MRI Feature Is Marker of Disease Progression in Preclinical Autosomal Dominant Alzheimer's Disease
Key findings
- Previous research at Massachusetts General Hospital determined an MRI-derived marker of the integrity of the locus coeruleus (LC) tracks with initial pathology in sporadic Alzheimer's disease
- To see whether that finding extends to autosomal dominant Alzheimer's disease (ADAD), this study examined correlations between LC integrity, in vivo tau pathology, and memory in carriers of the PSEN1 E280A mutation and non-carrier family members
- Reductions in LC integrity began about 12 years prior to clinical onset of ADAD, and lower LC integrity was more strongly associated with tau accumulation in carriers than in non-carriers
- Lower LC integrity was also associated with significantly worse memory recall in carriers than in non-carriers, and amounts of neocortical tau pathology accounted for this relationship in all carriers
- These findings confirm LC integrity as a proxy of tau-related processes in ADAD and support using it as a biomarker of disease progression in the preclinical stage of the disease
The locus coeruleus (LC), which is approximately the size of a rice grain that's located in the brainstem, provides norepinephrine to the entire brain. Through its widespread projections, the LC can modulate many cognitive functions and behaviors. In sporadic late-onset Alzheimer's disease, pathological hallmarks become apparent in a distinct pattern and at relatively predictable ages:
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- Age 40—Nearly every autopsy case exhibits tau in the LC
- About age 50—Tau pathology emerges in the entorhinal cortex
- About age 60—In a subset of people, amyloid beta (Aβ) and tau accumulate in the neocortex
- After age 65—Clinical symptoms begin
Because the LC is vulnerable to tau aggregation so early, it's an important potential target for preclinical intervention in AD. Researchers at Massachusetts General Hospital previously reported that in sporadic AD, "LC intensity relative to pontine tegmentum," an MRI measure of LC integrity, peaks and begins to decline at age 54, about the time cortical tau starts to accumulate. In Science Translational Medicine the team also showed that lower LC integrity predicted memory decline in preclinical sporadic AD, even before Aβ was readily detectable on positron emission tomography (PET).
Now the researchers have extended their findings to autosomal dominant AD, presenting further evidence that LC integrity can serve as a marker of disease progression in preclinical AD. The new data are presented in Alzheimer's & Dementia by Heidi I.L. Jacobs, PhD, an expert in neuroimaging and neuropsychology at the Gordon Center for Medical Imaging, Yakeel T. Quiroz, PhD, director of the Multicultural Assessment and Research Center, the Multicultural Alzheimer's Prevention Program, and the Familial Dementia Neuroimaging Laboratory in the Department of Psychiatry and Department of Neurology, and colleagues.
Methods
This analysis was part of the COLBOS (Colombia–Boston) biomarker study, which follows individuals from the world's largest kindred that has the AD-causing mutation E280A in the presenilin1 gene. The researchers compared MRI and PET results from 27 mutation carriers (19 cognitively unimpaired, eight mildly impaired; age range, 29–49) and 27 non-carriers (age range, 29–47) who are being followed in the study.
LC Integrity and Age
In ADAD, age is commonly used as a proxy of disease progression, because as carriers age they get closer to the time of expected symptom onset. In the Colombian kindred, the median age at clinical onset is 44.
In this analysis, LC integrity in carriers peaked at age 31.5, about 12 years before symptom onset in ADAD, and about 20 years before symptom onset in sporadic AD.
LC Integrity and Tau
Lower LC integrity was more strongly associated with tau aggregation in the entorhinal cortex in carriers than non-carriers. The difference was significant even after excluding the impaired carriers or controlling for Aβ.
Similarly, the relationship between lower LC integrity and tau aggregation in the neocortex was significantly greater in carriers than in non-carriers.
LC Integrity, Tau and Memory
Lower LC integrity was also associated with significantly worse memory recall in carriers than in non-carriers. The amounts of neocortical tau accounted for this relationship in all carriers.
Future Directions
These findings suggest decreases in LC integrity in people with ADAD predict the expansion of tau into the neocortex. That makes it a promising marker of disease progression even in the preclinical phase of the disease.
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