6. Normal Aging of the Brain/Alzheimer’s Disease


- Pre-Natal: Most neurons are generated pre-natally (second trimester)

- Post-Natal: 50-70% of neurons (and synapses) die

- Spine maturation: thin à stubby, mushroom-shaped

- third trimester to first two years: brain growth spurt due to:

                        1. increase in neuron size

                        2. elaboration of dendritic processes

                        3. myelination

                        4. increase in number and size of glial cells


I. Alzheimer’s Disease = pre-senile dementia

- progressive mental deterioration

- < 65 yo

- most common neurological disease in the U.S.

- most common cause of death due to AD:

                        1. Aspiration subsequent to pneumonia

                        2. cerebral hemorrhage


Gross Changes: Global cortical atrophy: narrowing of gyri, widening of sulci, compensatory ventricular dilation

·          atrophy is most pronounced in non-primary motor and sensory areas (higher order, association areas) of the frontal and temporal lobes

·          many of these areas are limbic (pre-frontal)


Number of Neurons: Loss is not uniform; Greatest in following 6 areas;



1. Neo-cortex


Limbic System

2. Hippocampus


3. Amygdala


Reticular formation

4. Nucleus basalis of Meynert


5. Nucleus Locus Coeruleus


6. Raphe Nuclei




1.         Neo-cortex

a.         higher order, association areas

b.         interneurons (ACh)

c.         Area 28 (entorhinal cortex: memory/smell): first area to show neuronal loss

2.         Hippocampus

- temporal lobe, learning, memory (autobiography), limbic

3.         Amygdala

- learned fear, other emotional behaviour, limbic

4.         Nucleus basalis of Meynert

- inferior to basal ganglia, basal forebrain

- part of reticular formation

- projects to cortex without relay in thalamus

- reward system (ACh)

5.         Nucleus Locus Coeruleus

- located in pontine reticular formation

- neurons contain melanin

- NE


a.         regulation of cerebral blood flow

b.         selective attention

c.         sleep/wake cycles and REM (decreased psychological integrity)

6.         Raphe Nuclei

- midline of medulla, pons, and midbrain reticular formation

- 5HT

- relays to frontal lobe without relay in thalamus


Changes in Neuron Cell Bodies

-           decreased stain in general (reduction in RNA)

-           silver stain reveals NFTs (neurofibrillary tangles): tau protein


Presence of Neuritic or Senile Plaques

-           found in areas of neuropil

-           diagnosis on the basis of plaques/view/age


Other Changes

-           decreased number of spines

-           synapse loss

-           amyloid deposits in brain blood vessels



Behavioural Changes


-           slight memory loss

-           decrease in initative

-           depression

-           faulty judgment


-           memory loss à long-term and short-term

-           inability to understand jokes, cartoons

-           sundowning (diurnal variations)

-           severe anxiety, fear, agitation, hallucinations, hypersexuality


-           Severe memory loss (forget self)

-           paranoid and irrational

-           severe language deficits

-           incontinence, cachectic


Diagnosis and Prognosis

-           no cure, attempts to increase ACh, NMDA antagonist

-           MMSE, MRI (glucose)

-           cortical biopsy: NFT’s and plaques

o          only found in a few other disorders (Down’s, postencephalitic Parkinson’s, boxers, toxins)



-           familial < 10%

-           association with Down’s, blood and lymphatic cancers

-           Chromosome 21: beta-amyloid precursor protein (normal and neurotropic in low concentrations, neurotoxic in higher concentrations)

-           HCHWA-Dutch (amyloidosis  in brain) do not have higher AD rates

-           Chromosome 13: presenilin 1 gene

-           Chromosome 1: presenilin 2 gene

-           Chromosome 19;

-           Chromosome 14: most familial forms


Other possible etiologies

1.         Autoimmune

2.         Infectious agent (1917 flu)

a.         supported by other infections à amyloid:

                                                                i.      scrapie

                                                              ii.      Jakob-Creutzfeldt

                                                             iii.      Kuru

3.         Trauma

4.         Toxins (zinc, aluminum)

a.         Aluminum (dialysis dementia from renal dialysis): cause/effect?; may à mild cognitive impairment (risk factor)

5.         E4 allele (ApoE): especially E4/E4 (binds beta amyloid)


Increased risk

1.         head injury

2.         high fat/cholesterol

3.         depression

4.         hormone replacement therapy

5.         Mild cognitive impairment



1.         E2 allele: especially E2/E2 (favours tau stability)

2.         Continuing mental challenge

3.         Vitamin E and NSAIDS

4.         omega-3 fats