Alzheimer Disease (AD)

Epidemiology and Etiology:

· Most common cause of dementia in the elderly

· 40% prevalence in 85-90y cohort

· Rarely symptomatic before 50y

· Sporadic mostly

· 5-10% familial

· Trisomy 21

· Nearly 100% over age 45y

· APP is on chromosome 21

· May result in overexpression and subsequent production of Aß

· Aß is thought to be a critical molecule in the pathogenesis

· Derived from cleavage of APP by beta- and gamma- secretase

Common sites:

· Earliest (stages I,II):

· Entorhinal cortex (at uncus) (anterior of hippocampus – squiggly part)

· Then (stages III, IV):

· Hippocampal formation

· Latest (stages V, VI)

· Neocortex / isocortex (take a section at the occipital pole with striate and peristriate cortex)

· Sparing of primary motor and sensory cortex

Gross features:

· Cortical atrophy

· Widening of gyri

· Most pronounced frontal, temporal, parietal

· Ventricular enlargement

Histologic features:

· Neuritic (senile) plaques

· 20-200 um diameter

· Spherical collections of dilated, tortuous, silver-staining neuritic processes

· Central amyloid core often

· Surrounded by a clear halo maybe

· Microglia and reactive astrocytes at the periphery

· Neurofibrillary tangles

· Bundles of filaments in the neuron cytoplasm that displace or encircle the nucleus

· Tau protein is a major component

· Basophilic fibrillary structures on H&E

· Silver (Bielchowsky) stain positive

· Remain after death of neuron

· Not specific to Alzheimer

· Braak staging:

· Stage I,II (transentorhinal):

· Involvement only of transentorhinal cortex (see above)

· Stage III, IV (limbic):

· Severe involvement of transentorhinal cortex

· Moderate involvement of CA1 of hippocampus

· None to mild involvement of isocortex

· Stage V, VI:

· Moderate involvement of peristriate, then striate cortex

· Neuronal loss

· Glial reaction

· Amyloid angiopathy

· Almost invariably accompanies Alzheimer

· Granulovacuolar degeneration

· Clear intraneuronal cytoplasmic vacuoles

· Argyrophilic granule within each one

· Hirano bodies

· Elongated, glassy, eosinophilic bodies

· Actin is major component

Immunophenotype:

Marker:	Sensitivity:	Specificity:
Congo red (core of neuritic plaques)
Aß (core of neuritic plaques)
Amyloid precursor protein (APP)
Silver (Bielchowsky) (neurofibrillary tangles)
Tau protein (neurofibrillary tangles)
MAP2 (neurofibrillary tangles)
Ubiquitin (neurofibrillary tangles)

Molecular features:

· Familial AD (5-10%):

· APP gene mutations on chromosome 21

· Result in increased Aß

· Presenilin-1 (PS1) mutations

· Component of gamma-secretase

· Presenilin-2 (PS2) mutations

· Component of gamma-secretase

· Epsilon-4 allele of apolipoprotein E (ApoE)

· Presence of this allele increases risk and lowers age of onset

Other features:

· EM

· Neurofibrillary tangles:

· Paired helical filaments

· Some straight filaments

· Number of neurofibrillary tangles correlates better with degree of dementia than number of neuritic plaques

· Transentorhinal stage:

· Preclinical

· Isocortical stage:

· Fully developed AD

References:

· Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004.

· Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59.