The first case of Alzheimer’s disease (AD), a 51-year-old woman, was described in 1906. For several years, AD was assumed to be a rare form of presenile dementia. In 1976, Robert Katzman claimed that AD and senile dementia should be considered the same disease, on the basis of the identical cerebral changes, senile plaques and neurofibrillary tangles. Nowadays, pathologic, genetic, and molecular evidence suggest a distinction between type 1 (late onset) and type 2 (early onset) AD.
Presenile AD (EOAD), conventionally beginning before 65, is either familial or sporadic. Familial EOAD, accounting for 30% of cases, is an autosomal dominant disease caused by mutations in three genes, APP, PSEN1, and PSEN 2. The mean age of onset is 45, with atypical presenting symptoms such as epilepsy, myoclonus, paraparesis, and cerebellar ataxia. Sporadic EOAD starts at 60 on average, and the topography of cortical impairment and the corresponding symptoms mainly depends on the apolipoprotein E (ApoE) genotype. Indeed, ApoE4 homozygous cases have mesial temporal hypometabolism and classical amnestic onset. On the other hand, ApoE3/3, that are the majority of sporadic EOAD cases, show fronto-parieto-occipital impairment with alteration of symbolic functions.
EOAD substantially differs from the senile form in that it has a quick course, less frequent amnestic onset, impairment of symbolic functions, ApoE3 genotype, and higher tau pathology. Moreover, EOAD has a greater metabolic impairment than expected for a given amyloid load, as shown by PET amyloid and metabolic measurements. This suggests that factors other than amyloid-β, such as mitochondrial damage, oxidative stress, and inflammation, play a pathogenic role in presenile AD. Alternatively, the explanation may rest on the different ‘strains’ of soluble amyloid-β, not detectable with PET tracers. In familial, autosomal dominant EOAD, N-terminal truncated amyloid-β peptides prevail on the full-length 1-42 isoform. Moreover, in cognitive normal elderly cases, the full-length amyloid-β 1-42 is the major peptide, in comparison with sporadic AD. Thus, the composition of soluble amyloid-β may dictate the toxicity of the molecule and explain the large spectrum of aging/AD.
In conclusion, in LOAD, amyloid deposition is the main pathologic event that is strictly correlated with ApoE genotype. In sporadic EOAD, diffuse tau pathology and severe neuronal atrophy predominate. Whether different conformers of amyloid-β are responsible for the two pathological pictures is still unclear.