Characteristics (Pinel, 2014)

• Early stages involve forgetting specifics (meetings or failure retrieve words/names)
• Intermediate stages increased confusion and difficulty more complex tasks.
  
  • Mild to moderate stages last anywhere from 2-10 years
• Memory deficit akin to anterograde amnesia of Korsakoff syndrome. Deficit recall recent events.
• Later stages inability to find way home, eventual bed-ridden, severe stages last 1-5 years
  
  • Brain changes may start 2 decades before diagnosis
  • Rate progression varies widely and average duration 8 years after diagnosis. Modulated though by age onset and other health conditions

Progression in the Brain (National Institute on Aging, 2017; Smith, 2002)

• Cortex shrivels, damaging areas involved in thinking, planning and remembering. Especially severe in CA1 region hippocampus and pyramidal cells entorhinal cortex
• Ventricles also grow larger
• Effectively every region becomes effected during progression:
  
  • hippocampus ▶ language region ▶ frontal logical thought (lose ability problem solve) ▶ emotion regulation (lose control moods and feelings) ▶ sensory areas (can spark hallucinations) ▶ episodic memories in back of brain ▶ balance and coordination ▶ heart breathing and functioning

Forms of Alzheimers

• Familial (fAD) - rare 1-5%, with 3 genes clearly impicated (APOE e4, PSEN1, PSEN2) caused by mutation single gene. Onset disease 30s-50s (Price & Sisodia, 1998)
• Sporadic (sAD) - much more common, multifactorial aetiology, APOE e4 implicated (Iqbal & Grundke-Iqbal, 2011)

Genetics many have been identified, but some include:

• APOE codes for ApoE which stimulates Aβ. APOE lipoprotein facilitates lipid transport in bloodstream and binds to hydrophobic Aβ peptide, which is thought to initiate toxic events leading to synaptic dysfunction and neurodegeneration in AD. (Chen Liu et al., 2013)
  
  • APOE3 most common form does not modulate AD risk
  • APOE2 relatively rare, meta-analysis suggests may provide limited protection against AD as few people contract AD (Farrer et al., 1997)
  • APOE4 (epsilon 4 allele of the apolipoprotein E) GWAS shows APOE4 strongest genetic risk sAD and fAD other than ageing (Harold et al., 2009). Associated with increased prevalence AD and lower age onset (Farrer et al., 1997). 50-60% sAD have the gene and one copy increases risk 4-fold, two copies 12-fold (Li et al., 2015). APOE4 leads to disruption normal lipid metabolism (Sienski et al., 2021)
• PSEN1,2 code for gamma (y) secretase, responsible for cleavage and release Aβ. PSEN1 functions catalytic subunit y-secretase, intramembranous protease cleaves variety type 1 transmembrane proteins, notably including APP. (Kelleher & Shen, 2017). PSEN2 subunit y-secretase too. (Cai et al., 2015)
• UBQLN1 codes for ubiquilin-1, reduce oxidative stress-induced neurotoxicity, regulate Aβ maturation and degradation. Transgenic mice overexpressing Ubqln1 better spatial learning and memory capabilities. 12 months age following onset AD, AD/UBQ mice better spatial learning and memory than AD mice. Also sig reduction amyloid plaques in cerebral cortex. Direct link between UBQLN1 levels and learning and memory. (Adegoke et al., 2017)
• Epigenetics - study of how behaviour and environment can cause changes that affect way genes work/are read. Important DNA methylation, hydroxymethylation, histone posttranslational modifications and non-coding RNA regulation in development AD. Dysfunctions mitochondria and lower mtDNA copy number associated with AD pathophysiology. (Perkovic et al., 2021)

Aβ

• Peptide 36-43 amino acids derived from amyloid precursor protein which codes for Aβ protein, and is coded for by APP gene
• Normal function includes protection against oxidative stress (Zou et al., 2002), apoptosis for genes implicated in cell death (Bailey et al., 2011), anti-microbial activity (Soscia et al., 2010) and responsible for synapse formation, signalling and cell adhesion in neurodevelopment (Minati et al., 2009)

Formation and Synthesis of Aβ

• APP gene on chromosome 21 encodes production APP (St George-Hyslop et al., 1987)
• APP chain approx 700 amino acids
• Normal functions synapse formation (Priller et al., 2006) and neural plasticity (Turner et al., 2003)
• Typical Aβ synthesis - APP cut into two pieces by secretase enzymes α and γ to produce correct chain of Aβ approximately 36-43 amino acids long
• Defective Aβ synthesis - APP chain cut too long by wrong secretase enzyme (β-secretase) ➡ causing issues with the number of amino acids in the Aβ protein ➡ codes for the wrong protein with the wrong functional properties. Approx 40 amino acids long. (Murphy & LeVine, 2010)
  
  • Approx 40% AD have long-form Aβ, only 5-10% typical development (Rodrigue et al., 2012).

Ubiquitination - process where ubiquitin molecules are attached to protein substrates for protein degradation. One of the most important posttranslational modifications (PTMs) regulating stability and functional activity of proteins. (Suresh et al., 2016)

• The long-form Aβ folds incorrectly and is potential toxin.
• Incorrect proteins usually tagged with ubiquitin to be identified by proteasomes
  
  • Proteasomes - protein complexes inside cells that break down damaged incorrectly-folded proteins by proteolysis. This chemical reaction breaks bonds b/w amino acids of mis-folded protein using enzyme proteases, and broken-down aminos are re-synthesised into new proteins using proteases.
• Ubiquitin Failure - example, Autosomal Dominant Cerebellar Ataxias (ADCA) neurodegenerative disorder characterised by progressive degeneration cerebellum, brain stem and spinal cord. Ataxin-1 protein encoded by ATXN1 gene. Some shapes mutant ataxin-1 cannot be broken down.
• AD - reduced activity ubiquilin-1 produces augmented production long-form Aβ and increased neuronal death. Ubiquilin-1 chaperone activity necessary regulating APP and its fragments, so diminished ubiq-1 levels may contribute to AD pathogenesis.
  
  • Ubiq-1 cannot keep up with very high volume long-form Aβ produced in AD, only with small volumes in TD brain (Stieren et al., 2011)

Aβ and Apoptosis

• Proteasome important role apoptosis (Haas et al., 1995)
• Destruction cellular components carried out by specialised proteases known as caspases
• Aβ known to bind to p75 neurotrophic receptor, responds to oxidative stress and stimulated apoptosis (Sotthibundhu et al., 2008). Aβ binds to p75 which causes apoptosis in healthy cells
• APP binds to death receptor 6 (Nikolaev et al., 2009) heavily implicated normal synaptogenesis, axon pruning and normal apoptosis.
  
  • APP acting via DR6 and caspase 6 contributes to AD. Perhaps not long-form Aβ itself, but rather enzymes downstream APP causes AD
• Normal development, amyloid-related mechanisms prune neural connections synaptogenesis early life and then appeaer triggered again by age-related processes later in life to cause apoptosis associated with AD, may lead to shrivelled cortex.
• INABILITY TO CLEAR long-form Aβ FOLLOWED BY COMMENCEMENT OF APOPTOSIS AND PROFOUND NEURONE LOSS

Evidence APP and Aβ

• Build-up Aβ follows similar hierarchical sequence neurodegeneration seen in AD. Begins hippocampus, to final phase in brainstem and cerebellum (Thal et al., 2002)
• Amyloid plaques in Religious Orders Study negatively related to cognitive function and education (Bennett et al., 2003)
• Immunotherapy Aducanumab antibody selectively targets amyloid plaques been shown to reduce Aβ in brains patients AD after one year monthly intervention. Slowing clinical decline compared to control groups too (Sevigny et al., 2016)
  
  • At 78 weeks of trials, significant decrease clinical decline based on clinical dementia rating scores patients high-dosage group (Song et al., 2022)
• APOE4 stimulates Aβ, strongest risk factor AD other than ageing (Li et al., 2015).

Education - 130 clergy religious orders study annual cognitive testing and measure plaques and NFTs post-mortem. No. years formal education strongly interacted with no. plaques and cognitive function. No effect NFTs. Mechanisms believed to be increased cognitive reserve, increased synaptic density due to neural firing, and covariance education other risk factors (Bennett et al., 2003)

Metal Exposure - higher concentration aluminium and iron AD brains in extracellular space. Link inconclusive (Pope et al., 2002)

Homocysteine - amino acid, substrate several enzymes including creatine kinase (essential normal metabolism) levels modulated by vitamin B intake. Slowing brain atrophy and mild cognitive impairment in those administered high dosage vitamin B in pre-AD individuals (Smith et al., 2010)

Type II Diabetes - higher rates AD adults w/ diabetes (Peila et al., 2002) such as 65% increase (Arvanitakis et al., 2004). Brain pathology type II mirror AD (Moran et al., 2015) e.g., reduced volumes grey and white matter and hippocamppus, grey loss most prominent in medial temporal, anterial, cingulate and frontal lobes which are maximally vulnerable to AD. Cognitive functions particular visuo-spatial skills markedly affected in diabetes group

• Advanced Glycation - proteins and fats sugar added to end products diabetes result increases amyloid deposition, tau synthesis and oxidative stress (corrosive effect on DNA synthesis and regulation) (Munch et al., 1998)
• Insulin Dysregulation increases Aβ and inflammatory agents
• Aβ Oligomers reduce insulin response (Norambuena et al., 2016). Neuron death AD often caused by CCR mediated by AβOs (precursor plaques) and tau. Results: CCR results from AβO-induced activation protein kinase complex mTORC1, and that CCR can be prevented by insulin-stimulated activation lysosomal mTORC1. Decreased insulin signalling provoked by AβOs unleashes toxic potential to cause neuronal cell cycle re-entry, and extension of neuron death.

Cholesterol - strong association vascular disease, suspected association AD (Pope et al., 2003). Mechanisms unknown. Perhaps indirect via vascular process, but effect APOE4 on lipid metabolism (increases cholesterol) may indicate direct mechanism

Environmental Enrichment

• Social Network
  
  • Longitudinal study 1203 'non-demented' people. Poor/limited social network increased risk Dementia by 60%. (Fratiglioni et al., 2000)
  • 89 elderly people, brain autopsy at time of death. Regardless no. NFTs, people lots social contact perform well in comparison those low social networks, even at more severe levels disease pathology. (Bennett et al., 2006)
• Environmental Enrichment - Transgenic mice overexpress APP and Aβ kept in standard cages develop substantial deficits learning and memory. Exposure complex housing before amyloid plaque formation eliminates deficits in single transgenic APP mice (Janowsky et al., 2005)

Exercise

• Walking Distance those walk 2 miles per day significantly less AD symptoms (Abbott et al., 2004)
• Leisure Time - longitudinal design, increased physical leisure time mid-life significantly decrease risk dementia and AD. Particularly strong those APOE e4 allele (Rovio et al., 2005)
• Grey Matter - 876 subjects caloric expenditure due to exercise. Those expended more calories in week in various activities had 5% greater grey matter volume than those more sedentary. Same pattern found AD patients (Raji et al., 2012; 2016)

Cognitive Activity

• t3XTg-AD transgenic mice develop Aβ and tau pathologies mimic human AD. Training mice maze task reduced Aβ levels and increased maze performance. Evidence cognitive activity can affect both performance and underlying pathology (Billings et al., 2007).
• In dementia, people played board games 15% lower risk dementia on adjustment other stuff. Less cognitive decline and less depression. (Dartigues et al., 2013)
• Autobiography nuns 75-95 y/o, ideas mean age 22 coded for complexity and richness of writing (idea density). Low idea density 22 significantly associated lower brain weight, increased cerebral atrophy, increased NFTs and increased likelihood AD (Riley et al., 2005)

Pharmacological Approaches

• Cholinesterase Inhibitors - galantamine, donepezil, rivastigmine. Often prescribed mild-moderate AD, reduce breakdown acetylcholine most profoundly lost transmitters plays role memory and learning. Delay worsening symptoms up to 12 months ~50% patients. Unlikely to alter pathology progress but some evidence donepezil slow progression (Minati et al., 2014)
• NMDA Receptor Antagonists - AD results in over-activation NMDA receptors, reducing synaptic plasticity and leads to neurodegeneration. Memantine reduces NMDA receptor activity in voltage-dependent matter (only rids excessive spikes activity) thus allowing normal glutamate function but reduces over-activity. Evidence of modest positive effects in pre-clinical studies, such as positive impact on AD brain neuropathology, preventing Aβ production, aggregation or downstream consequences. But no clear positive effects in clinical applications (Folch et al., 2018)
• Amyloid Target
  
  • BACE1 inhibitors - reduce Aβ, inhibit β-secretase. Knockout BACE1 gene reverses amyloid deposition and improves cognition mouse model AD (Hu et al., 2018). Most inhibitors failed clinical trials though
  • y-secretase inhibitors - reduce Aβ, inhibit secretase. All attempts failed, lack of efficacy, worsening symptoms and dangerous side-effects (Cao et al., 2018)
  • Immunotherapy - (see evidence APP/Aβ below)
• Tau Target
  
  • Inhibitors - several attempts. Encouraging initial results but failure phase 3 clinical trials (Cao et al., 2018)
  • Immunotherapy - several currently early clinical trials, same concerns regarding side-effects as for amyloid immunotherapy
• Non-Steroidal Anti-Inflammatory Drugs (NSAID) - lower risk AD found in self-reported use NSAID.
  
  • Flurbiprofen - similar ibuprofen. Sig better placebo in relation to activities daily living and overall function after 12 months (Wilcock, 2006) but no evidence efficacy phase 3 trial (Green et al., 2009)
  • Ibuprofen - reduce Aβ42 in model (effect up to 89%). Also produce results (inc. increase in short chain) suggests this not results of increased clearance or catabolism. Implication, ibuprofen modulating y-secretase to shift Aβ synthesis from long to short form (Weggen et al., 2001)