PATHOPHYSIOLOGY OF DEMENTIA

 Alzheimer’s Disease – most common form

 Vascular Dementia – problems of circulation of blood to the brain
 Lewy Body Disease – death of nerve cells in the brain
 Frontotemporal dementia – degeneration in one or both of the frontal and temporal lobes
of the brain (associated with brain injury, infections, alcohol abuse) – Less common

Alzheimer’s disease

Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are crucially involved in
Alzheimer's disease as the main component of the amyloid plaques found in the brains of Alzheimer
patients. They’re generated by sequential cleavage of the amyloid precursor protein (APP).

The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and
neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic
plaques are extracellular lesions and their main constituent is the amyloid-β42 peptide (Aβ42).
Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated
Tau protein (component of the neuronal cytoskeleton that interact with α- and β-globulin to
stabilize the microtubules).

Timeframe:

Amyloid-B plaques Tau mediated neuron injury and dysfunction  brain structural changes 
memory impairment  functional deficits

 Atrophy of hippocampus (which is important for memory) and accumulation of β-amyloid in

brain tissue resulting in prominent visualisation of ventricles

Autosomal/ dominantly inherited (early onset)  overproduction of Aβ (best target of disease

modifying drug)

Sporadic (Late Onset)  failure of Aβ clearance

Risk factors:

- Chr 21 (APP mutations)

- Chr 19 (Apolipoprotein E)
- Xhr 14 (Presenilin 1)
- Chr 1 (Presenilin 2)
- Down syndrome
- Head trauma
- Education (<7 years)
- Smoking, alcohol
- Diabetes
- Antioxidants, fish, wine
- Vascular diseases
- Menopause?

4 basic presentation sof AD:

- Amnestic (temporal)
- Visuospatial (R>L)  orientation of time and place
 - Aphasic (L>R)
- Frontal

Amyloidocentric Pathway in AD

Mutations in three genes (amyloid precursor protein,

presenilin 1 and presenilin 2) lead to an early form of AD.
These mutations causes increased production of a longer
version of b-amyloid peptide (42 amino acids; normal=40
amino acids); this aggregates to form a condensed core of
amyloid protein that becomes surrounded by degenerating
neurites. These relatively large extracellular structures are
known as plaques and are a characteristic feature of both
sporadic and inherited AD.

APP (Amyloid precursor protein) is a

transmembrane protein in the central nervous system (CNS). It is metabolized by two distinct routes,
i.e., the non-amyloidogenic (APP is cleaved by the enzyme γ-secretase), and the amyloidogenic
pathways (neurotoxic Ab peptides are released after sequential cleavage of APP by b and g-
secretases, and further accumulate into oligomeric aggregates).

Therapeutic strategies:

- BACE inhibitors
- γ-secretase inhibitor
- BAN2401
- Primary prevention (identification of people below cutpoint monitor)
- Secondary (over threshold but retains cognition)

Transmissible Spongiform Encephalopaties

Creutzfeld-Jakob Disease (Mad cow disease)

- Human prion disease

- Pathogenic conversion of PrPc to PrPres

Parkinson’s Disease

- Lewy bodies contain Α-synuclein

- α-synuclein aggregation

- disease modifying factors: PBT434, Cu11(atsm)