The Science of Alzheimer’s Disease

Brain Pathology of Alzheimer’s Disease

The brain pathology of Alzheimer’s disease (AD) patients is characterised by neuronal loss, tau-positive neurofibrillary tangles and amyloid plaques, consisting mainly of Aβ40/42 peptides generated by cleavage of the β-amyloid precursor protein (APP).

The finding that mutations in the tau gene are responsible for frontotemporal dementia proved that the formation of neurofibrillary tangles has neurotoxic consequences. The combination of genetic and biochemical data led to the amyloid cascade hypothesis which suggested that A deposition is the primary event in disease pathogenesis.

An abnormality in APP cleavage leads to abnormal tau deposition and further injures neurons, thereby compounding the severity of the disease. The longer and more neurotoxic isoform (Aβ42) appears to be elevated in the brains of individuals affected with either sporadic or familial AD, implying that they have a shared pathogenetic mechanism.

Genetics of AD

Twin-studies found a concordance rate for AD among identical twins to be ~80% versus ~40% among non-identical twin pairs, indicating a strong genetic influence. To date four genes responsible for AD have been identified. The common pathological effect imparted by all known AD-linked genes is to alter APP processing and promote A deposition. About 5-10% of AD cases are associated with early onset AD. The disease in these families is often transmitted as a pure genetic dominant trait. Analyses of such pedigrees have found three causal genes: APP; presenilin 1 (PSEN1); and presenilin 2 (PSEN2).

Another genetic locus for susceptibility to AD was resolved to the Apolipoprotein E (APOE) gene that acts as both a risk factor and age-at-onset modifier for the late onset form of AD.

APP gene

To date, 28 distinct AD-associated APP mutations have been published affecting 76 families with the age-at-onset ranging between 30 and 65 years. Most of these mutations either elevate the level of A42 or increase production of both the short and long forms of the A-peptide. APP can be cleaved by two separate pathways: one involves an α-secretase cleavage within the Aβ peptide sequence and another pathway requires cleavage by the β- and γ- secretases to generate the Aβ40-42 peptides. All pathological APP mutations are clustered near the α-, β-, or γ-secretase cleavage sites of APP.

PSEN1 and PSEN2 genes

Mutations in the PSEN1 gene, located on chromosome 14q24.3, are responsible for the most aggressive form of familial AD cases (age at onset 16-65 years) and account for 18%-50% of all early-onset AD cases. To date 165 different PSEN1 mutations have been found in 361 AD families. PSEN1 shares strong similarities with the PSEN2 gene located on chromosome 1q31-q42. However, the disease associated with PSEN2 mutations is rare and less severe. To date 10 different PSEN2 mutations have been reported in 18 families with age-at-onset ranging between 40 and 85 years.

Mutations in PSEN genes cause overproduction of the A-peptides. Both PSEN proteins have a complex functional profile as integrators of several signaling pathways, because in addition to APP processing, PSEN1 and PSEN2 are essential for the cleavage of several proteins including Notch1. It is possible that a dysfunction of these pathways can contribute to neurodegeneration in mutation carriers.

APOE gene

The three common forms of the APOE gene on chromosome 19q13.2 are encoded by the alleles 2, 3 and 4. The 4 allele acts as a risk factor and is significantly over-represented in AD subjects (~40% versus ~15% in the general population), whereas the frequency of the 2 allele is reduced from ~10% in the general population to ~2% in AD patients. The mean age-of-onset of AD is less than 70 years among the 4/4 patients, but over 90 years for the 2/3 population. The link between the 4 allele and AD has been confirmed in numerous studies across multiple ethnic groups.

Search for novel AD risk factors

Up to 68% of AD cases do not have an APOE-4 allele, indicating that additional factors are involved in the late-onset form of the disease. Many genes have been reported to be associated with AD; however most of these findings have not received the same robust replication as the association between AD and APOE. The conflicting results could be explained by the genetic and neuropathological heterogeneity of AD. Recently we assessed the common variations in the SORL1 gene and demonstrated that this gene is associated with AD in several datasets. SORL1 is involved in intracellular trafficking of the APP protein. AD-associated genetic variations lead to reduced levels of SORL1 and as result the APP protein is sorted into Aβ-generating compartments. This discovery provides new insight into the mechanisms of AD and the basis for novel therapies.

In order to further investigate the genetics of AD the Tanz CRND has been collecting blood samples through the Familial Alzheimer’s Disease Registry


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