Alzheimer / Parkinson / ALS / Huntington / prion: protein aggregation + misfolding; tau and amyloid and alpha-synuclein; neuroinflammation; biomarkers; disease-modifying therapeutics.
Neurodegenerative Disease
Alzheimer amyloid + tau
Hardy-Selkoe amyloid hypothesis (1992): A-beta plaques and tau tangles drive AD; APP/PSEN1/PSEN2 familial mutations; tauopathy spreads…
Parkinson alpha-synuclein
Lewy bodies of aggregated alpha-synuclein in substantia nigra dopaminergic neurons; SNCA mutations and triplications cause familial PD;…
ALS pathology (TDP-43 / SOD1 / C9orf72)
TDP-43 cytoplasmic inclusions in 97 percent of ALS cases; SOD1 misfolding; C9orf72 GGGGCC repeat expansion most common genetic cause; FUS…
Huntington CAG repeat
HTT gene CAG repeat expansion (more than 36 repeats causes HD); polyglutamine misfolds and aggregates; striatal medium spiny neurons…
Prion disease (CJD / kuru / scrapie)
Prusiner protein-only hypothesis (Nobel 1997): PrPSc templates conversion of PrPC; sCJD, fCJD, vCJD, kuru; transmissible without nucleic…
Protein aggregation and misfolding
Nucleation-elongation kinetics with lag phase; cross-beta amyloid fold common across disease proteins; secondary nucleation accelerates…
Anti-amyloid immunotherapy
Aducanumab FDA 2021 (controversial accelerated approval), lecanemab 2023 (Clarity-AD trial showed slowed cognitive decline), donanemab 2024.
Neuroinflammation and microglia
Microglial activation states (DAM, ARM, IRM); TREM2 risk variant; complement-mediated synapse loss (Stevens 2007); inflammation as drug…
Mitochondrial dysfunction in neurodegeneration
Complex-I deficit in PD, mitophagy failure (PINK1/Parkin), reactive oxygen species; selective neuronal vulnerability tied to high energy…
APOE epsilon-4 neurodegeneration risk
APOE epsilon-4 is the strongest common genetic risk for late-onset AD (about 3x heterozygous, 12x homozygous); affects A-beta clearance and…
Neurodegeneration biomarkers (CSF / PET / blood)
CSF A-beta42, p-tau, t-tau; amyloid-PET (florbetapir, flutemetamol) and tau-PET (flortaucipir); blood p-tau217 emerging non-invasive AD…
Disease-modifying therapy in neurodegeneration
ASOs (tofersen for SOD1-ALS), gene therapy (AAV-aducanumab), tau-targeted antibodies, alpha-synuclein vaccines (PD03A); decades of failed…
Braak staging (PD / AD progression)
Braak-Braak 1991-2003: histopathological staging of AD (NFT distribution stages I-VI) + PD (alpha-synuclein Lewy-pathology stages 1-6…
Prion-like spreading (tau / alpha-synuclein)
Clavaguera 2009 / Frost 2009: misfolded tau / alpha-synuclein injected into mouse brain seed templated-aggregation in distal regions…
C9orf72 GGGGCC repeat (ALS/FTD)
DeJesus-Hernandez 2011 / Renton 2011: hexanucleotide repeat expansion (>30 copies) in C9orf72 most common genetic cause of familial ALS +…
LLPS in neurodegeneration (TDP-43 / FUS)
Molliex 2015 / Patel 2015: stress-granule LLPS of TDP-43 / FUS / hnRNPA1 transitions to aberrant solid-state aggregates over time;…
Amyloid-PET imaging (PiB / florbetapir)
Klunk 2004 Pittsburgh-Compound-B (PiB) thioflavin-derivative binds A-beta plaques in vivo; FDA-approved florbetapir (Avid 2012) /…
Anti-amyloid trial (Clarity-AD lecanemab)
van Dyck 2023 Clarity-AD: lecanemab (Eisai/Biogen) reduced clinical-decline 27% vs placebo in early AD over 18 months;…