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The brain that defied alzheimer’s.

Genetic mutation found that could shed light on mechanism for disease resistance, lead to new therapies

Neil Osterweil

MGH News and Public Affairs

Illustration by Roy Scott

Aliria Rosa Piedrahita de Villegas should have developed Alzheimer’s disease in her 40s and died from the disease in her 60s because of a rare genetic mutation.

Instead, she lived dementia-free into her 70s, and now her brain is yielding important clues about the pathology of dementia and possible treatments for Alzheimer’s disease.

As researchers at Massachusetts General Hospital and other centers first described in 2019, the woman, from Medellin, Colombia, was a member of an extended family with a mutation in a gene labeled PSEN1. The PSEN1 E280A mutation is autosomal dominant, meaning that only a single copy of the gene is required to cause disease. Carriers of the mutation typically exhibit symptoms of Alzheimer’s in their 40s or 50s, and die from the disease soon after, but this woman did not begin to show signs of Alzheimer’s until her early 70s. She died in 2020 from metastatic melanoma at the age of 77.

The key difference in the Colombian woman’s ability to fend off the disease for three decades appeared to be that in addition to having the PSEN1 E280A mutation, she was also a carrier of both copies of a mutation known as APOE3 Christchurch.

“This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer’s: let’s observe, learn, and imitate nature.” Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellín, Colombia.

The APOE family of genes control production of apolipoproteins, which transport lipids (fats) in blood and other bodily fluids. The APOE2 variant is known to be protective against Alzheimer’s dementia, while the APOE4 variant is linked to an increased risk for the disease.

APOE3, the most common variant, is not typically associated with either reduced or increased risk for Alzheimer’s.

“This is a ground-breaking case for Alzheimer’s disease and has already opened new paths for treatment and prevention, which we’re currently pursuing with some collaborators. This work is now bringing light into some of the mechanisms of resistance to Alzheimer’s disease” says investigator Yakeel T. Quiroz

Quiroz is director of the  Multicultural Alzheimer Prevention Program (MAPP ) at Mass General, an associate professor of psychology at Harvard Medical School, and  Paul B. and Sandra M. Edgerley MGH Research Scholar 2020-2025 .

As Quiroz and colleagues now report in the neuropathology journal  Acta Neuropathologica , the woman did, in fact, have pathologic features of Alzheimer’s disease in her brain, but not in regions of the brain where the hallmarks of Alzheimer’s are typically found.

“This patient gave us a window into many competing forces — abnormal protein accumulation, inflammation, lipid metabolism, homeostatic mechanisms — that either promote or protect against disease progression, and begin to explain why some brain regions were spared while others were not,” says Justin Sanchez, co-first author, and an investigator at MGH Neurology.

Researchers identified in Aliria’s brain a distinct pattern of abnormal aggregation or “clumping” of  tau, a protein known to be altered in Alzheimer’s disease and other neurologic disorders.

In this case, the tau pathology largely spared the frontal cortex, which is important for judgment and other “executive” functions, and the hippocampus, which is important for memory and learning. Instead, the tau pathology involved the occipital cortex, the area of the brain at the back of the head that controls visual perception.

The occipital cortex was the only major brain region to exhibit typical Alzheimer’s features, such as chronic inflammation of protective brain cells called microglia, and reduced levels of APOE expression.

“Thus, the Christchurch variant may impact the distribution of tau pathology, modulates age at onset, severity, progression, and clinical presentation of [autosomal dominant Alzheimer’s disease], suggesting possible therapeutic strategies,” the researchers write.

“It is seldom that we have nice surprises while studying familial Alzheimer’s disease brains. This case showed an amazingly clear protected phenotype. I am sure our molecular and pathologic findings will at least suggest some avenues of research and elicit hope for a successful treatment against this disorder.” says co-first author Diego Sepulveda-Falla, research lead at University Medical Center Hamburg-Eppendorf in Hamburg, Germany.

“This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer’s: let’s observe, learn, and imitate nature,” concludes Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellín, Colombia. Lopera is a co-senior author and the neurologist who discovered this family and has been following them for the last 30 years.

Quiroz is a co-senior author of the report, along with Kenneth S. Kosik, University of California, Santa Barbara; Lopera, and Sepulveda-Falla. Sanchez contributed equally to the study.

The study was supported by grants from the National Institutes of Health, MGH Executive Committee on Research (MGH Research Scholar Award), Alzheimer’s Association, the Deutsche Forschungsgemeinschaft, Universidad de Antioquia, the Werner Otto Stiftung, and the Gernam Federal Ministiry of Education and Research.

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• v.14(4); 2017 Jul

A Case Report of a 37-Year-Old Alzheimer's Disease Patient with Prominent Striatum Amyloid Retention

Yoo hyun um.

1 Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Woo Hee Choi

2 Department of Radiology, Division of Nuclear Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.

Won Sang Jung

3 Department of Radiology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.

Young Ha Park

Chang-uk lee.

4 Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Hyun Kook Lim

With recent advancement in amyloid imaging, diagnostic application of this new modality has become a great interest among researchers. New ligands, such as 18F- florbetaben, florbetapir and flutemetamol, have been discovered to overcome limitations of preexisting ligand Pittsburgh compound B. We report here a case of a 37-year-old male patient whose initial complaints comprised of gradual cognitive decline, apraxia, disorientation and sleep disturbances. 18F-Florbetaben amyloid imaging of the patient showed diffuse amyloid retention with prominent striatal uptake. This finding supports the clinical utility of amyloid imaging in diagnostic process of early-onset AD. Moreover, striatal dominant uptake pattern demonstrated in this patient include some meaningful clinical implications that warrant special attention among clinicians.

INTRODUCTION

Amyloid deposition has long been considered one of the pathognomonic markers of Alzheimer's disease (AD). Moreover, disruption in amyloid hypothesis has been frequently discussed as important targets of intervention for many years. 1 To date, most validated research results have been narrowed down to yield a model for biological trajectory of AD, where amyloid deposition far precedes clinical symptoms. 2 Thus, early detection of amyloid deposition has emerged a major target of intervention in AD patients. In this regard, amyloid imaging has emerged as an effective diagnostic tool that could enable early intervention in patients in AD trajectory, and the clinical utility of amyloid imaging has become a main topic of interest among researchers over the recent years. 3 If validated further, clinical usage of amyloid imaging is expected to extend beyond confirming AD pathology in patients with high risk factors, helping to differentiate AD from various types of dementia in those who present with atypical course or symptoms. 4

Pittsburgh compound B has been the first ligand used to detect amyloid deposition in AD patients. 5 However, its short half-life and resultant limitations in applying it to clinical setting have resulted in the development of new ligands for detecting amyloid deposition, such as 18F-florbetaben, florbetapir and flutemetamol. 6 Amyloid deposition usually initiates from temporal and orbitofrontal cortices, which later extends to frontal, parietal, precuneus, anterior and posterior cingulate cortices. 7 However, differential uptake patterns in autosomal dominant gene carriers have been noted that warrant special clinical attention. While typical amyloid deposition occurs from cortical structures, those with autosomal dominant gene carriers demonstrated initial amyloid deposition in striatum. 8 , 9

We report here a case where a case of early-onset AD patient who received a confirmatory diagnosis of AD by beta-amyloid imaging. There is relatively few evidence on the clinical application of beta-amyloid imaging in early-onset AD patients, and therefore, we expect our case can contribute to this line of inquiry. Moreover, validity of utilizing beta-amyloid imaging in differential diagnosis of dementias will be discussed.

A 37-year old male patient visited outpatient clinic, with complaints of gradual cognitive decline which had started 3 years earlier. Working as an industrial researcher, he started to make serious calculation mistakes that made him quit the job and began working as a manager in a company. However, his frequent forgetfulness, along with aggravation in recent memory impairments hampered him from fulfilling his duties, making him change jobs frequently. Apraxia and apathy had started 2 years before his visit to our clinic, and disorientation to time and person was worsened to a degree which it became impossible to commute daily between his workplace and home. At time of his visit to our clinic, not only he was fired from his recent job, but also he needed frequent reminder from his family to maintain hygiene. His sleep disturbance became prominent, frequently waking up middle of the night self-talking.

Before his visit to our clinic, he had visited two hospitals for evaluation and management of his symptoms, but to no avail. For a thorough examination of his symptoms, he was immediately admitted to our psychiatric ward. His laboratory findings did not reveal any abnormalities, and his tests for human immunodeficiency virus, syphilis all turned out to be negative. Upon his psychiatric admission, a neuropsychological test battery was implemented to evaluate the patient's cognitive status. He scored 22 in Mini-mental status examination, 1 in Clinical dementia rating scale (CDR), 10 and 4.5 in Clinical Dementia Rating-Sum of Box score(CDR-SB). 11 In his cognitive tests, in contrast to his relatively preserved language function, he displayed serious impairments in free recall, 20-minute delayed recall and recognition.

Brain magnetic resonance imaging demonstrated global cerebral atrophy of grade 1 by cortical atrophy scale 12 and notable medial temporal lobe atrophy of grade 2 by medial temporal lobe atrophy visual rating scale ( Figure 1A and B ). 13 Atypically early onset of dementia symptoms made the patient an eligible candidate for amyloid positron emission tomography (PET) imaging. 14 18-Florbetaben PET images revealed diffuse amyloid deposition with score 3 in brain beta-amyloid plaque load (BAPL), 15 with predominant amyloid deposition in the striatum ( Figure 1C and D ).

The patient's history, along with neuroimaging results and cognitive test results all satisfied the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association Alzheimer's (NINCDS-ADRDA) criteria16 for probable Alzheimer's disease with high level of evidence. 5 mg of donepezil was prescribed, and the patient was discharged on the 10th day of his admission. To control his persistent cognitive decline even after the discharge, donepezil was increased up to 23 mg with combination of memantine, which was also increased up to 20 mg. His cognitive decline has been relatively plateaued, but we advised the patient and his caregiver to regularly visit the clinic for monitoring of his symptoms.

This is one of the few case reports that demonstrated diagnosis of early-onset AD by 18F-florbetaben PET imaging. The patient demonstrated early onset of cognitive decline with accelerated deterioration. The fact that he meandered along various departments at different hospitals for confirmatory diagnosis reflect major role amyloid imaging played in the diagnostic process of the patient.

Amyloid imaging is usually indicated in patients with progressive MCI with dubious etiology, patients with atypical presentations and clinical course, and patients with early-onset progressive dementias. 14 Considering the patient in the case exhibited dementia symptoms at atypically early age, amyloid imaging was appropriately prescribed to diagnose the etiology of his cognitive decline. Integration of information attained from his history, clinical data indicated his diagnosis to be early-onset AD.

There have been relatively few reports utilizing 18F-labelled amyloid beta PET tracers that include clinical implications related to autosomal dominant AD. One study adopted 18F-florbetaben PET imaging in Down syndrome patients, suggesting potential role of amyloid imaging in identifying population at risk of dementia. 17 Similar study was conducted on patients with Down syndrome, but with 18F-florbetapir tracer. 18 An attempt to differentiate Down Syndrome pathology from AD has also been made with 18F-florbetapir tracer. 19 Future studies on autosomal dominant AD with 18F-labelled amyloid beta PET tracers could increase validity of adopting these new ligands in the diagnostic process.

Most notable test results in the case report arise from uptake patterns of 18F-florbetaben PET imaging. Unlike typical uptake patterns demonstrated by late-onset AD patients, where striatum is usually involved in the later course of illness, there was a dominant striatal uptake pattern in the patient. A previous study conducted on nondemented young adults with Down syndrome compared their results with that of studies conducted on autosomal dominant early-onset AD patients, where two groups of subjects concordantly showed predominant striatal uptake. 8 Indeed, previous studies on autosomal early-onset AD patients consistently showed high striatal amyloid deposition. 20 , 21 The aforementioned finding could explain 18F-florbetaben uptake patterns in the case.

The underlying mechanisms have been discussed in prior studies on the relatively early involvement of the striatum in autosomal dominant early-onset AD patients. Axonal mistrafficking induced by presenillin-1 gene mutation has been suggested as a potential culprit for striatal amyloid deposition in one animal study. 22 Such axonal mistrafficking is considered to stem from disruption in APP processing. 22 Indeed, APP processing patterns differed between autosomal dominant AD patients and sporadic AD patients. 23 Striatal vulnerability to early stages of tau protein accumulation in autosomal dominant AD has also been elucidated, and such phenomenon is considered more toxic to induce significant striatal neuronal injury. 24

The most prominent limitation of our case report is lack of genotype testing in the patient. If the genetic testing had been done, one missing puzzle in the diagnosis of patient would have been complete. Nevertheless, we believe our case report affirms diagnostic usefulness and clinical application of amyloid imaging in the differential diagnosis of early-onset dementia. We expect more prevalent use of amyloid imaging with accumulation of evidences and validation studies over time.

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A02036578).

Early onset Alzheimer's disease - a case study

Affiliations.

• 1 Katedra i Zakład Podstawowych Nauk Medycznych, Wydział Nauk o Zdrowiu w Bytomiu, Śląski Uniwersytet Medyczny w Katowicach.
• 2 Katedra i Klinika Neurologii, Wydział Lekarski z Oddziałem Lekarsko-Dentystycznym w Zabrzu, Śląski Uniwersytet Medyczny w Katowicach.
• 3 Górnośląskie Centrum Rehabilitacji Repty, Tarnowskie Góry.
• 4 Faculty of Public Health in Bytom, Medical University of Silesia in Katowice.
• 5 Instytut Psychologii, Wyższa Szkoła Humanitas w Sosnowcu.
• PMID: 34365482
• DOI: 10.12740/PP/OnlineFirst/114122

Dementia syndromes constitute problem not only for the elderly. Early-onset dementia (EOD) starts below the age of 65 years. It accounts for 4-10% of all cases of dementia. EOD has significant psychosocial consequences because it affects people in their most productive years of life, with numerous family, professional and social responsibilities. There are many diseases that have been identified as the cause of the EOD. Among them, the most common are Alzheimer's disease, vascular dementia, fronto-temporal dementia, Lewy body dementia, traumatic brain injury, alcohol related dementia, Huntington's disease, Parkinson's disease, mixed dementia, Creutzfeldt-Jakob disease and Down's syndrome. Most studies have demonstrated Alzheimer's disease as the most common etiology of EOD. The article presents the case of a 33-year-old patient hospitalized in the Department of Neurology in Zabrze, with cognitive dysfunction, speech disordersand featuresof Parkinson's extrapyramidal syndrome that have been progressing for about 15 months. The MR of the head revealed cortical and subcortical atrophy, especially in parietal and temporal lobes. The cerebrospinal fluid examination showed decreased level of β-amyloid and significantly elevated level of H-tau. The patient was diagnosed with early-onset Alzheimer's disease, which was confirmed by genetic testing - the sequence change was identified in the gene for presenilin 1 in a heterozygous system.

Keywords: Alzheimer’s disease; dementia; early-onset dementia.

Publication types

• Case Reports
• Alzheimer Disease*
• Cognitive Dysfunction*
• Lewy Body Disease*
• Parkinson Disease*