Background Information

Recognition of two main types of Alzheimer Disease was an important first step in the search for genetic causes. Early-onset Alzheimer Disease is more rare, usually affecting people aged 30 to 60. The more common type is late-onset Alzheimer's disease which occurs in those 60-65 and older. Researchers working on Alzheimer Disease realized that in some families many family members had early-onset Alzheimer Disease. They used linkage analysis, an approach in which DNA samples from many members of such families are examined to see whether they shared an abnormal gene. Abnormalities (mutations) in three genes that can cause early onset familial Alzheimer Disease were discovered. On chromosome 21, the mutation causes an abnormal amyloid precursor protein (APP) to be produced. On chromosome 14, the mutation causes an abnormal protein called presenilin 1 to be produced. On chromosome 1, the mutation causes yet another abnormal protein to be produced. This protein, called presenilin 2, is very similar to presenilin 1. These genetic mutations were highly penetrant, meaning that an individual who inherits only one of these mutated genes will almost inevitably develop early-onset Alzheimer Disease. However, because early onset familial Alzheimer Disease is rare, these genetic abnormalities account for only a very small fraction of all Alzheimer Disease.

Relatively less is known about the genetic causes of the more common late onset Alzheimer Disease. Until recently, the only gene clearly shown to contribute to the risk an individual will develop late onset Alzheimer Disease is the epsilon 4 version of the Apolipoprotein E gene (APOE e4). Unlike the mutations in APP and the presenilins, having an APOE e4 gene does not definitely lead to Alzheimer Disease. Instead it acts as a risk factor, increasing the chances of developing Alzheimer Disease, and causing it to develop several years sooner. As newer approaches to genetic analysis have been developed, such as Genome Wide Association Studies (GWAS), additional genes that increase the risk of late onset Alzheimer Disease have been identified (see for example Seshadri et al., Wijsman et al., Hollingworth et al., and Naj et al.).

We have been exploring another approach, asking if late onset Alzheimer Disease may itself be divided into subgroups (similar to early versus late onset). We have been examining whether the presence of delusions or hallucinations (psychosis) during the course of Alzheimer Disease identifies a subgroup in which new Alzheimer Disease genes can be found. We have found that the presence of psychotic symptoms during Alzheimer Disease runs in families. We, and others, have also found it is associated with more severe cognitive impairments over the course of illness. Because psychosis is not unique to Alzheimer Disease, occurring in other mental illnesses such as schizophrenia and depression, and in neurologic illnesses such as Huntington Disease, it is possible that the search for psychosis genes in Alzheimer Disease will also lead to finding genes that can contribute to psychosis and cognitive disturbance in these other disorders.

There are several ways in which genes might contribute to psychosis in Alzheimer Disease (AD+P) and other disorders, shown in the Figure.
In Pathway A1, modifier genes lead to AD+P after onset of AD, which is due to distinct genetic and environmental influences. Some of these disease-modifying genes could also modify the course of other neurodegenerative (Pathway A2) or neurodevelopmental (Pathway A3) illnesses, contributing to psychosis risk in these conditions.  In pathway B, genes that increase the liability to onset of AD would also increase the risk for AD+P. In pathway C, genes contributing major risk for idiopathic psychoses such as schizophrenia would be seen to also contribute to AD+P risk.  See Psychotic symptoms in Alzheimer disease: Evidence for a distinct phenotype for additional details regarding existing data supporting or contradicting the proposed pathways.

In contrast to genetic studies, the neuropathologic changes correlated with psychosis in Alzheimer Disease have been less extensively studied. Alzheimer Disease is characterized by prominent neuropathologic features, deposition of Beta Amyloid protein into plaques, and aggregation of hyperphosphorylated microtubule-associated protein tau into neurofibrillary tangles. We have not found, however, that these pathologic lesions are increased in selected brain regions in those individuals who also develop psychosis. More recently, focus on the pathologic cascade in Alzheimer Disease has shifted to loss of synapses onto dendritic spines as the critical early event in the development of cognitive impairment. Emerging evidence indicates that synapse loss is driven by soluble forms of Beta Amyloid and that hyperphosphorylation of tau is a necessary intermediate in generating this loss. Brain concentrations of markers of synaptic integrity are most impaired in those subjects who develop psychosis during Alzheimer Disease (see Sweet et al, 2002), consistent with widely replicated clinical observations that psychosis during Alzheimer Disease is associated with greater cognitive impairments and more rapid cognitive decline. This has led us to hypothesize that there is greater loss of synaptic structures in those individuals with Alzheimer Disease who develop psychosis, and to examine whether this excess loss is due simply to increased accumulation of toxic Beta Amyloid and tau species, or due to an interaction of these proteins with an overly brisk synaptic plasticity cascade which leads to synapse elimination.
 

We are currently conducting both clinical genetic and postmortem tissue studies of Alzheimer Disease with Psychosis.

Current Studies

Prediction Of Psychosis In Alzheimer Disease

The Aims of this project are:

National Institute on Aging Late Onset Alzheimer Disease Family Study

The Aims of this project are:

1) To identify families with multiple members diagnosed with late-onset Alzheimer’s Disease. Families will be characterized clinically and blood samples will be collected to establish cell lines. The goal is to recruit 1,000 families.

2) To collect clinical and demographic data from these families and include coded data, without identifiers, in a national database of families with Alzheimer’s Disease. This database, along with the biological samples, will be housed at the National Cell Repository for Alzheimer Disease (NCRAD) at Indiana University.

3) To provide the biological samples and data from these families to qualified researchers, for the purpose of studying Alzheimer Disease.

National Institute on Aging Late Onset Alzheimer Disease Family Study - Psychosis SubStudy

The Aims of this project are:

Cortical Synapses and Psychosis in Alzheimer Disease

The Aims of this project are:

1) To quantitate soluble brain beta-amyloid concentrations in multiple cortical regions using postmortem brain tissue from individuals with Alzheimer Disease with Psychosis.

2) To examine number and density of dendritic spines in the same subjects.

3) To determine whether effectors of structural synaptic plasticity are altered in cerebral cortex in the same subjects, and correlated with measures of synapse loss.

4) To determine whether aggregation of tau protein is increased in the same brain regions in these subjects.