1. IS A VIRUS A FACTOR IN AD? FOR: 1. A number of persistent viruses cause neurological disease. 2. HSV1 is implicated because of a) its propensity for latently infecting neuronal cells. b) its ubiquity c) its affecting, in acute infection, the CNS regions which display the main pathological changes in AD. AGAINST: 1. AD has not been shown to be transmissible. 2. Most previous studies did not detect viral DNA in the CNS - but were done using Southern or dot-blotting, or in situ hybridisation.

2. HSV1 AND COLD SORES (HERPES LABIALIS)  Most humans are infected with HSV1 in infancy.  The virus persists in the peripheral nervous system as a latent infection throughout life. In latency, viral DNA is present, but only one set of transcripts is made, and no viral proteins.  HSV1 reactivates periodically due to stress, immuno-suppression, UV light, menstruation, etc.  In some people (approx 20-40%), for previously unknown reasons, it causes cold sores.

3. Proportion of human brains containing HSV1 DNA HSV1 DETECTION BY PCR (J.Med. Virol., 1991, et seq.)

4. HSV1 DETECTION VIA INTRATHECAL ANTIBODIES  Antibodies to HSV in the CSF can persist for several years after HSE encephalitis.  We found intrathecal antibodies in 14/27 (52%) AD patients and 9/13 (69%) elderly normals.  None of these was due to leakage from blood to CSF (which would give a false positive). Also, no antibodies were found in the CSF of 4 infants. Conclusion: viral DNA is present (a whole functional genome) in many elderly brains, and an acute infection has occurred there - and perhaps recurred.

5. APOE-  4 FREQUENCIES OF HSV1 +VE AND –VE AD SUFFERERS AND AGE- MATCHED NORMALS (Lancet, 1997, Alz Repts., 1998)

6. APOE-  4 FREQUENCY OF COLD SORE SUFFERERS AND NON-SUFFERERS (Lancet, 1997, Alz Repts., 1998)

7. INDIRECT EVIDENCE FOR REACTIVATION  Vaccination against various viruses protects against AD (Verrault et al., 2002).  Cognitive impairment in elderly cardiovascular patients correlates with herpes virus burden (Strandberg et al., 2003).  Cognitive impairment in AD patients declines for at least 2 months after peripheral infection). Microglial cells are activated (Holmes et al., 2003). Hypothesis: infection  brain inflammation  reactivation of latent HSV1.

8. *OR = 4.6, 95% CI 2.0-10.8 APOE ALLELE FREQUENCIES OF HSE PATIENTS (J. Neurol. Neurosurg. Psychiatry, 2001)

9. HSV1 and HIV INTERACTIONS WITH APOE-ε4  HIV-infected subjects (pre-AIDS) who are APOE-ε4 carriers have a higher frequency of dementia and peripheral neuropathy (Corder et al. Nature Med. 1998).  This strikingly parallels our findings with HSV1.

10. SUMMARY RE APOE AND HCV DAMAGE IN LIVER  APOE-  4 is strongly protective against HCV-induced liver damage.  But APOE does not affect susceptibility to HCV, nor clearance of the virus, nor extent of damage due to non-viral causes.  The association still holds when factors such as duration and alcohol intake are considered  An APOB polymorphism does not affect severity of liver damage, susceptibility or clearance. (Hepatology 2002)

11. APOE: A MAJOR FACTOR IN ONE’S RESPONSE TO INFECTION  APOE determines disease severity in 5 disorders known to be caused by viruses - 3 very different viruses: cold sores & HSE (HSV1); liver disease (HCV); dementia & peripheral neuropathy (HIV)*. Also,  APOE determines susceptibility to infection by the malaria protozoon (J.Med Genetics, 2003) *Corder et al., 1998.

12. HSV1 & AMYLOID TRIAL  A trial of an amyloid peptide as immunotherapy for AD has been halted because some patients developed brain inflammation.  In “some” CSFs, “a virus” was detected.  The virus is HSV1.

13. FUTURE POSSIBILITIES  Immunisation against the virus in infancy (more feasible now, as the age of primary infection is rising with increasing socio- economic level).  Use of anti-viral agents to retard the progression of the disease

14. PROTECTION OF MICE FROM HSV1 LATENCY IN BRAIN BY VACCINATION WITH ISCOMS. Neurobiol. Aging, 2001

15. SUMMARY  HSV1 DNA resides in a high proportion of brains of elderly people and AD patients, as shown by PCR and by detection of intrathecal antibodies.  HSV1 DNA in brain of APOE-  4 carriers confers a strong risk of AD.  HHV 6 DNA is present in a high proportion of AD brains (NB HHV6 augments damage caused by some other viruses). Risk factor?  Cytomegalovirus DNA is present in a high proportion of vascular dementia brains (NB CMV implicated also in coronary heart disease). Risk factor?  Vaccination of mice prevents HSV1 latency in brain. Feasible for humans?  HSV1 affects the breakdown of APP in human neuroblastoma cells.

16. Curtis Dobson Matthew Wozniak Ann Cookson Woan-Ru Lin Gordon Jamieson Dazhuang Shang Suzanne Shipley Gordon Wilcock Celia Yates Margaret Esiri Paul Klenerman Bob Cooper Paul Klapper Brian Faragher Roy Jennings Marc Combrinck Raj Kalaria Will Irving