As lens fiber cells age, they lose most of their organelles and become transparent – just the right state for a device meant to focus light. "They also make tons of Abeta," Dr. Goldstein said, and it appears to have a very specific function in the eye, one Dr. Rudolph Tanzi and his colleagues at Massachusetts General Hospital, Boston, identified in collaboration with Dr. Goldstein’s team (PLoS ONE 2010;5:e9505).
Dr. Lee Goldstein
"It turns out to be a very potent antimicrobial peptide," one of several the eye and brain produce to defend themselves. Amyloid’s sticky nature causes foreign invaders to clump together, so they’re more easily destroyed. This finding also suggests that Abeta could have a similar function in the brain, supporting some theories that Alzheimer’s might be at least partially triggered by a hyperinflammatory response toward an invading pathogen or another immunoreactive incident.
Testing lenses in Down syndrome patients
Interesting as all of that is, it doesn’t prove the theory that the lens amyloid record somehow tracks Alzheimer’s development. But other studies do explore that concept, including one Dr. Goldstein published in 2010. In this study, Dr. Goldstein and his colleagues examined lens amyloid in people with Down syndrome, a group predestined to develop Alzheimer’s (PLoS ONE 2010;5:e10659). The genetic mutation that causes the syndrome also increases production of the amyloid precursor protein (APP), Abeta’s antecedent.
The lenses from subjects with Down syndrome, aged 2-69 years, were compared with lenses from control subjects and people with both familial and late-onset Alzheimer’s. "The 2-year-old with Down syndrome in this study actually had more lens amyloid than the adults with familial Alzheimer’s," Dr. Goldstein said. In unpublished data, he added, the protein has even been observed in Down syndrome fetal lenses.
He expanded on this work in a poster presented at the 2013 Alzheimer’s Association International Conference. Dr. Goldstein and his team have developed and validated a laser eye scanning instrument that noninvasively measures how light is reflected from the tiniest particles – in this case clumps of Abeta protein – within the lens of living human subjects.
"We hypothesize that due to the trisomy of chromosome 21 in Down syndrome (and triplication of the APP gene), which results in increased expression of Abeta in the lens, the intensity of scattered light in Down syndrome patients will be higher than [in] age-matched controls," he noted in the poster.
Not everyone agrees with this idea, however. It has stirred controversy since he first introduced the idea, when, he said, "mainstream Alzheimer’s research simply didn’t believe it." In fact, at least two other researchers’ studies have come to quite different conclusions.
Dr. Charles Eberhart, a pathologist at Johns Hopkins University, Baltimore, published his data in the journal Brain Pathology (2013 June 28 [doi:10.1111/bpa.12070]). The study examined retinas, lenses, and brains from 11 patients with Alzheimer’s, 6 with Parkinson’s, and 6 age-matched controls. Eight eyes (five from Alzheimer’s patients and three from controls) did have cataracts. Dr. Eberhart and his colleagues used immunohistochemistry and Congo red staining to look for amyloid, phosphorylated tau, and alpha-synuclein.
"The short answer is – we didn’t find any amyloid deposits in the lens, or any abnormal tau accumulations," he said in an interview.
The study has two possible interpretations, he said: Either Abeta, tau, and synuclein don’t accumulate in Alzheimer’s eyes as they do in Alzheimer’s brains, or they are there, but simply not detected by his methods. "It certainly might be there. All we can say is that with this method, which is the accepted way of determining amyloid in brain tissue, we didn’t see it in eyes," he said.
The second study, conducted by Dr. Ralph Michael of the Universitat Autònoma de Barcelona and his colleagues, came to a similar conclusion (Exp. Eye Res. 2013;106:5-13). It involved 39 lenses and brains from 21 Alzheimer’s patients, and 15 lenses from age-matched controls. Six of the Alzheimer’s lenses and seven control lenses had cataracts. These investigators used staining methods similar to those in the Hopkins study.
"Beta-amyloid immunohistochemistry was positive in the brain tissues but not in the cornea sample," they wrote. "Lenses from control and AD [Alzheimer’s disease] donors were, without exception, negative after Congo red, thioflavin, and beta-amyloid immunohistochemical staining. ... The absence of staining in AD and control lenses with the techniques employed lead us to conclude that there is no beta-amyloid in lenses from donors with AD or in control cortical cataracts."
Dr. Goldstein said he doesn’t doubt these findings. Congo red staining yields a difficult-to-interpret sign, he said. Amyloid appears red under standard light spectroscopy, but takes on a very characteristic shade, called apple green under polarized light. "This is an old staining method that’s not very sensitive nor is it specific for Abeta – it’s also highly variable."