Is Alzheimer's disease hereditary

From: Alzheimer Info 2/17

Hereditary Alzheimer's dementia provides important information for research

In this post we introduce the hereditary form of Alzheimer's dementia. Although it is rare (less than 1% of all cases), it is of great importance for understanding how the disease develops and for developing new drugs.

Mutations as the cause

The hereditary form of Alzheimer's disease is caused by changes in certain parts of the genetic material (genes). These changes often only consist in the exchange of a single component of the genetic information. Such an exchange is called a mutation. In Alzheimer's disease, the mutations affect either the gene for the protein from which the harmful amyloid is cut by biological scissors (enzymes), or the genes for these enzymes. The patchy deposits (plaques), which Alois Alzheimer described as one of the microscopic features of the disease named after him, consist of amyloid. All known Alzheimer's mutations lead to an overproduction of amyloid.

What does hereditary Alzheimer's dementia look like?

In a family with hereditary Alzheimer's disease, there is a 50% chance that a mutation will be passed on to the next generation. If a mutation is inherited, the disease is all but inevitable. The symptoms usually appear much earlier than in the much more common non-hereditary form of the disease, namely before the age of 65.

Because the typical signs of dementia such as forgetfulness, lack of concentration, withdrawal and reduced performance in everyday life are unusual for people of this age, the symptoms are initially often interpreted as depression or burnout. The accumulation of the disease in family members, which would be expected on the basis of inheritance, is difficult to recognize in many cases. It is not uncommon for carriers of mutations to die for other reasons before symptoms appear or the correct diagnosis is not made.

Mutations that cause disease must be distinguished from changes in the genetic make-up, which increase the likelihood of Alzheimer's dementia in old age, but are not a cause. The most important known genetic risk factor for Alzheimer's disease is a variant of the gene for apolipoprotein E. This gene is involved in the control of lipid metabolism.

Research opportunities

For research, hereditary Alzheimer's dementia offers a unique opportunity to gain knowledge about the mechanisms of development and the possible influence of therapy. The observation that all known mutations lead to an overproduction of amyloid indicates that this protein fragment plays a key role in the gradual loss of nerve cells and the resulting symptoms.

Almost all of the new active ingredients currently in clinical trials are therefore directed against amyloid. Some of these reduce production by blocking the enzymes that cut the fragment out of the precursor protein (secretase blockers). Others remove amyloid from the brain by mobilizing the body's own defense cells against this protein (antibodies).

Recent studies have shown that the antibody solanezumab slows down the worsening of symptoms, but not to the extent hoped. One possible reason for this is that in the examinations carried out so far, the beginning of the treatment took place at a too far advanced stage of the disease.

Identifying people with mutations before the clinical signs of the disease appear (in the symptom-free stage) can determine what changes in the brain precede the symptoms. This knowledge enables the development of diagnostic methods for early detection and helps to understand how the progression of the disease can possibly be delayed or even prevented. Two large research projects are pursuing this approach. The Dominantly Inherited Alzheimer's Network (DIAN) regularly examines the offspring of patients with Alzheimer's mutations.

As part of the Alzheimer's Prevention Initiative (API), a therapy study on inherited Alzheimer's disease (Autosomal Dominant Alzheimers Disease Trial, ADAD) aims to treat healthy mutation carriers with an antibody against amyloid to prevent the Delaying symptoms. The participants in this study are members of a large family with hereditary Alzheimer's disease in Colombia. In both examinations, the tests for the presence of mutations are carried out in such a way that those affected do not learn their genetic findings if they prefer to forego this knowledge.

The comparison between asymptomatic offspring, from which one group inherited mutations and the other group did not, revealed significant differences. With the help of a method for displaying amyloid in the brain (positron emission tomography), it has been proven that carriers of a mutation already have increased deposits of amyloid up to 20 years before the first symptoms appear.

Amyloid testing may help diagnose and start treatment much earlier in the future than it is now. Early action against the disease is crucial because all previous therapeutic approaches are able to delay the progression of changes in the brain, but cannot reverse damage that has already occurred.

Dr. Felix Müller-Sarnowski
Center for Cognitive Disorders, Clinic for Psychiatry and Psychotherapy, Klinkum rechts der Isar, Technical University of Munich
Email: felix.mueller-sarnowski [at] tum.de

* The inheritance of the mutations of hereditary Alzheimer's disease is described as "autosomal" (not regarding the gender genes) and "dominant" (if one of the duplicate genes is changed, this is sufficient to cause the disease)

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