#8 |

Early-onset Alzheimer’s disease

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Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disorder of the brain, usually affecting the elderly, and recognised as the most common cause of dementia. There are two types of Alzheimer's - early-onset and late-onset with both having a genetic component as part of the aetiology. [1] [2] [3]

Introduction and background

The focus of this publication is early-onset Alzheimer’s disease (EOAD), due to its strong genetic link.[4] EOAD manifests before the age of 65 [5] [6], most frequently between the ages of 30 and 60 [1]. It is a less common variant of AD, accounting for approximately 1 to 6% of all AD diagnoses.[1]

Pathophysiologically, AD is characterised by impaired clearance of amyloid beta peptides, resulting in the development of amyloid plaques and tau protein accumulation, which results in neurofibrillary tangles, within the brain.[7] This pathology ultimately results in loss of neuronal connections, the death of neurons and brain atrophy, particularly in the hippocampus and cerebral cortex of the brain. From a clinical perspective, these pathological changes result in impaired memory and cognitive function, features which, in light of other positive diagnostic features, are pathognomic of AD.[3] [7]

Hallmarks of AD are progressive cognitive deterioration, ranging from loss of memory to impaired judgement and reasoning. AD manifests as impairment in both short and long-term memory, together with impairment of one or more of the following higher brain functions: [6] [8] [9] [10]

  • Perception
  • Judgment
  • Abstraction
  • Language
  • Problem solving
  • Personality

The diagnosis of EOAD, as with AD in general, involves a comprehensive evaluation which encompasses a clinical assessment including cognitive testing, neuroimaging, testing for biomarkers, and genetic testing.[8] [10]

The aetiology of AD involves a complex interplay of genetic, environmental, and acquired risk factors. However, genetics appears to predominate as the leading cause in a significant proportion of cases diagnosed with EOAD. Approximately 60 to 70 percent of EOAD cases are said to be attributed to genetic mutations [1]. Hence, it is assumed that 30-40% of EOAD cases are suspected to be associated with other unknown genetic factors, or alternatively to environmental or acquired risk factors, both of which remain under investigation (in clinical trials). In terms of genetics in the pathogenesis of EOAD, the disease follows an autosomal dominant inheritance pattern, linked to mutations in specific genes namely amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), with 10 to 15% of cases attributed to these three gene variants [2].

Genes affected [1]

Presenilin 1 (PSEN1)

  • PSEN1 gene is located on chromosome 14q
  • Encodes the protein product PSEN1
  • 150 PSEN1 mutations have been described in association with AD. Accounts for up to 50 percent of early-onset familial AD
  • Mutations are fully penetrant
  • Associated with an earlier median age of onset - 43 years
  • In longitudinal kindred studies, preclinical cognitive decline is evident more than 10 years before the onset of clinical impairment

Presenilin 2 (PSEN2)

  • PSEN2 gene is located on chromosome 1q
  • Encodes the protein product PSEN2
  • It is the rarest form of early-onset familial AD as fewer than 20 PSEN2 mutations have been described
  • The age of onset in reported cases is later and varies more widely with PSEN2 mutations than it does with mutations in APP or PSEN1
  • Mutations are estimated to be 95 percent penetrant, therefore up to 5 percent of patients carrying a disease-causing mutation will not develop symptoms of AD in their lifetime

Amyloid precursor protein (APP)

  • APP gene is located on chromosome 21q
  • Encodes the protein product APP
  • More than 30 mutations in this gene have been described in association with AD, accounting for 10 to 15 percent of early-onset familial AD
  • Mutations are fully penetrant, and age of onset is closely correlated with parental age of onset
  • The median age of onset across all mutation types is approximately 49 years

Epidemiology of EOAD

EOAD is quite rare, with the body of literature and population-based studies that are available for this disease entity being proportionately limited. Studies show a range of between 1% and 5.9 % of Alzheimer’s cases occur as EOAD disease [9]. Prevalence studies seem to vary according to the source. Medscape estimates the incidence of EOAD at approximately 7 per 100,000 new cases per year, with a prevalence of between 15 and 35 per 100,000 [11], while UpToDate cites one study from the United Kingdom with a proportion of 34% of the total incidence of dementia of 54 per 100,000 person years, and a separate population-based study from England reporting an incidence of 4.2 cases per 100,000 person years.[7]

Morbidity and mortality

With EOAD being recognised as an aggressive form of AD, the disease entity has significant morbidity and mortality implications, impacting those afflicted, their families and caregivers. The literature, albeit limited, suggests that EOAD or early-onset dementias are associated with higher 5-year mortality rates than the general population, inferring a shortened life expectancy. From a morbidity perspective, the aggressive nature of the disease leads to accelerated cognitive and functional decline, with behavioural, psychiatric, and physical health complications. The early diagnosis of EOAD often results in a devastating impact on individuals in the prime of their personal and professional lives, resulting in a decline in functioning, independence, and ultimately their disablement.

Treatment

The cornerstone of treatment of AD is symptom management, as there is no established cure for the disease currently, with certain progression in all those afflicted with the disease. Management usually involves a multidisciplinary medical team, with focus on the management of symptoms and improved quality of life. Medical therapy employs the use of cholinesterase inhibitors, NMDA receptor antagonists and adjunctive therapy (antidepressants, antipsychotics, anticonvulsants), depending on the clinical profile of the patient involved. A recombinant monoclonal antibody, has received FDA approval, however, still requires post approval clinical trials to confirm clinical efficacy and tolerability. [7] [11] [12]

Underwriting considerations

EOAD poses unique yet significant morbidity and mortality concerns when it comes to underwriting. [6] Familial inheritance patterns and highly penetrant genetic mutations, along with inevitable disease progression and impact on life expectancy and quality of life, make the risk assessment of EOAD extremely challenging. Consideration of industry regulations regarding genetic testing in some geographical regions further compound the complexity of underwriting EOAD. However, hope remains that evolving medical research and advances could improve the prognostic outlook of EOAD in the future.

Author

Dr Krishnaveni Govender

Medical Doctor

Hannover Re South Africa Limited

August 2024

References

  1. Rick Sherva, PhD, Neil W Kowall, MD. Genetics of Alzheimer Disease. 19 May 2022. Available from: https://www.uptodate.com/contents/genetics-of-alzheimer-disease?search=early%20onset%20alzheimers&source=search_result&selectedTitle=1~13&usage_type=default&display_rank=1 Viewed on 10 June 2024.
  2. National Institute on Aging. Alzheimer’s Disease Genetics fact Sheet. Content reviewed: March 1, 2023. Available from : https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet. Viewed on 10 June 2024.
  3. Shaheen E Lakhan, MD,Phd, MS, Med, FAAN; Chief Editor: Jasvinder Chawla, MD, MBA ; Heather S Anderson, MD.Alzheimer Disease Guidelines.7 July 2023. Available from: https://emedicine.medscape.com/article/1134817-overview#a7. Viewed on 5 June 2024.
  4. Benjamin A Raby, MD, MPH. Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian). 6 July 2023. Available from: https://www.uptodate.com/contents/inheritance-patterns-of-monogenic-disorders-mendelian-and-non-mendelian?search=autosomal%20dominant&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H1177464532. Viewed on 4 June 2024.
  5. Xi-Chen Zhu, Lan Tan, Hui-Fu Wang, Teng Jiang, Lei Cao, Chong Wang, Jun Wang, Chen-Chen Tan, Xiang-fei Meng, Jin-Tai Yu. Rate of early onset Alzheimer’s disease: a systematic review and meta-analysis. 3 March 2015. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356853/. Viewed on 10 June 2024.
  6. Albert Llado, Raquel Sanchez-Valle. Focusing on Atypical Symptoms for Improved Diagnosis of Early-onset Alzheimer's Disease, 2011. Available from: https://www.medscape.com/viewarticle/749070 and https://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-alzheimer-disease?topicRef=5073&source=see_link. Viewed on 5 June 2024.
  7. C.Dirk Keene, MD, PhD, Thomas J Montine, MD, PHD. Epidemiology, pathology, and pathogenesis of Alzheimer disease. 23 August 2022. Available from: https://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-alzheimer-disease?topicRef=5073&source=see_link. Viewed on 4 June 2024.
  8. David A Wolk, MD, Bradford C Dickerson, MD. Clinical features and diagnosis of Alzheimer disease. 8 October 2021. Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-alzheimer-disease?search=clinical%20features%20of%20alzheimers%20disease&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1. Viewed on 4 June 2024.
  9. Heyman A, Wilkinson WE, Hurwitz BJ, Helms MJ, Haynes CS, Utley CM, Gwyther LP : Early-onset Alzheimer's disease: clinical predictors of institutionalization and death. Neurology. 1987 Jun;37(6):980-4. Available from: https://pubmed.ncbi.nlm.nih.gov/3587649/ . Viewed on 10 June 2024.
  10. Juebin Huang, MD, PhD. Alzheimer Disease. February 2023. Available from: https://www.msdmanuals.com/professional/neurologic-disorders/delirium-and-dementia/alzheimer-disease#Pathophysiology_v8417862. Viewed on 3 June 2024.
  11. Daniel Press, MD, Stephanie S Buss, MD. Treatment of Alzheimer disease, 30 September 2021. Available from: https://www.uptodate.com/contents/treatment-of-alzheimer-disease. Viewed on 4 June 2024.
  12. Koedam EL, Pijnenburg YA, Deeg DJ, Baak MM, van der Vlies AE, Scheltens P, van der Flier WM: Early-onset dementia is associated with higher mortality. Dement Geriatr Cogn Disord. 2008;26(2):147-52. doi: 10.1159/000149585. Epub 2008 Aug 4. Available form: https://pubmed.ncbi.nlm.nih.gov/18679029/. Viewed on 10 June 2024.

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