At one end of the Alzheimer’s disease genetic spectrum lie the catastrophic mutations in APP and presenilin that lead to autosomal-dominant, early onset AD. At the other end are dozens of common variants that each contribute a smidgen to a person’s risk of late-onset AD. Between the two ends lie rare variants—glitches in the DNA that appear less frequently than common variants, but pack a punch when they do appear. The Alzheimer’s Association International Meeting, held July 14-18, 2019 in Los Angeles, California, featured new rare variants. They came out of the whole-genome and whole-exome sequencing projects geneticists are currently focusing on, and from a deep dive into existing GWAS data. Other newly published work identifies two new risk genes near the ApoE locus. Both contribute to AD risk independent of ApoE, and they may help explain variations in risk seen with the ApoE4 allele in different ethnic groups (see below and Part 5 of this series).

Genetic Landscape: The spectrum of genetic influences on Alzheimer’s disease spans rare to common variants that add more or less risk. [Image courtesy of Richard Mayeux.]

Families with genetic forms of early onset AD have fueled a better understanding of the disease (Aug 2019 conference coverage). Scouting for additional genes that cause early onset dementia, Kenneth Kosik, University of California, Santa Barbara, looked to Colombia. Kosik has worked with Francisco Lopera, Universidad de Antioquia, Medellin, for close to 30 years studying the Colombian AD kindred, a group with early onset AD that comprises nearly 30 families with a presenilin1 E280A mutation, some of whom are now in a prevention trial (Aug 2019 conference coverage).

While recruiting for this trial, Lopera, who is famous in Colombia, made a public appeal for people with familial or early onset dementia to come forward, and more than 1,000 did. Kosik’s group sequenced their genomes, which yielded 11 different presenilin missense mutations in 13 families, including three (I162S, Q223K, I427V) that had never been seen before. Other mutations were new to Colombia, but had been reported elsewhere, such as the widespread H163R mutation.

The analysis included other types of dementia, as well. It yielded 14 missense mutations in eight genes in families with frontal temporal dementia and amyotrophic lateral sclerosis (FTD/ALS). Kosik found mutations in the tau gene MAPT, progranulin (GRN), TARDP, TBK1, CHMP2B, UBQLN2, SOD1, and TUBA4A. Some families span a range of clinical phenotypes. For example, the I383V mutation in TARDP causes mostly behavioral-variant FTD, but also PPA and ALS/FTD. In the newly sequenced Colombian families, Kosik also detected a slew of TREM2 variants, including some homozygous cases.

While FTD is the most common form of dementia in younger people, it remains rare, and researchers are constantly challenged to gather enough affected or at-risk people for research and trials. Much like the families with E280A AD, these FTD families provide an opportunity to study progression, and develop instruments for early detection. For example, among three families with a newly discovered P397S MAPT mutation, two of the sequenced cases were diagnosed with bvFTD, and one with atypical AD. In neuropsychiatric testing of one family, mutation carriers in their 50s and 60s scored up to two standard deviations below normal on language, memory, and functional tests, corrected for age and education. Noncarriers had no such deficits. The carriers had early changes on the geriatric depression scale, suggesting that relatively simple tests could be used to detect and follow their disease, Kosik said.

“All of these people, including the new presenilin families and those with FTD, offer us more opportunities for clinical trials. These families are aware of the clinical trial being run now, and would be keen on participating in new trials,” Kosik said.

Does Colombia have a concentration of presenilin mutations? To find out, Kosik considered founder effects. Spanish conquistadors and African slaves likely brought the presenilin 1 Paisa E280A and I416T mutations to the country, respectively (Lalli et al., 2014Ramirez Aguilar et al., 2019). After 1492, the native population was decimated by diseases brought by the Spanish, and communities shrank into geographically isolated pockets. There, a rapid expansion occurred, as families numbering 10 to 15 children rebuilt the population. This likely allowed the proliferation of rare dominant mutations. Even today, mutations causing AD and other genetic diseases occur in regional clusters in Colombia.

“Why, at the time of massive population collapse due to disease, did a relatively few people survive?” Kosik asked. Did the presenilin mutations confer a fitness advantage? Kosik is examining genomes in search of a signature for selection during the time of rapid population expansion. At AAIC, he speculated that PS mutation carriers might be protected from infectious disease, given the postulated role of Aβ in the innate immune system.

Other whole-exome and whole-genome sequencing projects trawl for rare variants in late-onset AD. Rare variants interest scientists because, compared with the common SNPs that pop up in GWAS, they are more likely to change gene expression or protein function, revealing pathways that might yield therapeutic targets. So far, rare variants associated with AD include protein-truncating and missense variants in TREM2, SORL1, and ABCA7 (Aug 2017 news). The largest whole-exome sequencing effort published to date, from the Alzheimer’s Disease Sequencing Project (ADSP), added to that list the transcription factor ZNF655 and the long non-coding RNA AC099552.4 (Aug 2018 news).

More recently, Lindsay Farrer, Boston University, reported the discovery of a batch of new genes in ADSP participants selected for having a first-degree relative with AD (April 2019 conference news).

At AAIC, Richard Mayeux, Columbia University, New York, added PINX1. This gene encodes an enzyme that helps maintain telomeres. In previous work, Mayeux’s group had sought extremely rare variants, present in just one in 10,000 people, in whole-exome and whole-genome sequencing data from their multiethnic Washington Heights-Inwood Community Aging Project (WHICAP), the ADSP, and other cohorts. SORL1 came up as the only significant hit (Jun 2018 news).

To find more, the new study widened the lens. It included variants that were present in one in 20 people and likely affected expression or function, but used an analysis that counted multiple variants per gene toward the association. The combined cohorts totaled 15,030 cases and controls. This study recently reported multiple variants in PINX1 that, at the gene level, reached significance. No single variant reached genome-wide significance. TREM2 did, if the scientists considered only highly damaging variants that reduced the receptor’s expression at least 20-fold (Tosto et al., 2019).

The PINX1 news ties into a previous report that associated shortening of telomeres with aging, dementia and mortality (Honig et al., 2006). PINX1 has been found to be overexpressed in postmortem brain from people with late-onset AD (Myers et al 2007Narayanan et al., 2014). However, it’s still unclear how the identified variants relate to either telomere length or PINX1 expression.

At AAIC, Mayeux described work defining the effects of rare variants in another gene, SORL1, using induced pluripotent stem cells and organoids. Current theory holds that reduced expression, or loss of function, of SORL1 in AD allows more secretion of Aβ (Campion et al., 2019). Mayeux’s collaborator, Andrew Sproul, also at Columbia, found that neurons derived from human IPSCs expressing the SORL1 mutant E270K process more APP, increase tau, and enlarge their endosomes, compared with isogenic control neurons with no mutation. Organoids derived from the cells reduce cell cycling and accumulate extensive Aβ. The group is currently converting the IPSCs into microglia to learn how the SORL1 mutation affects those cells, Mayeux said.

Also at AAIC, Adam Naj, University of Pennsylvania Perelman School of Medicine, talked about mining existing genotyping data to identify rare variants. Based on a newly released haplotype reference panel, scientists can now use genotypes at common SNPs to impute genotypes at linked, rarer SNPs.

An International Genomics of Alzheimer’s Project (IGAP) meta-analysis of genome-wide associations earlier this year identified 30 susceptibility loci, of which a majority were present in more than one in 50 people (Mar 2019 news). To identify rare variants, Naj imputed genotypes of SNPs present in less than 1 percent of the 64,859 subjects in this dataset. The top hits were in TREM2 and APOE, two genes that reached genome-wide significance, as did SORL1.

No other genes crossed this bar, but several SNPs in novel genes reached the p<10-5 significance level considered suggestive of an association. They include GCA, CTNND2, DYDC2, DYX1C1, B4GALT6, and PWP2. The implicated genes are involved in innate immunity, neuronal differentiation, or had previously been identified as candidate genes for LOAD, ALS, or brain development. Gene-based analysis implicated new signals in SORL1, plus SIRPD, a gene heavily expressed in macrophages; CYB561, which is associated with amyloid processing and inflammation; BLNK, which is coregulated with TREM2; and SLX4; which is involved in aging and telomere shortening. Replication is ongoing, Naj said.

Naj also looked for new common variants, present in more than 1 percent of the subjects, by imputation. He replicated almost all know IGAP loci, and identified one new genome-wide significant locus. The SIL1 gene encodes a protein involved in ER stress, and can reverse some types of tau hyperphosphorylation. They also found 43 other genes, albeit with lower significance, including almost all known IGAP loci. Most of the 18 new genes slotted into familiar pathways of cardiac-related metabolism, immunity, and neuron function.

In recent years, AD researchers have begun to grapple with how ethnicity affects AD genetics. Take ApoE. The risk imparted by its E4 risk allele is known to vary among ethnic groups. Its impact is greatest among Japanese people, intermediate in Caucasians, lower in Hispanics and lower still in African Americans (Farrer et al., 1997Tang et al., 1998). According to work by Margaret Pericak-Vance and colleagues at the University of Miami Miller School of Medicine, the relative protection of African Americans seems to stem from outside the ApoE coding region, and involve the surrounding gene ancestry (Rajabli et al., 2018Apr 2019 conference news).

Pericak-Vance and colleagues are trying to nail down just what those surrounding influences are. One hypothesis is that variants in the TOMM40 gene, which lies adjacent to APOE, could bestow the protection. Previous work suggested that an intronic polyT repeat in TOMM40 tended to be longer in non-Hispanic white people who had the ApoE 3/3 genotype and AD, compared to those without AD (Cruchaga et al., 2011). Alas, data presented at AAIC suggests repeat length is not what protects African Americans. Parker Bussies from the Pericak-Vance lab, measured the length of the polyT variant in cases and controls of 100 African Americans and 100 non-Hispanic whites. Half were ApoE3/E3, half E4/E4. The TOMM40 repeat had no length-dependent protective effect in E4/E4 African Americans.

To further proble local ancestry effects, Derek Dykxhoorn of the same group has made IPSC’s from people with African or European gene ancestry around the ApoE locus, with either E4/4 or E3/3 genotype, and will use the cells to look at molecular mechanisms underlying the ethnic-specific differences.

He may be helped by a recent publication from Nancy Ip, Hong Kong University of Science and Technology, China, and colleagues, which identifies AD causal variants in two genes near ApoE (Zhou et al., 2019). In that study, the authors fine mapped the APOE region using whole-genome sequencing and imputed array data from Chinese and non-Asian AD cohorts. They identify variants in two genes, PVRL2 and APOC1, that are associated with AD. The variants form extended haplotypes with ApoE, which appear more frequently in people with AD. The genes also act independently to raise risk in the absence of ApoE4. The extended risk haplotypes were associated with decreased cognitive performance, lower brain volume, particularly hippocampal, and with plasma and CSF biomarkers.

In the brain, the risk haplotypes were also associated with higher ApoE expression, which may play a role AD. Interestingly, the haplotype frequencies vary greatly among different ethnic groups. Almost no Africans carry the minor, risk haplotypes of PVRL2, ApoC1, or the extended minor haplotypes of ApoE, whereas 2 to 10 percent of Europeans do, perhaps explaining some of ApoE’s local ancestry effects.—Pat McCaffrey


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News Citations

  1. Rare Luck: Two Copies of ApoE2 Shield Against Alzheimer’s
  2. Genetics Propels DIAN Toward Therapies
  3. Crenezumab Update: Baseline Data from Colombian Prevention Trial
  4. The Search for the Missing AD Heritability Turns Up New Rare Variants
  5. Largest AD Whole-Exome Study to Date Finds Two New Risk Genes
  6. At AD/PD Conference, New Alzheimer’s Genes Reinforce Known Pathways
  7. Gaining Notoriety, SORL1 Claims Spot Among Top Alzheimer’s Genes
  8. Paper Alerts: Massive GWAS Studies Published

Mutations Citations

  1. PSEN1 E280A (Paisa)
  2. PSEN1 H163R
  3. MAPT P397S
  4. PSEN1 I416T

Paper Citations

  1. . Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease. Alzheimers Dement. 2014 Oct;10(5 Suppl):S277-S283.e10. Epub 2013 Nov 13 PubMed.
  2. . Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. Epub 2019 Feb 10 PubMed.
  3. . Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease. JAMA Neurol. 2019 May 6; PubMed.
  4. . Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann Neurol. 2006 Aug;60(2):181-7. PubMed.
  5. . A survey of genetic human cortical gene expression. Nat Genet. 2007 Dec;39(12):1494-9. Epub 2007 Nov 4 PubMed.
  6. . Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases. Mol Syst Biol. 2014 Jul 30;10:743. PubMed.
  7. . SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
  8. . 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. 1997 Oct 22-29;278(16):1349-56. PubMed.
  9. . The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998 Mar 11;279(10):751-5. PubMed.
  10. . Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 2018 Dec;14(12):e1007791. Epub 2018 Dec 5 PubMed.
  11. . Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Arch Neurol. 2011 Aug;68(8):1013-9. PubMed.
  12. . Non-coding variability at the APOE locus contributes to the Alzheimer's risk. Nat Commun. 2019 Jul 25;10(1):3310. PubMed.

Further Reading