isolation, alcohol consumption, and exposure to pesticides [269, 270]”

What the sources say

• Not checked yetcites [269] Eid A, Mhatre I, & Richardson JR (2019). Gene-environment interactions in Alzheimer’s disease: A potential path to precision medicine. Pharmacology & therapeutics, 199, 173– 187. 30877021 PMC6827882 source
• Not checked yetcites [270] Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, … Mukadam N (2017). Dementia prevention, intervention, and care. The Lancet, 390(10113), 2673– 2734. 28735855 source

In the paper

“suggesting these genetically diverse models may represent improved preclinical resources than traditional approaches.”

In the paper

“suggesting similar genetic mechanisms underlie AD susceptibility across species.”

In the paper

“suggest variants in an individual’s genetic background modify the effect of specific variants on phenotypic penetrance.”

In the paper

“Across the population, patients clinically diagnosed with AD display a wide variation in the onset, duration, and severity of symptoms across multiple functional domains”

What the sources say

• Not checked yetcites [275] DeTure MA, & Dickson DW (2019). The neuropathological diagnosis of Alzheimer’s disease. Molecular neurodegeneration, 14(1), 32. 31375134 PMC6679484 source

In the paper

“This heterogeneity is observed even in carriers of highly penetrant APP and PSEN mutations [276]”

What the sources say

• Not checked yetcites [276] Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, … Dominantly Inherited Alzheimer Network. (2014). Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology, 83(3), 253– 260. 24928124 PMC4117367 source

In the paper

“it has been estimated that up to 90% of EOAD may be caused by recessive mutations [24]”

What the sources say

• Not checked yetcites [24] Wingo TS, Lah JJ, Levey AI, & Cutler DJ (2012). Autosomal recessive causes likely in early-onset Alzheimer disease. Archives of neurology, 69(1), 59– 64. 21911656 PMC3332307 source

In the paper

“The large variability in the age at onset of AD symptoms even among families who share common pathogenic mutations [31]”

What the sources say

• Not checked yetcites [31] Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, … Frebourg T (1999). Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. American journal of human genetics, 65(3), 664– 670. 10441572 PMC1377972 source

In the paper

“we now understand that common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants seem to be enriched for localization to regulatory elements active largely in human monocytes, macrophages, and microglia.”

What the sources say

• Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334 source
• Not checked yetcites [183] Gagliano SA, Pouget JG, Hardy J, Knight J, Barnes MR, Ryten M, & Weale ME (2016). Genomics implicates adaptive and innate immunity in Alzheimer’s and Parkinson’s diseases. Ann Clin Transl Neurol, 3(12), 924– 933. 28097204 PMC5224821 source
• Not checked yetcites [184] Tansey KE, Cameron D, & Hill MJ (2018). Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome medicine, 10(1), 14. 29482603 PMC5828245 source

In the paper

“This has resulted in highly efficient techniques to derive microglia-like cells from human induced pluripotent stem cells (iPSCs) [278, 279].”

What the sources say

• Not checked yetcites [278] McQuade A, Coburn M, Tu CH, Hasselmann J, Davtyan H, & Blurton-Jones M (2018). Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Molecular neurodegeneration, 13(1), 67. 30577865 PMC6303871 source
• Not checked yetcites [279] Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, … Blurton-Jones M (2017). iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron, 94(2), 278– 293 e9. 28426964 PMC5482419 source

In the paper

“Finally, some of the “missing heritability” of AD may be attributable to the heterogeneity of the disease itself.”

In the paper

“most GWAS are conducted using a standard additive model [266], where it is hypothesized heterozygous variant carriers exhibit a phenotype approximately intermediate in severity relative to each homozygous genotype.”

What the sources say

• Not checked yetcites [266] Sebastiani P, Timofeev N, Dworkis DA, Perls TT, & Steinberg MH (2009). Genome-wide association studies and the genetic dissection of complex traits. American Journal of Hematology. 10.1002/ajh.21440 PMC2895326 19569043 source

In the paper

“These recessive effects may be missed by standard GWAS.”

In the paper

“Several additional loci, including APOE [264], have been identified as exhibiting sex-specific association with AD endophenotypes”

What the sources say

• Not checked yetcites [264] Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, … the Alzheimer’s Disease Neuroimaging, Initiative. (2018). Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA neurology, 75(8), 989– 998. 29801024 PMC6142927 source
• Not checked yetcites [258] Dumitrescu L, Mayeda ER, Sharman K, Moore AM, & Hohman TJ (2019). Sex Differences in the Genetic Architecture of Alzheimer’s Disease. Current genetic medicine reports, 7(1), 13– 21. 31360619 PMC6662731 source
• Not checked yetcites [265] Deming Y, Dumitrescu L, Barnes LL, Thambisetty M, Kunkle B, Gifford KA, … Hohman TJ (2018). Sex-specific genetic predictors of Alzheimer’s disease biomarkers. Acta neuropathologica, 136(6), 857– 872. 29967939 PMC6280657 source

In the paper

“including these complex cases in the AD pool will likely reduce statistical power to identify genetic variants associated specifically with AD.”

In the paper

“A significant majority of patients diagnosed with AD also exhibit signs of additional pathologies including vascular lesions, Lewy bodies, TDP43 pathology or cerebral amyloid angiopathy [275]”

What the sources say

• Not checked yetcites [275] DeTure MA, & Dickson DW (2019). The neuropathological diagnosis of Alzheimer’s disease. Molecular neurodegeneration, 14(1), 32. 31375134 PMC6679484 source

In the paper

“efforts to expand existing AD mouse models through the inclusion of genetic diversity [288, 289] have resulted in resources that show a more significant overlap with human AD transcriptional profiles than models on a single genetic background [288]”

What the sources say

• Not checked yetcites [288] Neuner SM, Heuer SE, Huentelman MJ, O’Connell KMS, & Kaczorowski CC (2019). Harnessing Genetic Complexity to Enhance Translatability of Alzheimer’s Disease Mouse Models: A Path toward Precision Medicine. Neuron, 101(3), 399– 411 e5. 30595332 PMC6886697 source