More than 20 years ago, Bird’s lab came across a handful of German-American families with early-onset AD and several shared surnames. The scientists went on to find 11 such families and trace them all to a single ethnic group, the Volga Germans, who lived in or near present-day Frankfurt, in Hesse. Lured by the Russian Empress Catherine the Great’s offers of land—and assurance that they could keep their German heritage and avoid the Russian draft—the families migrated in the late 1770s to Russia’s Volga River region. They lived there in relative social and genetic isolation. When the going got tough, some came to the U.S. between 1880 and 1920 seeking cheap land and opportunities that came with the construction of transcontinental railroads in the Great Plains. Their descendents eventually came to the attention of Bird and colleagues, who speculated that these families’ AD came from an autosomal dominant gene inherited from a single ancestor (Bird et al., 1988). “We thought they probably represented a genetic founder effect,” Bird said.

Their hunch was correct. All 11 families had the same mutation in PS2 (Levy-Lahad et al., 1995), the early-onset AD gene with the fewest identified pathogenic mutations to date. (See Jayadev et al., 2010 for a comprehensive analysis of AD phenotypes and genotypes linked to PS2 mutations.) Knowing that Auguste D., Alois Alzheimer’s original patient, lived in the Frankfurt area and developed early-onset AD around age 50, just like the Volga German families, Bird and colleagues wondered whether she could have had the same PS2 mutation. “It’s perfectly conceivable that this woman was an ancestor of some of the Volga German families who stayed behind in Germany,” Bird said. “But we didn’t have any evidence for that.”

Since then, a few developments bolstered their fledgling hypothesis. The first came in 1995 when a team of curious doctors found—fully intact in a University of Munich basement—a photo of Alzheimer’s first AD patient, his original notes on her, and the brain tissue taken at autopsy. Analyzing DNA from tissue on her histopathological slides, researchers showed that Auguste D. did not have the ApoE4 late-onset AD risk allele (in fact, she was homozygous for ApoE3), and that her APP gene had no known AD mutations (Graeber et al., 1997; Graeber et al., 1998). They had begun screening for presenilin mutations but, due to limited tissue availability, postponed the analyses until the field had a deeper understanding of AD genetic defects.

While the ApoE and APP findings were consistent with the idea that Auguste D. had the N141I PS2 mutation, a key piece of evidence had yet to emerge. “If our hypothesis was true,” Bird said, “somebody with the mutation ought to appear in modern-day Germany.”

In 2008, scientists reported for the first time a family living in Hesse with early-onset AD caused by the N141I PS2 mutation (Nikisch et al., 2008). “We thought this was one of the missing links,” Bird told ARF. “A case has popped up in modern-day Germany that says there are people left in Germany who have this mutation.” Bird took this as additional evidence that Alzheimer's original case was one of those left-behind individuals.

To establish further evidence, first author Chang-En Yu and colleagues did a haplotype analysis on a DNA sample from the proband of the present-day German early-onset AD (EOAD) family. They compared it to DNA from 130 people from existing Volga German pedigrees, and showed that chromosomal markers flanking the N141I mutation were the same for all subjects. “Not only do they have the same mutation,” Bird said, “but there’s strong evidence they have the same piece of chromosome 1.” This suggests the same gene region has segregated in the current Hesse family as in those Volga German families over the years, he said. That Auguste D. lived in the same Hesse region and had AD with similar onset age (47 years vs. 55.5 years for American Volga German families) further suggested that she might be the connection between the modern-day Hesse family and the U.S. Volga Germans.

The largest Volga German AD pedigree to date comes from the family of Gary Reiswig, a retired city planner and educator in East Hampton, New York. Reiswig was 25 when he learned that his father had early-onset AD, as did 10 of his 13 paternal aunts and uncles. Now 70, Reiswig chronicles his family’s experience with the disease in his recently published book, The Thousand Mile Stare (see ARF related news story). Reiswig shares end-of-life anecdotes of several afflicted family members that bear a resemblance to descriptions of Auguste D. in the final stage of her disease.

“While this does not add any scientific evidence, I think these observations could be more than interesting coincidences,” Reiswig noted in an e-mail to ARF. He also remarked on a striking familial resemblance between Auguste D. and his own family (see full comment below).

However, definitive evidence that Auguste D. had the PS2 N141I mutation has yet to come. “The potential to prove it and document it is there,” said Bird, referring to targeted mutation analysis of brain tissue from Auguste D.’s autopsy slides. He said the scientists in Germany who control access to those specimens have thus far been “extraordinarily cautious.”

In the meantime, some researchers are happy merely to have an early-onset AD family to analyze, noting that such families have been exceedingly hard to find in Germany.—Esther Landhuis.

Reference:
Yu CE, Marchani E, Nikisch G, Müller U, Nolte D, Hertel A, Wijsman EM, Bird TD. The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. Abstract