Introduction

Early-onset Alzheimer’s disease (EOAD) is a rare presentation of dementia manifesting before the age of 65 years and often associated with autosomal dominant mutations, particularly in PSEN1, APP, and PSEN21. Among these, PSEN1 mutations are the most common genetic cause of EOAD, frequently leading to an aggressive disease course with earlier onset and more rapid progression compared to sporadic Alzheimer’s disease (AD)2. We present a case of a Colombian male diagnosed at 48 years of age carrying a PSEN1 mutation, c.519 G > T (p.Leu173Phe).

Non-cognitive symptoms, such as psychiatric disturbances and motor dysfunction, are reported in association with mutations affecting the third transmembrane domain of PSEN1, and these include seizures, spastic paraparesis, and behavioral symptoms that may resemble frontotemporal dementia3,4. In Latin America, several founder mutations in PSEN1 are described, such as the E280A variant in Colombia, L174M in Cuba, G206A in Caribbean Hispanic populations, and A431E in Mexico, all of which present with a variable combination of cognitive and neuropsychiatric symptoms5,6,7,8.

Our case adds to the growing body of knowledge on PSEN1-related EOAD, reinforcing the importance of genetic counseling and testing in familial cases. Additionally, it underscores the need for continued research into disease-modifying therapies, as current pharmacological treatments, including cholinesterase inhibitors and glutamate receptor modulators, have shown only modest symptomatic benefits9,10.

Results

A 47-year-old Colombian man with 11 years of education and no other medical diseases presented at the neurology clinic with a one-year history of progressive cognitive and behavioral symptoms. His maternal grandfather, mother and sister were previously diagnosed with EOAD with disease presenting in their early 50 s (Fig. 1). Over the course of the prior year, the patient developed memory impairment with symptoms including misplacing items and repeatedly asking the same questions. He also experienced disorientation to time, disorganized behaviors such as placing his shoes in the refrigerator, and paranoia related to his neighbors. Social isolation, lack of motivation, and anhedonia further characterized his initial clinical presentation.

Fig. 1
figure 1

Pedigree. This pedigree illustrates three generations of a Colombian family affected by Early-Onset Alzheimer’s Disease (EOAD), suggestive of autosomal dominant inheritance. The proband is indicated by the black arrow and was diagnosed with EOAD at age 48. He was found to carry a pathogenic PSEN1 mutation.

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His neurology evaluation was initially unremarkable. A brain computed tomography (CT scan) performed at a disease duration of 1 year showed an age-appropriate volume of white and gray matter, with no signs of acute or chronic bleeding nor space-occupying lesions as well as a normal ventricular system and intact bone structures. There were also no signs of ischemic changes, including infarcts or leukoaraiosis. An electroencephalography (EEG) revealed normal tracing with no evidence of paroxysmal foci or baseline rhythm abnormalities. He was referred for a psychiatric examination, where he was found to exhibit normal motor activity yet had limited emotional expression (i.e., “flat affect”). Speech was coherent and relevant but with perseverative tendencies and depressive thoughts. He exhibited impaired insight and judgment. Delusions, suicidal ideations, and perceptual disturbances were absent.

Cognitive screening with the Mini-Mental State Examination (MMSE)11 after 2 years of symptom onset revealed a score of 24 out of 30, missing points for orientation, attention, recall, calculation, and language. Comprehensive laboratory testing for metabolic and nutritional deficiencies, including vitamin B12 and thyroid function tests, identified no abnormalities. Testing for human immunodeficiency virus (HIV) and syphilis were also negative (supplementary table 7). A 1.5 T brain magnetic resonance imaging (MRI) later in 2012 demonstrated age-related volume loss, no acute or chronic lesions of possible vascular origin nor space-occupying lesions.

The patient was preliminarily diagnosed with EOAD with associated neuropsychiatric symptoms that included irritability. Treatment with sertraline (50 mg) and a rivastigmine patch (9.5 mg) was initiated. Rivastigmine was later discontinued due to adverse effects, including a rash at the application site.

A comprehensive neuropsychological testing battery, using Rey Auditory Verbal Learning Test (RAVLT)12, Wisconsin Card Sorting Test (WCST)13, Verbal Fluency test, Rey–Osterrieth Complex Figure Test (ROCF)14, and Barcelona Neuropsychological Battery (BNB)15 revealed cognitive decline, with mild to moderate deficits, particularly in memory and executive functioning (Supplementary Tables 1–6). The clinical record indicated that he exhibited disorientation, impaired attention, difficulty learning new information, and visuo-constructional errors, consistent with EOAD (Supplementary Tables 1–6). His score on the Frontal Behavioral Inventory (FBI)16 was unremarkable, without significant deficit or disinhibited behaviors.

A brain single-photon emission computed tomography (SPECT) after 2 years of disease evolution, revealed frontal, temporal, and parietal hypoperfusion, supporting the diagnosis of EOAD. We extracted the relevant information from the patient’s medical history; the original images are unavailable. Treatment with donepezil (5 mg) and memantine (20 mg) was initiated.

Clinical progression and symptom management

Symptoms progressively worsened over time; memory decline, prosopagnosia, and executive dysfunction became prominent. Donepezil, which had been started earlier, was increased to 10 mg daily. He became apathetic, watched cartoons all day, fought with his grandson over the remote control, took toys away from his grandson, and showed poor impulse control as well as aggressive tendencies. Antipsychotic management was initiated with haloperidol and gradually increased, improving behavioral control.

Over time, haloperidol was discontinued due to extrapyramidal side effects, and olanzapine (10 mg) was initiated. Cognitive and behavioral deterioration continued despite these interventions. Approximately nine years after initial presentation, he presented bradykinesia and experienced several tonic-clonic seizures with sphincter relaxation and postictal amnesia. Levetiracetam (500 mg every 8 h) was added to his regimen.

Twelve years following initial presentation, he enrolled in a new research study allowing for genetic testing. At this time, his Clinical Dementia Rating (CDR)17 was three and a Global Deterioration Scale–Functional Assessment Staging Test (GDS-FAST)18 score of seven, consistent with severe dementia. His research neuropsychological testing revealed profound cognitive impairment, including a score of zero on the Montreal Cognitive Assessment (MoCA)19. Severe anxiety, apathy, and moderate appetite disturbances were noted. Whole-genome analysis with variant classification following the American College of Medical Genetics (ACMG) guidelines20 identified a likely pathogenic mutation in the Presenilin 1 (PSEN1) gene with a novel PSEN1 variant, c.519 G > T (p.Leu173Phe). Although this case was previously included in a larger dataset21, we present it here in detail as a clinical case report to highlight its diagnostic complexity and clinical relevance. (Table 1).

Table 1 Timeline: Clinical progression, cognitive evaluations, imaging studies, and treatment (2010–2022)
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Discussion

Pathogenic variants in PSEN1 are the most common genetic cause of EOAD, typically inherited in an autosomal dominant pattern with high penetrance2. These mutations are frequently associated with a more aggressive disease course, earlier symptom onset, and shorter disease duration than sporadic forms of AD or cases caused by mutations in other genes such as APP or PSEN222,23,24. The phenotypic heterogeneity among individuals with PSEN1 mutations is considerable and is believed to be influenced in part by the specific location and functional impact of the mutation25. In our case, the patient carried a novel variant, c.519 G > T (p.Leu173Phe), which affects the third transmembrane domain of the presenilin-1 protein, a region previously implicated in modulating γ-secretase cleavage and the formation of substrate-binding pores25. This particular amino acid substitution, though rare, has been documented before in an Iberoamerican individual aged 5026, and in a Japanese family with EOAD. In the Japanese family, the clinical presentation shared core features with our case, including psychiatric disturbances and motor symptoms27. However, clinical presentation in that case lacked seizures, highlighting the variability even among individuals with the same variant. Also, their ages at symptom onset were 40 and 47 years, and both had an APOE ε3/ε4 genotype. In comparison, our patient presented with symptom onset at 46 years and carried an APOE ε3/ε3 genotype. While the siblings were noted to exhibit depression and parkinsonism, our patient initially presented with memory impairment and disorientation, followed by prominent behavioral and executive dysfunction and later development of seizures. This phenotypic divergence may reflect the influence of additional genetic modifiers or environmental factors and highlights the importance of detailed clinical characterization in rare variant cases. Notably, the proband’s daughter has a history of depression—a feature also observed in the previously reported siblings—which may suggest a shared underlying vulnerability or early manifestation in mutation carriers.

In our patient, the disease trajectory began with mild cognitive symptoms and progressed to severe memory impairment, executive dysfunction, neuropsychiatric disturbances, and ultimately motor involvement and seizures. These clinical findings mirror the broader phenotype of PSEN1-associated EOAD, which often includes non-cognitive features such as hallucinations, agitation, anxiety, irritability, myoclonus, and seizures22,25,27,28. Notably, mutations affecting the third transmembrane domain of PSEN1, like the one seen in this case, have been linked with a higher frequency of motor symptoms such as spastic paraparesis, tremor, and ataxia, as well as seizures, which occur in up to 47% of individuals with PSEN1 mutations25,27,29. This constellation of symptoms can resemble the behavioral variant of frontotemporal dementia (bvFTD), particularly when behavioral disinhibition, aggression, and personality changes precede or outweigh memory loss. Such clinical overlap complicates the differential diagnosis, especially in early stages of disease when neuroimaging and cognitive testing may be unrevealing3,4. In this case, CSF biomarkers and PET imaging were not performed, as these diagnostic tools were not available within our health system, further limiting early diagnostic certainty.

The difficulty in distinguishing EOAD from frontotemporal lobar degenerations (FTLD) based on clinical symptoms alone underscores the importance of comprehensive genetic testing in patients presenting with early-onset dementia and a suggestive family history. This is particularly true in regions with known founder effects or high frequencies of certain mutations30,31. In Europe, several PSEN1 variants have been reported, including M146L, M146V, I143T —many of which are associated with early onset, rapid progression, and, in some cases, atypical features such as spasticity or seizures32,33,34,35. In Asia, multiple variants have been reported in Japanese and Chinese families, often accompanied by early psychiatric or motor symptoms36,37. In Latin America, several populations with a high burden of familial EOAD have been described, including the E280A mutation in Antioquia, Colombia; the L174M variant in Cuba; the G206A variant in Caribbean Hispanic families; and the A431E variant in Mexico5,6,7,8. The E280A variant, prevalent in the Colombian ‘paisa’ population, typically presents with a mean age of onset around 46.8 years and includes early memory deficits followed by behavioral symptoms, language decline, and ultimately seizures and gait disturbances in later stages5. While our patient’s clinical presentation showed significant overlap with the E280A phenotype, disease progression in this case extended over a decade—longer than the average 8-year course reported in those cases—suggesting possible differences in the pathogenic mechanism or influence of additional genetic or environmental modifiers.

The patient’s participation in research enabled the characterization of a novel pathogenic variant and added valuable genetic and clinical data to the global understanding of EOAD. While experimental validation of the c.519 G > T variant was not performed in this study, previous work using neuroblastoma-derived cell models expressing the same amino acid substitution demonstrated significantly elevated levels of Aβ42 and increased Aβ42/40 ratios, consistent with known pathogenic mechanisms in PSEN1 mutations27. This functional evidence, coupled with the clinical phenotype observed in our case, strongly supports the pathogenicity of the variant. In addition to the functional evidence presented, we evaluated the variant using multiple in silico prediction tools. This missense substitution (G > T) has a PHRED-scaled CADD score of 25.8, placing it among the top 0.7% most deleterious variants in the genome. It also has a REVEL score of 0.923 and a REVEL ranked score of 0.996, indicating it is in the top 0.4% of all missense variants genome-wide in terms of predicted deleteriousness38,39,40. Importantly, this case underscores the diagnostic value of genomic testing in EOAD, not only for patient care but also for family counseling and potential inclusion in clinical trials targeting genetically defined subgroups.

As our understanding of EOAD continues to expand, the integration of clinical, neuroimaging, neuropsychological, and genetic data will be essential for refining diagnosis and tailoring therapies. Collaborative efforts that include underrepresented populations, such as those in Latin America, are particularly important for capturing the full spectrum of phenotypic and genetic diversity in EOAD. Further studies focusing on the natural history, biomarker trajectories, and treatment responsiveness of PSEN1-associated dementia will be critical to improving care and outcomes for patients and families affected by this devastating disease. Genetic diagnosis also allows for genetic counseling in at-risk family members, including presymptomatic testing, family planning, and preimplantation genetic diagnosis. Early identification of pathogenic variants is therefore crucial to reduce the risk of transmitting a devastating mutation to the next generation.

This case highlights the clinical trajectory and management challenges of EOAD, compounded by genetic predisposition. The patient’s family history and the identification of a PSEN1 mutation underscore the significance of genetic counseling and testing in such cases. The PSEN1 mutation, known for its association with autosomal dominant AD, typically leads to earlier onset and more rapid progression compared to sporadic forms. The patient’s participation in research contributed valuable genetic and phenotypic data, emphasizing the importance of collaborative studies in rare neurodegenerative disorders. Notably, the extended follow-up period—spanning over a decade from the early symptomatic phase to death—represents a unique and particularly informative aspect of this case, offering rare insights into the full natural history of genetically determined EOAD.

Methods

Participants

The patient described in this case report was identified through a case-control observational study of Colombian adults aged 40–80 years, conducted between April 2022 and January 2023. Patients with dementia were recruited from the outpatient clinics at the Psychiatric Public Hospital (HDPUV) and Fundación Valle del Lili (FVL) in Cali, Colombia. The dementia cohort included individuals with EOAD (EOAD; n = 23) and behavioral variant frontotemporal dementia (bvFTD; n = 20). Inclusion criteria required participants to meet clinical diagnostic criteria for probable AD or probable bvFTD [9,10]. Individuals with primary language deficits were excluded.

Additional inclusion criteria were: (1) fluency in Spanish sufficient to complete evaluations, (2) adequate visual and auditory function for cognitive testing, and (3) the availability of an informant with regular contact (e.g., family member, caregiver) capable of reporting on the participant’s daily functioning and cognition.

Exclusion criteria included acute intoxication during assessment or any comorbid neurological or systemic condition that could impact cognition (e.g., multiple system atrophy, brain tumors, multiple sclerosis, prion disease, Huntington’s disease, cerebrovascular disease, untreated hypothyroidism or vitamin B12 deficiency, HIV, liver or kidney failure, or large white matter lesions [Fazekas grade 3]).

Clinical assessment

We conducted a retrospective review of the patient’s medical records to establish the clinical chronology and extract laboratory results, neuroimaging reports, and the neuropsychological assessment. During the study visit, sociodemographic data were collected, including sex, age, education, marital status, and region of birth/residence. A psychiatrist performed the neuropsychiatric evaluation in person using the Neuropsychiatric Inventory (NPI)41. All examinations since 2012 were completed by one trained clinician (J.R.). Additional clinical information included medical history (e.g., hypertension, diabetes mellitus type 2, coronary artery disease, traumatic brain injury) and family history of dementia.

Genetic analysis

Family history was collected from patients and their study partners via self-report in the Genetic Pedigree Software-Progeny®42 to construct a three-generation pedigree (Fig. 1). Peripheral blood samples were collected at FVL. DNA extraction was performed at FVL using a silica column-based method. Samples were then sent to HudsonAlpha Institute for Biotechnology (USA), where genetic analysis was carried out by the ReDLat genetics team. Manual curation of variants was performed in genes commonly associated with neurodegenerative diseases: APP, CHMP2B, FUS, GRN, MAPT, PSEN1, PSEN2, TARDBP, TBK1, VCP, and expansion testing in C9orf72. Variant classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines20.

Neuroimaging

We reviewed clinical records to retrieve previous neuroimaging findings, including a brain CT scan, a 1.5 T MRI, and a SPECT study.

Neuropsychological testing

The patient’s neuropsychological evaluations from 2012 and 2019 were obtained from clinical records and revealed mild-to-moderate deficits in memory and executive function. In the current study, cognitive assessments were conducted in person by a trained neuropsychologist. The MoCA19 was used to evaluate multiple domains, including memory, executive function, attention, visuospatial abilities, and language19.

Ethical approval

The study was approved by the Institutional Review Board of Fundación Valle del Lili and HDPUV. Written informed consent was obtained from the participant and his legally authorized representative in accordance with the Declaration of Helsinki and the Belmont Report. Consent explicitly included permission to publish all data and findings presented in this report.