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Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes gradual loss of memory and judgement, along with other important brain functions (such as thinking, speaking, and social skills). It is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain.  

 

Early-onset familial Alzheimer’s disease (EOFAD) is a form of Alzheimer’s disease that develops in individuals before the age of 65, usually between the ages of 30 – 60 years. Unlike the common form of Alzheimer’s disease that occurs in the elderly, EOFAD is a rare genetic disorder that is inherited in an autosomal dominant manner. For this reason, many families with EOFAD often see multiple family members over multiple generations affected by this disease.  

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Synonyms

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There are many names for early-onset familial Alzheimer’s disease (EOFAD), however, they all refer to the same disease:

 

  • Familial Alzheimer’s disease (FAD)

  • Early-onset familial autosomal dominant Alzheimer’s disease

  • Autosomal dominant Alzheimer’s disease (ADAD)

  • Dominantly inherited Alzheimer’s disease (DIAD)

  • Genetic Alzheimer’s disease

Disease overview

The two main types of Alzheimer’s disease are early-onset familial Alzheimer’s disease (EOFAD) and late-onset Alzheimer’s disease (LOAD) – also referred to as sporadic Alzheimer’s disease (sAD).

 

LOAD: As the name suggests, LOAD tends to affect older individuals, usually after the age of 65. It is a far more common disease and tends to have a less aggressive disease course than EOFAD. Although some risk factors have been identified, we do not know what causes LOAD.

 

EOFAD: EOFAD affects much younger individuals compared to LOAD. Unlike LOAD, EOFAD is a rare genetic disorder, and we know exactly what  causes the  disease. EOFAD is caused by changes (mutations) in one of three genes: (1) amyloid precursor protein (APP), (2) presenilin-1 (PSEN1), or (3) presenilin-2 (PSEN2). It is important to note that the age of onset and disease duration can vary among different mutations, and some mutations present some unique symptoms. In other words, EOFAD can look very different from person to person.

 

Learn more about the differences between EOFAD and LOAD.

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Types of Alzheimer’s disease

Overview & Types of Alzheimer's Disease

Alzheimer’s disease affects more than 5.8 million people in the US and 24 million globally (Hebert et al., 2013). Early-onset familial Alzheimer’s disease (EOFAD) represents less than 1% of all Alzheimer’s disease cases (Bateman et al., 2011), affecting 5.3 out of 100,000 individuals (Campion et al., 1999). However, it has been estimated that ~45,000 individuals are affected globally by EOFAD.

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Disease prevalence

Early-onset familial Alzheimer’s disease (EOFAD) is inherited in an autosomal dominant manner. This means that if a person inherits just one copy of a faulty gene (or a gene with a mutation) from their parent, they will develop the disease. A person who is affected by EOFAD has a 50% chance of passing on the altered (mutated) gene to their children.

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Learn more about genetics and autosomal dominant inheritance: EOFAD 101 - Genetics

Autosomal dominant inheritance

Impact & Inheritance

All cases of early-onset familial Alzheimer’s disease (EOFAD) have a known cause. EOFAD is caused by mutations in either APP, PSEN1, or PSEN2. For reasons yet unknown, these mutations result in the accumulation/alterations of amyloid and tau proteins that lead to a cascade of events resulting in the formation of amyloid plaques and neurofibrillary tangles and ultimately neuronal and synaptic loss. Although there are known risk factors in late-onset Alzheimer’s disease, there is no evidence that food, lifestyle, or specific environment exposures are associated with causing EOFAD.

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Learn more about mutations: EOFAD 101 - Mutations

Causes

The initial symptoms of early-onset familial Alzheimer’s disease (EOFAD) are similar to those seen in late-onset Alzheimer’s disease (LOAD) and are mainly seen as changes in a person’s memory or behavior. These early symptoms include: forgetting newly learned information, having trouble solving problems (keeping track of bills), losing navigational skills (losing track of where they are), having trouble finding the right word, misplacing things, showing poor judgement, withdrawing from social activities, and showing changes in mood/personality.

Unlike LOAD, however, EOFAD patients develop atypical clinical features/neurological signs, including: spastic paraparesis, intracerebral hemorrhages, seizures, extrapyramidal syndrome and exceptionally cerebellar ataxia.

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Common symptoms in EOFAD:

  • Abnormal social behavior

  • Agitation

  • Confusion/disorientation

  • Hallucinations

  • Hypertonia (arms/legs are difficult to move/reduced flexibility)

  • Language impairment

  • Dementia/Memory impairment/forgetfulness

  • Myoclonus (sudden involuntary twitching)

  • Parkinsonism (movement abnormality: tremor, slow movement, muscle stiffness)

  • Seizures

  • Disinhibition

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Neurological signs as assessed by medical professionals: cerebral cortical atrophy, beta-amyloid protein deposits, neurofibrillary tangles

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References: GARD and John Hopkins

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Signs & Symptoms

Early-onset familial Alzheimer’s disease (EOFAD) can be difficult to diagnose as many physicians are not aware that there is a rare genetic form of Alzheimer’s disease that can affect people in their 30s-60s. Furthermore, the affected individual is usually in denial or unaware of their own neurological deficits. Thus, it is important that the diagnosis is carried out with the help of a family member.

General

Conditions with similar signs and symptoms to EOFAD:

 

  1. Depression

  2. Other genetic early-onset dementias:

  • Frontotemporal dementia (FTD)

  • Lewy body dementia (LBD)

  • Huntington’s disease (HD)

  • Creutzfeldt-Jakob disease (CJD)

  • Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL)

Related Disorders

  1. Family history/pedigree – to assess family history of early-onset Alzheimer’s (usually found in at least three generations, or at least more than one family member with an age of onset before 65 years of age)

  2. Physical and neurological exam – to evaluate overall neurological health

  3. Blood tests - to rule out other causes of memory loss (thyroid disorder or vitamin deficiency)

  4. Mental status and neuropsychological testing – more thorough assessment of memory and thinking skills

  5. Brain imaging:

  • magnetic resonance imaging (MRI) – to evaluate brain shrinkage

  • computerized tomography (CT) – to rule out tumors, strokes, head injuries

  • positron emission tomography (PET)

    • fluorodeoxyglucose (FDG) PET: evaluates brain metabolism

    • amyloid PET: measures amyloid in the brain (primarily used in research rather than clinical settings)

    • tau PET: measures tau in the brain (primarily used in research rather than clinical settings)

    • Lumbar puncture – to measure amyloid and tau in the cerebrospinal fluid

    • Genetic testing for mutation in APP, PSEN1, or PSEN2 (only recommended for individuals with family history of early-onset Alzheimer’s disease)

 

References: Mayo Clinic

Assessments to Assist with EOFAD Diagnosis

Genetic testing can identify whether an individual has a mutation in one of the three genes (APP, PSEN1, or PSEN2) that cause EOFAD. Such testing can be instrumental in confirming a diagnosis.

 

Learn more about genetic testing: Guide to Genetic Testing Part 1 & Part 2

Genetic testing

Diagnosis

There are three classes of drugs that have been approved by the U.S. Food and Drug Administration for the treatment of Alzheimer’s disease:

  • Cholinesterase inhibitors (Aricept, Exelon, Razadyne),

  • N-methyl-D-aspartate (NMDA) receptor antagonist (Namenda)

  • Amyloid beta-directed antibody (as of 2021, Aducanumab)

Standard therapies (approved U.S. Food and Drug Administration (FDA))

The good news is that there has been an explosion in Alzheimer’s disease research over the last few decades. There are several types of exciting drugs and technologies in development that could help modify, slow, or prevent disease progression in EOFAD patients.

  • Amyloid-directed antibodies (Gantenerumab, Crenezumab, Lecanemab)

  • Tau-targeting therapies (E2814)

  • Gene-editing technologies (CRISPR, anti-sense oligonucleotides, siRNA)

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Learn more: EOFAD 101 - Treatment

Investigational therapies

Treatment

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