Early onset Alzheimer’s disease with V180I variant of prion protein gene and a family history of dementia: a case report

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. The apolipoprotein E (APOE) ε4 allele represents the strongest genetic risk factor for late-onset AD, and individuals homozygous for APOE ε4 typically develop cognitive impairment at a mean age of 65 years. Here, we report a case of early-onset AD with an apparent autosomal dominant family history who was homozygous for the APOE ε4 allele and harbored a prion protein gene (PRNP) variant involving a valine-to-isoleucine substitution at codon 180 (PRNP-V180I). The patient developed memory impairment at 47 years of age, and presented to our hospital eight months after symptom onset. His older brother experienced memory decline beginning at 47 years of age, which progressed to dementia, and died at 55 years of age. The patient’s mother also developed memory impairment at 65 years of age, followed by a diagnosis of dementia, and his maternal grandmother reportedly had a history of marked forgetfulness. Neurological examination revealed cognitive impairment predominantly characterized by disorientation and deficits in recent memory, with a Mini-Mental State Examination score of 20/30. No neurological abnormalities were identified apart from the cognitive deficits. Brain magnetic resonance imaging demonstrated mild bilateral hippocampal atrophy, while diffusion-weighted imaging showed no abnormal signal changes. Cerebrospinal fluid analysis revealed normal cell counts, protein, and glucose levels. However, the amyloid-β protein (Aβ)42/Aβ40 ratio was reduced to 0.036 (normal: ≥0.067), and phosphorylated tau was elevated to 175 pg/mL (normal: 21.5–59.0 pg/mL). Based on these findings, a diagnosis of early-onset AD was established. Given the strong family history of dementia, whole-exome sequencing was performed, and revealed no pathogenic variants in the amyloid precursor protein, presenilin 1, or presenilin 2 genes. The APOE genotype was ε4/ε4, and the PRNP-V180I variant was also identified. We describe a case of early-onset AD with a family history of dementia in the context of APOE ε4 homozygosity and the PRNP-V180I variant. APOE ε4 homozygosity likely played a central role in the early disease onset and familial aggregation observed in this patient.