Roughly one
hundred years ago at a meeting of Bavarian psychiatrists, Dr. Alois Alzhiemer
presented the intriguing case of his patient, Auguste D., a 51 year-old female
admitted to the local asylum with presenile dementia. He would argue that
specific lesions in and around neurons were responsible for dementia. In the
ensuing decades, studies of her disorder, which would be named Alzheimer’s
disease (AD), were largely limited to descriptive neuropathological and
psychological assessment of this disease with little understanding of the
molecular and cellular mechanisms underlying neurodegeneration and dementia.
This would change in the 1980’s when the protein components of the major
neuropathological hallmarks of the disease, senile plaques (and cerebral blood
vessel amyloid) and neurofibrillary tangles were first determined. The
identification of the β-amyloid protein (Aβ) and the
microtubule-associated tau protein as the main components of plaques and tangles,
respectively, would pave the way for the molecular genetic era of AD research.
By the late-1980’s, the genes encoding the β-amyloid precursor protein (APP)
and tau (MAPT) were identified and would subsequently be shown to harbor
autosomal dominant mutations causing early-onset familial AD and frontal
temporal dementia (FTD), respectively. Later, in the early 1990’s the ε4
variant of the apoliprotein E gene (APOE) would be found to be associated
with increased risk for late-onset AD. Fundamental differences were soon noted
between these two AD genes: APP and APOE. First, while APP mutations
caused AD with virtual certainty, the APOE-ε4 variant increased susceptibility
for, but not guarantee onset of AD. Second, while APP mutations increased
the generation of the neurotoxic peptide, Aβ42, in brain, APOE- ε4
affected aggregation of Aβ into fibrils and its clearance from brain. In
1995, two more familial AD genes, presenilin 1 and 2 (PSEN1, PSEN2)
were identified, and mutations in MAPT were linked to frontal temporal
dementia. Thus, by 1995, the stage was set for molecular studies of age-related
dementias with APP, presenilin 1 and 2, APOE, and tau playing the major roles.
