Using the first reported case of co-occurring PSEN1 and HTT mutations, we illustrate how hyperkinesia complicates the differentiation of early-onset familial Alzheimer’s disease (EOFAD) and Huntington’s disease (HD).

EOFAD and HD are difficult to distinguish clinically given their overlapping ages of onset and neurocognitive profiles. Here we examine these conditions from a hyperkinetic perspective, which is often neglected in EOFAD. 

A 44-year-old female started exhibiting short-term memory impairment culminating in job loss by age 48. She developed disinhibition and aggression requiring psychiatric hospitalization by age 49. Both her father and sister were diagnosed with dementia around age 50. Exam showed disorganized thinking, apraxia, global aphasia, and occasional non-rhythmic jerks in random limbs. Brain MRI demonstrated minimal frontotemporal atrophy; toxic, metabolic, and infectious etiologies of dementia were also excluded. Genetic testing revealed 30 CAG repeats in HTT and a pathogenic variant within PSEN1 (c.849T>G heterozygous).

The constellation of early-onset dementia, personality changes, hyperkinesia, and strong family history is reminiscent of HD. However, EOFAD must also be considered due to significantly higher incidences of myoclonus and hyper-reflexia in EOFAD compared to sporadic, late-onset Alzheimer’s. Moreover, it may be tempting to differentiate EOFAD and HD based on hyperkinetic profile (i.e. myoclonus in the former and chorea in the latter). However, this dichotomy is misleading since patients can harbor genetic abnormalities related to both conditions. Notably, this is the first report of any mutation in PSEN1, PSEN2, or APP co-occurring with abnormal HTT. The phenomenon of co-occurring neurodegenerative diseases is under-explored, and further studies are needed to characterize the true extent of comorbid EOFAD and HD.

We caution against regarding Alzheimer’s as a purely neurocognitive syndrome since the EOFAD subtype may exhibit hyperkinesia. We also caution against relying solely on hyperkinetic phenotype to differentiate EOFAD and HD since patients may have co-occurring mutations.