Many abnormal findings have been found in Alzheimer's patients.  The current thinking is either that amyloid deposit cause plaques which then cause tau protein transport tubules to become tangles or that hyperphosphorylation of tau protein causes the tubules to become tangles and result in amyloid build up and deposits.  These two features are the classical pathological findings in the brains of individuals with Alzheimer's disease.  The meaning of the various differences from normal is still being debated, but much is known as can be read below.

Abeta Triggers Caspase Which Creates Tangles: Amyloid beta (Abeta) accumulation triggers caspase activation, leading to caspase-cleavage of the cytoskeletal protein tau, which precedes hyperphosphorylation in the evolution of neurofibrillary tangles. Inhibiting tau caspase-cleavage may prove beneficial. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT, Cotman CW. University of California, Irvine. J Clin Invest. 2004 Jul;114(1):121-30

Amyloid Beta-Derived Diffusible Ligands: Proceedings of the National Academy of Sciences 8/18/03. William L. Klein found up to 70 times more small, soluble aggregated proteins called "amyloid b-derived diffusible ligands" (ADDLs, pronounced "addles") in human AD brain tissue. ADDLs interfere with memory synapses. AD poorly correlated with plaques, but correlates well with ADDLs. Antibodies to ADDLs relief dementia in mice without affecting plaques. Northwestern U. 

Altered Lipid Homeostasis: Decreased cholesterol, phospholipids, and fatty acids in cerebral spinal fluid suggest altered lipid homeostasis independent of apoE4. Mulder, Netherlands, Alzheimer Dis Assoc Disorder 9/98;12:198

Esterified 2- & 4-Isoprostanes Increased: Free radical peroxidation of AA results in 2-isoprostane; of EPA results in 3-isprostane; and of DHA results in 4-isoprostane. The levels of 4-Isoprostane have been found elevated in some regions of the AD brain. Nourooz, London, J Neurochem 2/99;72-734; 2-Iso was found increased by Pratico, U Penn, FASEB J 12/98

Calcium Dependent K+ Channels Abnormal in AD Platelets: Lancet 11/14/98 de Silva, UK

Bimodal Distribution of MMSE: Freie Universitat in Berlin followed two populations of elderly for four years prospectively found that one was deteriorating at a faster rate than the other. Thus, not a single population with a normal variation but two populations suggesting that dementia in old age is a disease and not a simple aspect of aging. Friedel Reischies, APA 5/99.

Cypin Protein Affects Neuronal Branching: Cypin is found throughout the body. In the brain it regulates nerve cell branching. Branching or dendrite growth is thought to increase when a person learns. A reduction in branching is associated with certain neurological diseases. Cypin acts as a glue and causes tubulin to form the dendrite skeleton. Bonnie Firestein, Nature Neuroscience 1/19/04.

Microglia & Astrocytes Can Degrade Amyloid: microglia cells, which surround the plaques, can ingest and destroy the plaque's proteins in cell culture. normal astrocytes can also degrade plaque proteins, Nature Medicine 4/03.

Kinesin-1, Numerous lines of evidence indicate that some of the neurotoxicity associated with Alzheimer's disease (AD) is due to proteolytic fragments of the amyloid precursor protein (APP). Kinesin-1 is the locomotive pulling neuronal substances along tubules to periphery of nerve. APP's role appears to be to hook the cargo to the locomotive. Finding kinesin-1 in protein complexes that also contain NF1 and NF2 clearly ties neurofibromatosis and Alzheimer's disease to a common cellular pathway. +1 Frame-shifted proteins such as amyloid precursor protein (+1) and ubiquitin-B(+1) have been identified in the neuropathological hallmarks of Alzheimer's disease. These frameshifts are caused by dinucleotide deletions in GAGAG motifs of messenger RNA encoded by genes that have maintained the unchanged wild-type DNA sequence. This process is termed 'molecular misreading'. These are also present in non-neuronal cells. L-Carnitine facilitates the transport of fatty acids into the mitochondrial matrix where they are used for energy production. FEBS Lett 2000 Jul 28;478(1-2):19. Presenilin-1 is an integral membrane protein involved in the production of amyloid beta protein. Mutations of the presenilin-1 gene are associated with familial Alzheimer's Disease and are thought to alter g-secretase cleavage of the b amyloid precursor protein, leading to increased production of longer and more amyloidogenic forms of Ab.

Presenilin mutants increase beta-amyloid and AD: These are the most common cause of familial, early-onset AD. The mutations alter gamma-secretase that cleaves APP. Amyloid accumulates in the cortex in AD. However, presenilin plays a role in Notch activity signal transduction.  Blocking it may increase leukemia. Thus, drug companies are looking for ways to partially inhibit presenilin but without success to date. Lancet 4/10/99

Presenilin-1 and Amyloid Precursor Protein Mutations Explain Most Early AD: Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Neurology 2003 Jan 28;60(2):235-9; Presenilin-2 also in some families. Brain Res Bull. 2003 Jun 30;61(1):1-24

Tau Axon Transport Dysfunction May Cause Alzheimer's: Jeff Goldstein of the University of California, San Diego, has shown that in a mouse model, blockages in the axon nerve cells in the brain of the tau transport system cause of build-up of beta amyloid plaques.  This suggests that a tau protein problem, whose long structures serve as a transportation system in nerve cells, are the initial cause.  The tau protein also becomes hyperphosphorylated and forms tau fibillary tangles, but this is after the amyloid build-up. Science 2/24/05.

Tau Proteins Predate Amyloid: Northwestern University neuroscientists have reported the first evidence showing that tau must be present to enable beta-amyloid to induce the degeneration of brain cells that occurs in Alzheimer’s disease. 5/20/02

Apolipoprotein E epsilon-4 Allele More Common in Late-Onset: ApoE is a plasma lipoprotain and an important regulator of lipid metabolism with 3 major isoforms: E2, E3, E4. They are encoded by three epsilon alleles of the apoE gene. ApoE is present in senile plaques and neurofibrillary tangles. The ApoE epsilon-4 allele a powerful risk factor. The mechanism by which it influences risk of AD occurs before onset of brain atrophy. Yasuda, Kobe U, Am J Psychiatry 6/98;155:779-84

Homocysteine Higher in Alzheimers: Framingham study found quartile with highest homocysteine had double the rate of AD after more than 10 years of follow-up. Folic acid can lower homocysteine, but its benefit on AD is unknown. Folic acid does lower heart and stroke and present in greens and fruits. Boston U. NEJM 2/14/02

More AD in Women: Women reportedly have 3 times the AD of men. NEJM 2/14/02. Blacks have somewhat more than European-Americans.

Transferrin C2 Increased: Says research has found increases in transferrin C2 genetic subtype in AD and this can cause accumulation of aluminum which creates pores and iron which creates damaging hydroxyl groups damaging lipoproteins. Med Hypotheses 4/95;44:296

Increased cPLA-2: An increase in cytosolic phospholipase A-2, an enzyme which initiates AA cascade, in immunoreactive astrocytes was found. Suggests inflam role in AD. Stephenson, Lilly, Indianapolis, Neurobiol Dis 2/96;3:51

IL-6 Increased in AD: Inflammatory cytokine IL-6 increased in AD, CNS infections, stroke, schizophrenia, and myocardial infarction. MacArthur Study of Successful Aging studied adults ages 70-79. The tertile highest in IL-6 had more cognitive decline at 2.5 and 7 year follow-up. Neurol 02;59:371

Decreased Linolenic & DHA in AD: An rapid autopsy study found decreases in 18:2 and 22:6 fatty acids and an excess in 18:0 in AD patients in cholesterol esters but not in lipoproteins. No difference in apoE or apoA-1 the two major apolipoproteins in the brain. Tom Montine, Vanderbilt, Am J Pathol 12/97;151:1571

Membrane Phospholipids Changes: Changes found suggestive of oxidative stress. Phosphatidyl ethanolamine, phosphatidylinositol, and phosphatidylcholine measured. PE and PI decreases in hippocampus and PE decrease in inferior parietal lobe. These are rich in AA and DHA. Prasad, U Kentucky, Neurochem Res 1/98;23:81

HDL Low in AA: High Density Lipoproteins small particles that can cross blood-brain barrier. Compared to controls, HDL in AD low in AA (20:4n-6). Corrigan, UK, PLEFA 2/98;58:125

Cholesterol Up in AD: Although other studies have been mixed, a Stanford Palo Alto VA women study of 1037 aver age 71 found cholesterol over 245 linked with 77% increase in AD. High LDL also linked. Arch Neurol 3/2002. Statin users at 5 year follow-up had 6% AD vs. 9% in non-users. Women with decreases in cholesterol at follow-up had 50% lower AD risk regardless if they were on statins or not.

No Link AD with Cholesterol in Framingham: 5209 adults followed for 50 years with 77 developing AD by 1992-2000. After correcting for other factors, no link found with cholesterol. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Tan ZS, Seshadri S, Beiser A, Wilson PW, Kiel DP, Tocco M, D'Agostino RB, Wolf PA. Harvard. Arch Intern Med. 2003 May 12;163(9):1053-7

Urine Test for Isoprostanes Predictive: Mild Cognitive Impairment (MCI) – a recognized precursor to AD. The test detects isoprostanes, fatty acids that are formed as the result of free radical damage in the brain – damage that correlates with clinical diagnosis of AD. Within four years of initial diagnosis, up to 50% of people with MCI develop Alzheimer's disease. Domenico Pratico, U Penn, Arch Neurology 6/02