Diagnostic challenges in early-onset Alzheimer's disease: Case report of a patient with PSEN1 p.Asn135Ser mutation

Introduction

Age is the strongest risk factor for the development of Alzheimer's disease (AD). However, a subset of patients, approximately 5–10% of all AD cases, develop symptoms before the age of 65, a form classified as early-onset Alzheimer's disease (EOAD). ¹ In 10–15% of EOAD patients, the condition is associated with pathogenic variants in the PSEN1, PSEN2, or APP genes, inherited in an autosomal dominant pattern. Among these, PSEN1 mutations are the most prevalent.^1,2 While many PSEN1 carriers present with the typical amnestic phenotype of AD, a substantial proportion exhibit atypical features as well.^2,3

We describe the case of a 46-year-old woman with EOAD due to a pathogenic PSEN1 variant, whose clinical course was marked by early significant behavioral symptoms, later developing myoclonus and pyramidal signs, culminating in a progression to akinetic mutism and death.

Case presentation

A 46-year-old woman from Angola with no relevant personal or family history presented to our hospital in 2020. According to her daughter, in 2015 the relatives first noticed the patient would repeatedly ask the same questions, followed by difficulties performing tasks at work and slowed reasoning, which demonstrated severe memory impairment, executive dysfunction, and reduced processing speed. These symptoms prompted her first medical evaluation in 2016. At that time, a CT scan was reportedly normal. Her symptoms continued to worsen, and by 2017 relatives reported behavioral changes, including agitation and aggression. The following year, she developed insomnia, apathy, depressed mood, and increasing social isolation. She was evaluated by a psychiatrist and started on venlafaxine 75 mg under the diagnosis of major depressive disorder. Additionally, olanzapine 5 mg was later introduced. Despite treatment, her condition worsened, leading to an inability to work or perform instrumental activities of daily living, resulting in dependence on her relatives. She also developed what the relatives described as involuntary movements in the upper limbs. During this period, she developed persecutory delusions regarding her mother as well as progressive language impairment. An MRI performed in 2018 was allegedly normal.

Due to this deterioration, her daughter brought her to Portugal to take care of her in 2020. Only a few days after her arrival, she presented to our emergency department due to worsening behavioral changes, disorientation, and loss of speech. On examination, she exhibited impaired attention and fluctuations in alertness, including somnolence and marked psychomotor agitation. Neurological findings included myoclonus, marked generalized spasticity and a right extensor plantar reflex. Autonomic signs such as elevated temperature and abnormal heart rate variability were also noted. Blood testing and lumbar puncture performed in the ER excluded infectious or inflammatory conditions. An MRI scan demonstrated cortical and subcortical atrophy involving the hippocampi, leukoencephalopathy, and bilateral microbleeds, in the absence of acute ischemic lesions or hematomas. Possible diagnostic hypothesis of catatonia or side effects of her treatment regimen were considered, and she was admitted to the Psychiatry department. Investigations for treatable causes were negative, and she initiated lorazepam and underwent electroconvulsive therapy. Initially, slight improvement in reactivity and attenuation of spasticity were observed; however, the patient soon progressed to akinetic mutism and myoclonus recurred. Due to the latter, levetiracetam 500 mg twice daily was initiated. Despite the lack of evidence for an inflammatory etiology, in view of an apparent rapidly progressing cognitive decline in a young patient with no family history, we initiated a trial of intravenous methylprednisolone 1 g for 5 days, which was unsuccessful.

During etiological investigations, lumbar puncture was repeated: cerebrospinal fluid (CSF) biochemical, immunological, and histological analyses were normal; immunophenotyping was normal; antineuronal and anti-cell surface membrane antibodies were negative. AD biomarker measurements showed Aβ₄₂ at 211 pg/mL (reference > 543 pg/mL), Aβ₄₂/Aβ₄₀ ratio at 0.075 (reference > 0.068), total tau at 349 pg/mL (reference < 335 pg/mL), and phosphorylated tau (p-tau) at 68 pg/mL (reference < 51 pg/mL). Protein 14-3-3 in CSF was negative. Repeated MRI scans revealed worsening leukoencephalopathy and an increasing number of microbleeds in susceptibility-weighted imaging, predominantly in cortico-pial and juxtacortical regions, with additional involvement of the cerebellum (including vermis and hemispheres), without evidence of lobar hemorrhage or superficial siderosis. Serial EEGs showed generalized periodic waves with fronto-temporal predominance and progressively worsening diffuse slowing. CT scans of the thorax, abdomen, and pelvis were normal. Genetic testing for NOTCH3 and PRNP mutations was negative. An AD genetic panel was ordered, but results were only available postmortem, revealing a mutation in the PSEN1 gene (NM_000021.3) – c.404A > G (p.(Asn135Ser)).

During her last hospital admission, from April to December 2021, the patient remained in akinetic mutism. Her eyes were open, but she did not follow nor react to the observer's presence. She produced no speech and did not follow commands. The visual threat reflex was absent. Cranial nerves were otherwise intact. She exhibited symmetric spasticity in all four limbs, predominantly in the upper limbs, which maintained a flexed posture. Deep tendon reflexes were symmetric. Plantar responses were bilaterally extensor. Noxious stimulation of the nail beds elicited withdrawal only in the lower limbs. She exhibited touch-sensitive myoclonus of the upper limbs.

She was discharged to a palliative care institution, where she later passed away due to an infection. Pathological examination of the brain revealed extensive cerebral amyloid angiopathy characterized by dilated and congestive blood vessels with perivascular hemosiderin, hyalinization of periventricular vessels, and small focal signs of previous ischemia/hemorrhage. Additionally, there was evidence of moderate neuronal loss in the neocortex and hippocampus, associated with the presence of Aβ plaques (Thal phase 5), neurofibrillary degeneration (Braak stage 5) and neuritic plaques (CERAD score 2), establishing the diagnosis of advanced AD.

Discussion

We describe the case of a 46-year-old woman carrying a PSEN1 mutation that presented with early-onset cognitive decline that rapidly evolved to include atypical features, namely behavioral changes, myoclonus, pyramidal signs, and, finally, akinetic mutism.

Given the swift progression and early onset, a broad differential diagnosis was considered. Initially, the description of cognitive decline associated with executive dysfunction, psychomotor slowing, and social withdrawal was interpreted as a severe depressive episode with catatonic features. This impression was supported by reports of apathy and an early description of mood and behavioral changes, leading to trials of antidepressants and electroconvulsive therapy, but without significant improvement. While catatonia can be associated with neurologic conditions, including dementia, ⁴ this case's atypical features and progression make this diagnosis less likely. The emergence of fever, hypertonia, and autonomic instability in a patient under SSRI treatment led us to consider possible iatrogenic complications, prompting drug withdrawal and adjustment of her regimen, yet her cognitive state remained unchanged.

Given the rapid worsening, atypical neurological features, and neuroimaging findings, alternative diagnoses were considered. We expanded our working hypothesis and investigations in accordance with recommendations to exclude treatable or rapidly progressive neurodegenerative conditions in early-onset dementia with atypical features. ⁵ In particular, the presence of myoclonus and pyramidal signs were suggestive of prion disease, but supportive investigations, including MRI, CSF 14-3-3, and EEG, as well as PRNP mutations, were negative. Autoimmune encephalitis was also considered; however, the chronic presentation together with unremarkable antibody panels and inflammatory markers and lack of response to corticosteroids made the diagnosis less likely. The discovery of white matter abnormalities and multiple cerebral microbleeds on MRI broadened the differential to include cerebral amyloid angiopathy–related inflammation and hereditary small vessel disease, prompting NOTCH3 testing to exclude CADASIL, which was negative. ⁶

Despite the absence of family history and its several atypical features, the presence of cognitive decline with a memory dysfunction onset coupled with suggestive CSF findings lead us to order an AD genetic panel, which revealed a PSEN1 mutation. As these mutations assume a pattern of autosomal dominant inheritance, we therefore suspect that this is a de novo mutation in our patient, although we have not been able to confirm it. In fact, de novo PSEN1 mutations and apparently sporadic presentations have been reported in the literature, as noted by a report that identified 23 cases across 14 articles, ⁷ supporting that absence of a family history does not exclude a pathogenic PSEN1 variant.

When compared to PSEN2 or APP, atypical features are much more common in PSEN1 mutations and may even be the initial presentation.^2,3,8 These features encompass language and visuospatial impairments, behavioral and mood disturbances, psychotic symptoms, pyramidal and extrapyramidal signs, myoclonus, seizures, and cerebellar signs.^2,3,8,9 A previous study has reported in their cohort of 85 PSEN1 mutation carriers that 47% exhibited myoclonus, 24% seizures, 25% pyramidal signs, 14% extrapyramidal signs, and 4% cerebellar signs. ³

The p.Asn135Ser variant lies in the pre–codon 200 region of PSEN1, a segment in which mutations are frequently associated with earlier onset disease and more severe atypical neurological features compared with later codon changes.^3,9–11

This specific PSEN1 mutation has already been previously described. Finckh et al. first reported a Greek family that presented with short-term memory impairment in the fourth-decade, followed by rapid progression. ¹² The family exhibited a heterogeneous pattern of atypical neurological signs, including myoclonic jerks, seizures, limb spasticity, bilateral dysdiadochokinesia, and ataxia. Brain biopsy of one of the patients demonstrated AD pathology. All died at ages of 40–42 years. Rudzinski and colleagues published the case of a woman and her two children. ¹³ All three presented with memory impairment starting in their early thirties, later developing atypical features, such as seizures, spastic dysarthria and limb spasticity, and the cognitive impairment evolved to include language, attention, and executive function. MRI scans of both daughter and son demonstrated the presence of white matter lesions due to small vessel disease. Autopsies performed on the woman and the daughter revealed widespread neurofibrillary tangles and neuritic plaques, as well as mild amyloid angiopathy.

Unlike the patients described, our patient had a slightly later disease onset, in her early forties. However, similarly to these descriptions, she initially presented with memory impairment and her condition deteriorated rapidly, developing marked global cognitive impairment, limb spasticity, and myoclonic jerks, culminating in akinetic mutism.

Our patient's CSF biomarker profile showed decreased Aβ₄₂ and increased Aβ₄₂/Aβ₄₀ ratio, alongside elevated total tau and phosphorylated tau levels. Although in sporadic AD we expect a reduction in the Aβ₄₂/Aβ₄₀ ratio, some PSEN1 mutations have been associated with an increased Aβ₄₂/Aβ₄₀ ratio due to changes in cleavage that favor the production of Aβ₄₂ over Aβ₄₀,^2,11,14 while amyloid deposition still leads to decreased Aβ₄₂ in the CSF. As a decreased Aβ₄₂/Aβ₄₀ ratio is considered rather specific of AD, a different presentation may mislead the clinician away from the correct diagnosis.

Interestingly, repeated MRI scans revealed multiple cerebral microbleeds in cortico-pial and juxta-cortical areas, as well as cerebellar involvement. Such microbleed distribution is suggestive of cerebral amyloid angiopathy (CAA), which has been described in PSEN1 mutation carriers, albeit microbleeds have not been reported in this particular mutation.^3,10–13

Neuropathological examination demonstrated widespread Aβ deposition, neurofibrillary degeneration, and moderate neuritic plaques compatible with advanced AD. Furthermore, severe CAA was a prominent feature, including the presence of microbleeds. CAA is increasingly recognized as a common characteristic in autosomal dominant forms of AD, particularly in PSEN1, and its extensive presence probably contributed to the rapid decline and atypical features.^3,9–11 Unfortunately, an important limitation of this case report is that we were not able to obtain the histopathological images from the autopsy showing these findings.

As the patient had arrived at our center already in advanced akinetic mutism, disease progression was reconstructed retrospectively based on collateral information provided by the patient's daughter, leading to a lack of precision in its chronology. Together with an AD CSF biomarker profile, it suggested a neurodegenerative etiology, although the exact diagnosis remained undetermined before death. The neuropathological changes observed, coupled with the genetic analysis revealing a pathogenic PSEN1 mutation, confirmed the diagnosis of familial EOAD.

Conclusion

PSEN1-associated EOAD presents a broad phenotypic variability, and its atypical clinical features and non-specific early findings frequently contribute to delayed diagnosis, as demonstrated in this case by the long interval between symptom onset and final diagnosis. While memory impairment often dominates the clinical picture in typical EOAD, PSEN1 mutations’ broader spectrum of symptoms can mislead physicians away from the diagnosis of AD. The complex heterogeneity of EOAD presentations underscores the importance of maintaining a high index of suspicion for genetic forms of dementia in young patients with rapidly progressive and multifaceted presentations, even in the absence of family history.

While our case is limited by the advanced clinical presentation, the combination of clinical features, CSF biomarkers, MRI findings, genetic testing, and pathological assessment establishes the diagnosis and contributes to expanding the known phenotype of the p.Asn135Ser mutation. Reporting such cases is critical for refining genotype–phenotype correlations and improving early recognition. A timely diagnosis has significant implications, as delays can result in potentially postponing access to targeted symptomatic treatments, delaying appropriate counseling for patients and families, and limiting management options in the era of emerging disease-modifying therapies.