Is Young Onset Dementia (YOD) really any different from typical Alzheimer’s Dementia (AD), except for age? Could a younger person living with dementia, compared to older patients, have better results from newer treatments, including aducanumab or lecanemab? Or will the meds just prolong the period of disability until death, without meaningful clinical improvement? [All links underlined and clickable].
The average age in the recently approved lecanemab P3 study was 71; for the aducanumab studies 71 or 73. Both had subjects that ranged from ~ 50 to ~90. [Note: FDA labels state that these IV antibodies are indicated for “mild cognitive impairment or mild dementia stage of disease…There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied….”]
US medical records use the ICD-11 system; its lookup function calls persons < age 65 with clinical AD “Early Onset Alzheimer Dementia” (EOAD) (the age is an arbitrary number with a social and economic history). Many academic centers use the EOAD term (Johns Hopkins or IU).
Ironically, Dr. A. Alzheimer’s index patient was aged 51 when she died with dementia, but the terms Alzheimer’s Disease or Dementia of the Alzheimer Type usually refer to older individuals.
Many recent research papers are now referring to any dementia below age 65 as YOD, even sometimes using the term Younger Onset Dementia. YOD is more of a basket term; it doesn’t appear in ICD-11.
Some include Frontal Temporal Dementia (said to be affecting actor Bruce Willis) in YOD, along with Dementia with Lewy Bodies (found in actor Robin Williams), and some vascular dementias. The first may be associated with abnormal neuronal filament proteins, the second with abnormalities in alpha-synuclein, and the third with blood vessel diseases. Posterior Cortical Atrophy (Oliver Sacks described the case of Anna H.) and Primary Progressive Aphasia, along with a few more “atypical” diagnoses might be also included.
On the other hand, some now think there is a variant with an even later onset than typical AD, with the acronym LATE, associated with abnormal TDP-43. Got it?
In general, EOAD itself does not seem to have specific distinguishing features that have been found so far (see figure from Sirkis, et al. below, showing that the genetic contribution is minor). Yet this condition seems vaguely described: some might deteriorate to late stage dementia and death before age 65, while others have a longer, slower duration of worsening disability.
Confusing for clinicians, academicians and families is the considerable overlap in cognitive performance and behavioral issues. Even with newer imaging agents for abnormal proteins, and spinal fluid analyses, hard definitions leading to diagnosis seems to lack consensus, even with the ATN imaging system and a clinical correlation study from Mayo using ATN.
Patient information is usually vague about basics like progression rate, “natural history,” later stage details, duration, etiologies (why) or underlying pathophysiology (how)…. so despite a spate of recent papers in the last few years, do we have a better understanding than decades ago?
The Nat’l Inst Aging gave the LEADS (EOAD) observational study >$40M in 2018 to answer these questions. In a 2021 report, the investigators confirm the lack of consensus details about EOAD in their goals. “…The scientific goals of LEADS are to (1) collect clinical, genetic, and biomarker data in this under-studied AD population; (2) explore the unique features of EOAD yielding novel insights into the mechanisms, heterogeneity, and heritability of AD; (3) develop clinical trial outcome measures sensitive to detect baseline deficits and track longitudinal changes in EOAD; …”
For younger patients with dementia, their care partners and family caregivers, all exasperated after waiting years for answers already, better late than never, right??? And something as basic as the clinician’s neuro exam (reflexes, strength, gait) in genetic AD was just published this year.
BTW, ~200K patients is often mentioned as the number of US patients with EOAD/YOD. That would seem like a lot, but it actually fits the CDC definition for a “rare disease,” and the FDA might invoke the Orphan Drug Act to help Pharma if a specific therapy were available.
Spoiler alert for citations below: For those wanting to do their own deep dive, over the past three years some interesting reviews and reports have appeared. Here’s a selection:
Raising the basic question of whether there is a difference: Reitz C: Late onset vs…EOAD, Distinction without a difference? 2020. Caldwell A: Transcriptosomic profiling…2022. Only 30 autopsy cases, but suggests no difference between YOD and LOAD using RNA sequencing.
Reviews: Sirkis D ….clinical heterogeneity in EOAD…[perhaps the best overall review of the bunch, nuances of imaging, catalogs variations / heterogeneity, but lacks specific clinical natural history details]
Studies of cognitive natural history: Tort-Merino A: EOAD shows…more aggressive trajectories of cognitive decline…2022 [this seems to contradict some duration data, but consistent with other studies]; Hendriks S: Pre-diagnostic symptoms of YOD…2022; Roßmeier C: How do persons with young and late onset dementia die? 2021 [Well detailed palliative/end of life study from Germany].
Genetic findings and issues: Ayodele T: EOAD What is missing in research? 2021. Another review, but it emphasizes genetic and molecular issues.
Imaging & Biomarkers: Graff-Radford J: New insights into atypical Alzheimer’s disease in the era of biomarkers 2021, discusses overlaps in various YOD diagnoses.
Special needs of YOD patients: Cations M: Call to action… for YOD, 2021 in an Australian/NZ journal.
Specific therapy: Sturchio A: High soluble amyloid-B42 predicts normal cognition….2022. [the issue of soluble vs insoluble A-B42 (implications for antibody therapies) study from subjects with genetic AD, the discussion mentions that synthetic A-B42 monomers had a beneficial affect in a rodent model. Otherwise, AdGadfly could not find anyone declaring a specific YOD/EOAD therapy target, so nahhhh, no human YOD therapy, would’ve been big news!
Star Wars Blue Book question: Compare and contrast Baby Yoda (aka Grogu, pictured above) with Master Yoda (below), who died with his cognitive faculties intact (Return of the Jedi, 1983). Carefully analyze the importance of such cognitive preservation factors as diet, exercise (light saber practice) and The Force.
“When 900 years old you reach, look as good you will not!”
