In Down Syndrome, the risk of early onset of Alzheimer’s dementia by age 60, is said to be 50%, much higher than the general population, which is said to be 5% for those aged 71–79, and over 30 % of those aged 90 and older.
The report this month of a research meeting on Alzheimer’s Dementia (AD) and Down Syndrome (DS), a recent review in NEJM about DS, The Lancet article a few months ago about DS and AD biomarkers, and last year’s review of DS and dementia in Nature Reviews Neurology gives one an opportunity to consider this unusual association. Similarities in brain pathology were noted decades ago, but newer technologies are being studied.
There are many fewer people living in the US with DS than with AD: 200,000 with DS vs. 5 Million with AD. Recent publications feature more PET scans for tau, amyloid and glucose, measurements in cerebral spinal fluid chemistry, and even research retinal imaging. Some report similarities to Autosomal Dominant AD (ADAD), found in an extended family in Columbia with the presenilin PSEN1 mutation.
Down Syndrome is also known as Trisomy 21, because all or parts of the 21st chromosome may be in triplicate (instead of the normal duplicate). The amyloid precursor protein gene APP is found on chromosome 21; those DS folks without the triplicate don’t seem to be at increased risk for dementia. There does not seem to be a consensus view about “why” or “how” DS dementia happens, but this chromosomal link to increased amyloid production is suggestive.
On the other hand, some are still skeptical about whether amyloid is the primary problem, or just a late marker of some other problem. Amyloid burden doesn’t always correlate with cognitive problems, as in one remarkable case from the ADAD family with the PSEN1 mutation and an unusual APOE3ch mutation. By the way, the presenilin genes are found on chromosomes 1 and 14, not 21; their putative role is to increase abnormal amyloid production indirectly.
The fact that dementia happens at all in this group might modify, negate or enhance some of the many hypotheses about normal aging risk factors, pathophysiology, prevention, infections, inflammation or even APOE variants (since studies seem to be conflicting).
So there are at least three groups with onset of dementia at ages earlier than typical: Down Syndrome, Autosomal Dominant Alzheimer Dementia (the kindred living in Columbia) and sporadic Early Onset AD, which some now call Younger Onset AD. [I won’t mention the early onset of related dementia’s such as LBD, or FTD, or the opposite LATE onset of TDP-43 related changes].
Besides studying their similarities and differences to gain insight into the mysteries of dementia, could these groups be offered therapeutic trials? Interestingly, the drug memantine, FDA approved for typical AD, is thought not to work well in DS. A pilot study for AD prevention, using the cholesterol drug simvastatin in DS patients, was done, but there were logistics problems, and no current trial is listed. There is an amyloid vaccine trial in DS subjects; for the Columbia kindred, an amyloid agent is being used in a prevention study.
A few weeks ago, Dr. Jeff Cummings and colleagues published a nice review (click here) of AD drugs in the 2020 pipeline. They list 121 drugs in current development, 29 in Phase 3 studies, including more non-amyloid and more repurposed agents than last year. Stem cell trials are mentioned, along with a discussion of some drug failures. They mention an agent approved in China, GV-971. However, no agents have been approved by the US FDA in dementia for over fifteen years. In contrast, FDA has approved over 30 novel agents (and more “non-novel” approvals) for cancer just since 2018.
[An aside about DS, cancer and cognitive outcomes: our pediatric oncology teams had the privilege of providing professional care to several children with Down Syndrome and cancer, each one wonderful, charming and individualistic, brimming with joy and terrific attitudes, with loving parents. Their cancer diagnoses included ALL, AML, AMKL, (TMD) and NHL.
There are now a few publications about long term Down Syndrome cancer survivors. There is an increase in chronic problems in DS leukemia survivors by self-report, but it is unclear how cognitive issues were explicitly explored in that paper. At St. Jude’s, they found long term neurocognitive issues in their typical childhood leukemia survivors, but there were few patients with DS, and they were excluded from some of their analyses. (K. Krull, personal communication, 2018).]
Perhaps something in the current drug development pipeline will make it all the way through this year. One would hope such an agent could help with all the subgroups of people living with dementia, and that further studies will reveal some common disease-modifying pathways with new targets for real therapy.